Microglia and HIV/AIDS
Morner A, Thomas JA, Bjorling E, Munson PJ, Lucas SB,
McKnight A (2003) Productive HIV-2
infection in the brain is restricted to macrophages/Microglia.
AIDS 17:1451-1455
Abstract:
OBJECTIVES: HIV-2 can use a
broader range of co-receptors than HIV-1
in vitro, and is less dependent on CD4 for infection. The aim of
this study was to detect productive HIV-2
infection in the brain and investigate whether HIV-2
has an expanded tropism for brain cells in vivo, in comparison with
HIV-1, which productively
infects macrophages/Microglia.
DESIGN: Brain samples taken at autopsy from eight patients who died
from AIDS, six HIV-2
and two HIV-1/HIV-2
dually seropositive, with HIV
encephalitis (HIVE),
collected in Abidjan, Cote d'Ivoire in 1991, were examined for the
presence and localization of productive HIV-2
infection. METHODS: Using immunohistochemistry, the presence of
HIV-2 p26 in
formalin-fixed, wax-embedded brain tissue sections was investigated.
Double-staining with glial fibrillary acidic protein (GFAP),
Bell JE, Arango JC, Robertson R, Brettle RP, Leen C, Simmonds
P (2002) HIV and drug
misuse in the Edinburgh cohort. J.Acquir.Immune.Defic.Syndr. 31
Suppl 2:S35-S42
Abstract: The Edinburgh cohort of intravenous
drug users (IVDUs) became infected with HIV
between 1983 and 1984. Before the era of effective therapy, many of
these infected IVDUs displayed cognitive impairments on progressing
to AIDS and were found to
have HIV encephalitis
(HIVE). Full autopsies were
conducted on these patients, providing an opportunity to study the
intersecting pathology of pure HIVE
and drug use. High proviral load in the brain correlated well with
the presence of giant cells and HIV
p24 positivity. In presymptomatic HIV
infection, IVDUs were found to have a lymphocytic infiltrate in the
central nervous system (CNS). Apart from the expected Microglial
activation in the presence of HIV
infection of the CNS, drug use in its own right was found to be
associated with Microglial
activation. Examination of HIV-negative
IVDUs revealed a number of neuropathologic features, including
Microglial
activation, which may underpin HIV-related
pathology in the CNS. HIV
isolated from different regions of the brain was exclusively of
R5-tropic type throughout the course of infection. Detailed studies
of p17 and V3 sequences suggest that viral sequestration occurs in
the CNS before the onset of AIDS
and that increasing diversity of HIV
variants within the brain is associated with increasing severity of
HIVE. Because brain
isolates have proved to be different from those in lymphoid tissue
(and blood), it is likely that selective neuroadaptive pressures
operate before HIVE
supervenes. Drug abuse may be synergistic in this process through
activation of Microglia,
breakdown of the blood-brain barrier, and direct neurotoxicity.
Collections of clinically well-characterized HIV-infected
tissues such as those in the Edinburgh Brain Bank are a vital
resource to support ongoing studies of viral pathogenesis in the CNS
and interactions with drug abuse
Clements JE, Babas T, Mankowski JL, Suryanarayana K, Piatak
M, Jr., Tarwater PM, Lifson JD, Zink MC (2002) The central nervous
system as a reservoir for simian immunodeficiency virus (SIV):
steady-state levels of SIV DNA in brain from acute through
asymptomatic infection. J.Infect.Dis. 186:905-913
Abstract:
Latent reservoirs of human immunodeficiency virus (HIV)
present significant challenges for eradicating HIV
from infected persons, particularly reservoirs in the brain
established during acute infection. A simian immunodeficiency virus
(SIV)/macaque model of HIV
dementia was used to show that viral DNA levels in the brain
remained at constant levels from acute through asymptomatic
infection, despite significant down-regulation of viral RNA in the
brain after the acute phase of infection. Viral replication in the
brain coincided with activation of macrophages and Microglia
in the central nervous system; down-regulation of viral replication
coincided with increased infiltration of cytotoxic lymphocytes and
reduced activation of macrophages and Microglia
in the brain. Comparison of viral genotypes in the central nervous
system and peripheral blood mononuclear cells suggests that
recrudescence of viral replication in brain occurs by reactivation
of latent viral DNA. Latent virus in the brain must be considered in
therapeutic strategies to eliminate HIV
from infected persons
Cosenza MA, Zhao ML, Si Q, Lee SC (2002) Human brain
parenchymal Microglia
express CD14 and CD45 and are productively infected by HIV-1
in HIV-1 encephalitis.
Brain Pathol. 12:442-455
Abstract: Microglia
are endogenous brain macrophages that show distinct phenotypes such
as expression of myeloid antigens, ramified morphology, and presence
within the neural parenchyma. They play significant roles in a
number of human CNS diseases including AIDS
dementia. Together with monocyte-derived (perivascular) macrophages,
Microglia
represent a major target of HIV-1
infection. However, a recent report challenged this notion based on
findings in SIV encephalitis. This study concluded that perivascular
macrophages can be distinguished from parenchymal Microglial
cells by their expression of CD14 and CD45, and that macrophages,
but not Microglia,
are productively infected in SIV and HIV
encephalitis. To address whether parenchymal Microglia
are productively infected in HIV
encephalitis, we analyzed expression of CD14, CD45 and HIV-1
p24 in human brain. Microglia
were identified based on their characteristic ramified morphology
and location in the neural parenchyma. We found that parenchymal
Microglia
are CD14+ (activated), CD45+ (resting and activated), and constitute
approximately two thirds of the p24+ cells in HIV
encephalitis cases. These results demonstrate that Microglia
are major targets of infection by HIV-1,
and delineate possible differences between HIVE
and SIVE. Because productively infected tissue macrophages serve as
the major viral reservoir, these findings have important
implications for AIDS
D'Aversa TG, Weidenheim KM, Berman JW (2002) CD40-CD40L
interactions induce chemokine expression by human Microglia:
implications for human immunodeficiency virus encephalitis and
multiple sclerosis. Am.J.Pathol. 160:559-567
Abstract: CD40 is a
protein on Microglia
that is up-regulated with interferon (IFN)-gamma and is engaged by
CD40L, found on CD4+ T cells, B cells, and monocytes. These
interactions may be important in central nervous system inflammatory
diseases. Microglia
have been shown to be a source of chemokines, whose expression plays
a key role in central nervous system pathologies. We examined the
expression of CD40 on Microglia
in human immunodeficiency virus (HIV)
encephalitic brain, and the effects of CD40-CD40L interactions on
the expression of chemokines by cultured Microglia.
We found significantly increased numbers of CD40-positive Microglia
in HIV-infected brain
tissue. Treatment of cultured Microglia
with IFN-gamma and CD40L increased expression of several chemokines.
IFN-gamma- and CD40L-induced MCP-1 protein was mediated by
activation of the ERK1/2 MAPK pathway, and Western blot analysis
demonstrated phosphorylation of ERK1/2 upon stimulation of
Microglia.
In contrast, IFN-gamma- and CD40L-induced IP-10 protein production
was mediated by the p38 MAPK pathway. Our data suggest a mechanism
whereby CD40L+ cells can induce Microglia
to secrete chemokines, amplifying inflammatory processes seen in HIV
encephalitis and multiple sclerosis, and implicate CD40-CD40L
interactions as a target for interventional strategies
Garden GA (2002) Microglia
in human immunodeficiency virus-associated neurodegeneration. Glia
40:240-251
Abstract: Infection with the human immunodeficiency
virus (HIV) is associated
with a syndrome of cognitive and motor abnormalities that may
develop in the absence of opportunistic infections. Neurons are not
productively infected by HIV.
Thus, one hypothesis to explain the pathophysiology of
HIV-associated dementia
(HAD) suggests that signals released from other infected cell types
in the CNS secondarily lead to neuronal injury. Microglia
are the predominant resident CNS cell type productively infected by
HIV-1. Neurologic
dysfunction in HAD appears to be a consequence of Microglial
infection and activation. Several neurotoxic immunomodulatory
factors are released from infected and activated Microglia,
leading to altered neuronal function, synaptic and dendritic
degeneration, and eventual neuronal apoptosis. This review
summarizes findings from clinical/pathological studies, animal
models, and in vitro models of HAD. Most of these studies support
the hypothesis that altered Microglial
physiology is the nidus for a cascade of events leading to neuronal
dysfunction and death. Several molecular mediators of neuronal
injury in HAD that emanate from Microglia
have been identified, and strategies for altering the impact of
these neurotoxins are discussed
Garden GA, Budd SL, Tsai E, Hanson L, Kaul M, D'Emilia DM,
Friedlander RM, Yuan J, Masliah E, Lipton SA (2002) Caspase cascades
in human immunodeficiency virus-associated neurodegeneration.
J.Neurosci. 22:4015-4024
Abstract: Many patients infected with
human immunodeficiency virus-1 (HIV-1)
develop a syndrome of neurologic deterioration known as
HIV-associated dementia
(HAD). Neurons are not productively infected by HIV-1;
thus, the mechanism of HIV-induced
neuronal injury remains incompletely understood. Several
investigators have observed evidence of neuronal injury, including
dendritic degeneration, and apoptosis in CNS tissue from patients
with HAD. Caspase enzymes, proteases associated with the process of
apoptosis, are synthesized as inactive proenzymes and are activated
in a proteolytic cascade after exposure to apoptotic signals. Here
we demonstrate that HAD is associated with active caspase-3-like
immunoreactivity that is localized to the soma and dendrites of
neurons in affected regions of the human brain. Additionally, the
cascade of caspase activation was studied using an in vitro model of
HIV-induced neuronal
apoptosis. Increased caspase-3 proteolytic activity and
mitochondrial release of cytochrome c were observed in
cerebrocortical cultures exposed to the HIV
coat protein gp120. Specific inhibitors of both the Fas/tumor
necrosis factor-alpha/death receptor pathway and the mitochondrial
caspase pathway prevented gp120-induced neuronal apoptosis. Caspase
inhibition also prevented the dendrite degeneration observed in vivo
in transgenic mice with CNS expression of HIV/gp120.
These findings suggest that pharmacologic interventions aimed at the
caspase enzyme pathways may be beneficial for the prevention or
treatment of HAD
Gartner S, Liu Y (2002) Insights into the role of immune
activation in HIV
neuropathogenesis. J.Neurovirol. 8:69-75
Abstract: How does HIV
infection lead to the development of central nervous system disease?
Central to this question is identification of the relative
contributions of (1) the virus, (2) its host cells, and (3)
secondary or downstream events to the pathological process. These
are re-examined in this brief review. Also, a greater appreciation
for the role of systemic events in neuroinflammation is emerging,
with likely relevance to HIV-associated
dementia. We propose here a model for HIV
neuropathogenesis that highlights the role of systemic monocyte
activation and subsequent neuroinvasion in initiating the disease
Grassi MP, Clerici F, Vago L, Perin C, Borella M, Nebuloni M,
Moroni M, Mangoni A (2002) Clinical aspects of the AIDS
dementia complex in relation to histopathological and
immunohistochemical variables. Eur.Neurol. 47:141-147
Abstract:
To correlate cerebral histopathological and immunohistochemical
changes in the neuroclinical features of the AIDS
dementia complex (ADC), autopsy results of 28 ADC patients were
related, in a retrospective analysis, to scores on a standardised
neurological examination performed at neurologic onset. From a
histopathological point of view, the cases were classified as
follows: 9 cases of HIV
leucoencephalopathy (HIVL;
diffuse myelin damage and rare Microglial
nodules), 7 cases of HIV
encephalitis (HIVE; several
Microglial
nodules and no myelin damage) and 12 cases of mixed HIVL
and HIVE (HIVL-E).
The groups differed significantly with respect to symptoms and CD4
count at neurologic onset, survival and neurological impairment.
Immunohistochemically, the interstitial component (p24-positive
cells scattered singly within the white matter) was significantly
more prevalent in HIVL, and
the micronodular component (p24-positive cells confined within
Microglial
nodules) in HIVE.
Neurological damage was worse in cases with a high prevalence of
interstitial component or a low prevalence of micronodular
component. HIVE, HIVL
and HIVL-E are distinct
clinical forms of ADC. Neurological impairment is related to white
matter damage
Hatori K, Nagai A, Heisel R, Ryu JK, Kim SU (2002)
Fractalkine and fractalkine receptors in human neurons and glial
cells. J.Neurosci.Res. 69:418-426
Abstract: Fractalkine has been
identified as a novel chemokine that exhibits cell adhesion and
chemoattractive properties in the central nervous system (CNS), and
the fractalkine receptors, CX3CR1, are also expressed in the CNS. In
the present study, the expression of fractalkine and fractalkine
receptors was investigated in enriched populations of human CNS
neurons, astrocytes, and Microglia.
In addition, the regulatory role played by protein kinase C (PKC) in
fractalkine secretion in neurons was determined in A1 human hybrid
neuronal cell line produced between a human cerebral neuron and a
human neuroblastoma cell. Human neurons and astrocytes expressed
fractalkine mRNA as determined by the revserse
transcriptase-polymerase chain reaction (RT-PCR) analysis, while
human Microglia
preparation did not express the fractalkine message. Human neurons
and Microglia
expressed CX3CR1 mRNA, but astrocytes did not. These results suggest
that fractalkine secreted by CNS neurons and astrocytes produce
biological effects in neurons and Microglia.
Although phorbol ester did not change the expression of fractalkine
mRNA level in A1 hybrid neurons, it did upregulate fractalkine
secretion over unstimulated controls. This upregulation of
fractalkine production was suppressed by the treatment with
Ro32-0432, a PKC inhibitor. These results indicate that
intracellular signals transduced by PKC play an important role in
the regulation of soluble fractalkine at the post-transcriptional
level in human neurons. As for the biological function of
fractalkine, extracellularly applied fractalkine increased the
number of bromodeoxyuridine-labeled Microglia
3-fold over the untreated controls, indicating fractalkine induces
proliferation of human Microglia.
These observations suggest that fractalkine released by injured
neurons could induce proliferation, activation and/or migration of
Microglia
at the injured brain sites
Hughes PM, Botham MS, Frentzel S, Mir A, Perry VH (2002)
Expression of fractalkine (CX3CL1) and its receptor, CX3CR1, during
acute and chronic inflammation in the rodent CNS. Glia
37:314-327
Abstract: In this study, we investigate the expression
of fractalkine (CX3CL1) and the fractalkine receptor (CX3CR1) in the
naive rat and mouse central nervous system (CNS). We determine if
the expression of this chemokine and its receptor are altered during
chronic or acute inflammation in the CNS. In addition, we determine
if CX3CL1, which has been reported to be chemoattractant to
leukocytes in vitro, is capable of acting as a chemoattractant in
the CNS in vivo. Immunohistochemistry was performed using primary
antibodies recognizing soluble and membrane-bound CX3CL1 and the
N-terminus of the CX3CR1. We found that neurons in the naive rodent
brain are immunoreactive for CX3CL1 and CX3CR1, both showing a
perinuclear staining pattern. Resident Microglia
associated with the parenchyma and macrophages in the meninges and
choroid plexus constituitively express CX3CR1. In a prion model of
chronic neurodegeneration and inflammation, CX3CL1 immunoreactivity
is upregulated in astrocytes and CX3CR1 expression is elevated on
Microglia.
In surviving neurons, expression of CX3CL1 appears unaltered
relative to normal neurons. There is a decrease in neuronal CX3CR1
expression. Acute inflammatory responses in the CNS, induced by
stereotaxic injections of lipopolysaccharide or kainic acid, results
in activation of Microglia
and astrocytes but no detectable changes in the glial expression of
CX3CL1 or CX3CR1. The expression of CX3CL1 and CX3CR1 by glial cells
during inflammation in the CNS may be influenced by the surrounding
cytokine milieu, which has been shown to differ in acute and chronic
neuroinflammation
Kandanearatchi A, Zuckerman M, Smith M, Vyakarnam A, Everall
IP (2002) Granulocyte-macrophage colony-stimulating factor enhances
viral load in human brain tissue: amelioration with stavudine. AIDS
16:413-420
Abstract: BACKGROUND: Granulocyte-macrophage
colony-stimulating factor (GM-CSF) is elevated in cerebrospinal
fluid in HIV- associated
dementia; in addition, therapeutic GM-CSF elevates plasma viral
load. OBJECTIVE: To assess the effect of GM-CSF on viral replication
and the potential ameliorative effect of antiretroviral therapy.
DESIGN: A primary human brain aggregate system is used as a model of
the in vivo situation. METHOD: Cultured aggregates were infected
with the macrophage tropic strain HIV-1SF162
and then exposed to varying GM-CSF concentrations and 0.3 micromol/l
stavudine. Viral replication was assessed by p24 expression in the
supernatant and aggregates. Immunohistochemistry identified neurons,
astrocytes, Microglia
and oligodendrocytes. RESULTS: A GM-CSF concentration of 1 ng/ml
resulted in a fivefold increase in Microglial
cells, the main HIV
cellular reservoir (P = 0.0001). Prior GM-CSF exposure before
infection of the aggregates resulted in sixfold increase in p24
levels compared with non-GM-CSF-exposed infected aggregates.
Infected aggregates with or without GM-CSF had significant neuronal
loss of 50% and 45%, respectively, and astrocytosis. Addition of
stavudine to the infected aggregates, even in the presence of
GM-CSF, reduced p24 levels to zero and prevented neuronal loss and
astrocytosis. CONCLUSIONS: This study demonstrates that GM-CSF
enhances viral replication while addition of stavudine prevents this
potentially detrimental process
Kanmogne GD, Kennedy RC, Grammas P (2002) Infection of baboon
Microglia
with SIV-HIV recombinant
viruses: role of CD4 and chemokine receptors. AIDS
Res.Hum.Retroviruses 18:557-565
Abstract: Microglia
constitute the primary cell type infected with HIV
in the brain and play a major role in viral persistence in the CNS
and in the development of AIDS
dementia. Lack of a suitable animal model and limitations in the
availability of human tissues hinder most HIV/AIDS
studies investigating the neuropathogenesis of AIDS
dementia. The aims of this study were to determine whether baboon
Microglia
can be productively infected with SIV-HIV
(SHIV) recombinant viruses
in vitro and whether they express HIV-1
receptors and coreceptors. Our results show the presence of mRNA for
CD4, CCR5, and CXCR4 chemokine receptors on baboon Microglial
cells. Microglia
lacked mRNA for the CCR3 chemokine receptor. We also show productive
infection of baboon Microglial
cells by two SHIV isolates,
SHIV-KU and SHIV-89.6P,
and blockade of the infection with soluble CD4 protein, CCR5, and
CXCR4 monoclonal antibodies. This study demonstrating the
feasibility of infecting baboon Microglia
with SHIV isolates is an
important first step in using the baboon as an alternative nonhuman
primate model to study HIV
neuropathogenesis
Kolson DL (2002) Neuropathogenesis of central nervous system
HIV-1 infection. Clin.Lab
Med. 22:703-717
Abstract: Neuronal damage and death are
consistent pathologic findings in the brains of patients with ADC,
and multiple cell model systems have demonstrated neurotoxicity
through the effects of HIV-1
infection in macrophages and Microglia.
Brain MRI studies (1H-MRS) indicate that reversible neuronal cell
dysfunction occurs early during the course of HIV-1
infection, long before overt symptoms of ADC appear. Epidemiologic
studies suggest that a high viral load in the CNS is a major risk
factor for ADC and that HAART may significantly reduce, but not
eliminate, the risk of developing ADC. Targeted adjunctive therapies
administered early are likely necessary to maximize CNS protection
against HIV, and rational
approaches to such therapy are rapidly evolving through in vitro
analysis of the mechanisms of HIV-associated
neurotoxicity. Soluble factors released by infected cells may
directly or indirectly damage neurons and induce apoptosis at the
level of NMDA subtype of glutamate receptors, and NMDA receptor
antagonists represent a major therapeutic option currently under
intense clinical investigation. Likewise, drugs with antioxidant or
free radical scavenging effects offer another rational approach to
adjunctive therapy and are also under intense clinical scrutiny.
Finally, agents that inhibit neuronal death-signaling pathways
(e.g., p38 MAPK inhibitors) and that stimulate cell survival
pathways (e.g., Akt/PKB) may represent the next investigational step
in designing anti-ADC therapies
Li Y, Wang X, Tian S, Guo CJ, Douglas SD, Ho WZ (2002)
Methadone enhances human immunodeficiency virus infection of human
immune cells. J.Infect.Dis. 185:118-122
Abstract: Opiate abuse
has been postulated to be a cofactor in the immunopathogenesis of
acquired immunodeficiency syndrome (AIDS).
This study evaluated whether methadone, a drug widely prescribed for
the treatment of drug abusers with opioid dependence, affects human
immunodeficiency virus (HIV)
infection of human immune cells. When added to human fetal Microglia
and blood monocyte-derived macrophage cultures, methadone
significantly enhanced HIV
infection of these cells. This enhancement was associated with the
up-regulation of expression of CCR5, a primary coreceptor for
macrophage-tropic HIV entry
into macrophages. Most importantly, the addition of methadone to the
cultures of latently infected peripheral blood mononuclear cells
from HIV-infected patients
enhanced viral activation and replication. Although the in vivo
relevance of these findings remains to be determined, the data
underscore the necessity of further studies to define the role of
opioids, including methadone, in the immunopathogenesis of HIV
infection and AIDS
Mankowski JL, Queen SE, Tarwater PM, Fox KJ, Perry VH (2002)
Accumulation of beta-amyloid precursor protein in axons correlates
with CNS expression of SIV gp41. J.Neuropathol.Exp.Neurol.
61:85-90
Abstract: Axonal damage represented by accumulation of
beta-amyloid precursor protein (beta-APP) develops in numerous
central nervous system (CNS) diseases including human
immunodeficiency virus (HIV)
infection. To study the underlying mechanisms of axonal damage
associated with HIV CNS
infection, the amount of axonal beta-APP immunostaining in the
corpus callosum of 24 simian immunodeficiency virus (SIV)-infected
macaques and 3 control macaques was measured by computerized image
analysis. The amounts of beta-APP accumulation were then compared
with time post-inoculation, extent and character of CNS
inflammation, and viral load in the CNS measured by the amount of
immunohistochemical staining for the viral transmembrane protein
gp41. Significant increases over control values were present in 10
of 24 SIV-infected animals. SIV encephalitis was present in 9 of the
10 animals with elevated beta-APP Increases in beta-APP correlated
most strongly with levels of SIV gp41 in the brain (p = 0.005), but
significant associations with macrophage infiltration and Microglial
activation (p = 0.04) and infiltration by cytotoxic lymphocytes (p =
0.05) also were identified. These data demonstrate that beta-APP
accumulation in the white matter of SIV-infected macaques develops
during SIV infection in close correlation with levels of viral
replication and may serve as a sensitive marker of neuronal/axonal
damage mediated by viral proteins
McCarthy M, He J, Auger D, Geffin R, Woodson C, Hutto C, Wood
C, Scott G (2002) Cellular tropisms and co-receptor usage of HIV-1
isolates from vertically infected children with neurological
abnormalities and rapid disease progression. J.Med.Virol.
67:1-8
Abstract: The longitudinal evolution of HIV-1
phenotypes was studied in a cohort of six vertically infected
children with early onset and rapid progression of clinical disease.
Among 30 viral isolates obtained from peripheral blood, tropisms for
both human blood-derived cells (macrophages, T-lymphocytes), and for
human neural (brain-derived) cells (Microglia,
astrocytes) were determined, as was chemokine co-receptor usage. All
children harbored from birth macrophage-tropic isolates using the
CCR5 co-receptor. Two children later developed T-cell tropic
isolates with CXCR4 and CCR3 usage. While all six patients developed
neurological abnormalities, only three produced neural cell tropic
isolates, which used CCR5. However, early and persistent finding of
both astrocyte- and Microglia-tropic
isolates in one patient did associate with the most rapid
progression to brain atrophy among the six patients. Viral
phenotypic properties determined in cell culture did not
specifically predict clinical features or course, and the
development of AIDS did not
coincide with, or depend on, the appearance T-tropic,
syncytia-inducing viruses
Nath A (2002) Human immunodeficiency virus (HIV)
proteins in neuropathogenesis of HIV
dementia. J.Infect.Dis. 186 Suppl 2:S193-S198
Abstract: Human
immunodeficiency virus (HIV)
infection of the nervous system is unique when compared with other
viral encephalitides. Neuronal cell loss occurs in the absence of
neuronal infection. Viral proteins, termed "virotoxins,"
are released from the infected glial cells that initiate a cascade
of positive feedback loops by activating uninfected Microglial
cells and astrocytes. These activated cells release a variety of
toxic substances that result in neuronal dysfunction and cell loss.
The virotoxins act by a hit and run phenomenon. Thus, a transient
exposure to the proteins initiates the neurotoxic cascade. High
concentrations of these proteins likely occur in tight extracellular
spaces where they may cause direct neurotoxicity as well. The
emerging concepts in viral protein-induced neurotoxicity are
reviewed as are the neurotoxic potential of each protein. Future
therapeutic strategies must target common mechanisms such as
oxidative stress and dysregulation of intracellular calcium involved
in virotoxin-mediated neurotoxicity
Rauer M, Pagenstecher A, Schulte-Monting J, Sauder C (2002)
Upregulation of chemokine receptor gene expression in brains of
Borna disease virus (BDV)-infected rats in the absence and presence
of inflammation. J.Neurovirol. 8:168-179
Abstract: Infection of
adult rats with Borna disease virus (BDV) causes CD8 T cell-mediated
meningoencephalitis. Previously, we described a complex pattern of
chemokine gene expression in the central nervous system (CNS) of
such rats. We now found that expression of chemokine receptor genes
CXCR3, CCR5, CX(3)CR1, and CXCR4 was also upregulated, which is in
agreement with the predominance in brains of adult infected rats of
T cells and monocytes/macrophages that express these receptors. In
contrast to these rats, neonatally infected rats (designated PTI-NB)
develop a persistent CNS infection associated with neurodegenerative
processes in the absence of inflammation. In brains of PTI-NB rats,
sustained expression of chemokines also takes place. We therefore
analyzed mRNA expression of selected chemokine receptor genes, as
well as of the chemokine fractalkine in brains of PTI-NB rats. We
observed a marked increase of CCR5 and CX(3)CR1 transcripts in
brains of these rats. CX(3)CR1 expressing cells were predominantly
Microglia,
and upregulation of CX(3)CR1 was mainly due to an increase in the
number of CX(3)CR1 expressing Microglia.
Fractalkine gene expression was found to be reduced to similar
extents in brains of adult and newborn infected rats. These findings
might be of relevance with respect to the selective neuronal cell
loss observed in brains of PTI-NB rats
Ryan LA, Cotter RL, Zink WE, Gendelman HE, Zheng J (2002)
Macrophages, chemokines and neuronal injury in HIV-1-associated
dementia. Cell Mol.Biol.(Noisy.-le-grand) 48:137-150
Abstract:
Human immunodeficiency virus type-one (HIV-
1)-associated dementia (HAD) is manifested as a spectrum of
behavioral, motor and cognitive dysfunctions. The disorder commonly
occurs during late stage HIV
disease and remains an important complication despite highly active
antiretroviral therapies. A metabolic encephalopathy, fueled by
neurotoxic secretions from brain mononuclear phagocytes (MP)
(macrophages and Microglia)
underlies HIV- I
neuropathogenesis. One pivotal question, however, is how brain MP
evolve from neurotrophic to neurotoxic cells. The interplay between
the virus, the macrophage and the neuron has just recently begun to
be unraveled. Along with a multitude of other MP secretory products,
chemokines effect neuronal function by engaging neuronal receptors
then activating pathways that alter synaptic transmission, cell
growth, injury and protection. Both neurons and glia secrete
chemokines. Interestingly, HIV-1
and its gene products can mimic chemokine neuronal signaling by
binding to neuronal chemokine receptors or by other non-specific
mechanisms. The elucidation of mechanisms involved in
chemokine-mediated neural compromise will likely provide unique
insights into the pathogenesis and treatment, not only of HAD, but
of a wide range of neurodegenerative disorders
Ryzhova EV, Crino P, Shawver L, Westmoreland SV, Lackner AA,
Gonzalez-Scarano F (2002) Simian immunodeficiency virus
encephalitis: analysis of envelope sequences from individual brain
multinucleated giant cells and tissue samples. Virology
297:57-67
Abstract: Simian immunodeficiency virus (SIV)-infected
macaques develop an encephalitis (SIVE) that is pathologically
virtually indistinguishable from that associated with HIV
infection, with multinucleated giant cells (MNGCs) being the
principal histopathological manifestation. To dissect SIV variants
responsible for MNGC development, we examined the relationships
between env sequences transcribed in individual MNGCs and those from
genomic DNA of brain and spleen tissues. The brain-specific variant
found in all brain clones was dominant among the clones from MNGCs,
suggesting a role in the formation of giant cells. Furthermore, two
additional minor groups of sequences were present in MNGCs. One
group consisted of sequences closely related to those from spleen,
indicating recent and probably multiple episodes of neuroinvasion.
The second group represented clones similar or identical to the
initial inoculum. The survival of arcHIVal
sequences and their activation presumably by the fusion of
productively and quiescently infected macrophages/Microglia
identify the central nervous system as a possible anatomical
reservoir for latent infection
Sharshar T, Gray F, Poron F, Raphael JC, Gajdos P, Annane D
(2002) Multifocal necrotizing leukoencephalopathy in septic shock.
Crit Care Med. 30:2371-2375
Abstract: OBJECTIVE: Multifocal
necrotizing leukoencephalopathy, characterized by multiple
microscopic foci of necrosis involving the white matter of the pons,
has been described mainly after chemotherapy or radiotherapy for
brain cancer and in HIV
infection. The role of circulating cytokines has been suggested but
remains to be assessed. DESIGN: Prospective case series. SETTING: A
26-bed general medical intensive care unit at a university hospital.
PATIENTS: Septic shock patients. MEASUREMENTS AND PATIENTS: In three
patients who died from septic shock, careful postmortem examination
of the brain was performed, including studies of neuronal apoptosis
and cytokine expression. MAIN RESULTS: In one patient, typical
lesions of multifocal necrotizing leukoencephalopathy were seen. As
compared with control 1 and control 2 who did not have multifocal
necrotizing leukoencephalopathy, marked lesions of the pons,
including vacuolization, apoptosis, Microglial
activation, and expression of tumor necrosis factor-alpha and
interleukin-1beta, were observed in the case. Simultaneously, case 1
had markedly increased circulating levels for tumor necrosis
factor-alpha, interleukin-1beta, interleukin-6, interleukin-8,
interleukin-10, soluble tumor necrosis factor receptor II, and for
interleukin-1 receptor antagonist. CONCLUSION: Septic shock is a
newly described cause of multifocal necrotizing leukoencephalopathy,
probably mediated by an excessive systemic inflammatory response
Si Q, Kim MO, Zhao ML, Landau NR, Goldstein H, Lee S (2002)
Vpr- and Nef-dependent induction of RANTES/CCL5 in Microglial
cells. Virology 301:342-353
Abstract: Microglia
are pivotal in the pathogenesis of AIDS
dementia, as they serve as the major target of HIV
infection in the CNS. In addition, activation of Microglia
correlates best with clinical dementia. Although the beta-chemokine
RANTES/CCL5 is important in modulating HIV
infection as well as cellular activation, no information is
available regarding how its expression is regulated in Microglia
by HIV-1. Here we report
that RANTES/CCL5 expression is induced in Microglia
by HIV-1, but that this
requires infection by HIV-1.
This conclusion was supported by (1) the delayed kinetics coinciding
with viral replication; (2) the lack of effect of X4 viruses; (3)
inhibition by the reverse transcriptase inhibitor AZT, and (4) the
lack of effect of cytokine antagonists or antibodies. Interestingly,
RANTES/CCL5 production was dependent on the viral accessory protein
Vpr, in addition to Nef, demonstrating a novel role for Vpr in
chemokine induction in primary macrophage-type cells. Furthermore,
the specific p38 MAP kinase inhibitor SB203580 augmented chemokine
expression in Microglia,
indicating a negative role played by p38. These data suggest unique
features of RANTES/CCL5 regulation by HIV-1
in human Microglial
cells
Si Q, Cosenza M, Zhao ML, Goldstein H, Lee SC (2002) GM-CSF
and M-CSF modulate beta-chemokine and HIV-1
expression in Microglia.
Glia 39:174-183
Abstract: Significant numbers of patients with
acquired immunodeficiency syndrome (AIDS)
develop CNS infection primarily in macrophages and Microglial
cells. Therefore, the regulation of human immunodeficiency virus
type 1 (HIV-1) infection
and activation of the brain mononuclear phagocytes subsequent to
infection are important areas of investigation. In the current
report, we studied the role of granulocyte-macrophage
colony-stimulating factor (GM-CSF) and macrophage-CSF (M-CSF) in the
expression of antiviral beta-chemokines and HIV-1
p24 in cultures of primary human fetal Microglia.
We found that stimulation with GM-CSF or M-CSF induced macrophage
inflammatory proteins (MIP-1alpha and MIP-1beta) and augmented
RANTES expression, after HIV-1
infection of Microglia.
This was not due to the effect of GM-CSF on viral expression because
GM-CSF was neither necessary nor stimulatory for viral infection,
nor did GM-CSF enhance the expression of env-pseudotyped reporter
viruses. Blocking GM-CSF-induced Microglial
proliferation by nocodazole had no effect on beta-chemokine or p24
expression. The functional significance of the GM-CSF-induced
beta-chemokines was suggested by the finding that, in the presence
of GM-CSF, exogenous beta-chemokines lost their anti-HIV-1
effects. We further show that although HIV-1-infected
Microglia
produced M-CSF, they failed to produce GM-CSF. In vivo, GM-CSF
expression was localized to activated astrocytes and some
inflammatory cells in HIV-1
encephalitis, suggesting paracrine activation of Microglia
through GM-CSF. Our results demonstrate a complex interplay between
CSFs, chemokines, and virus in Microglial
cells and may have bearing on the interpretation of data derived in
vivo and in vitro
Su ZZ, Kang DC, Chen Y, Pekarskaya O, Chao W, Volsky DJ,
Fisher PB (2002) Identification and cloning of human astrocyte genes
displaying elevated expression after infection with HIV-1
or exposure to HIV-1
envelope glycoprotein by rapid subtraction hybridization, RaSH.
Oncogene 21:3592-3602
Abstract: Neurodegeneration and dementia
are common complications of AIDS
caused by human immunodeficiency virus type 1 (HIV-1)
infection of the central nervous system. HIV-1
target cells in the brain include Microglia,
infiltrating macrophages and astrocytes, but rarely neurons.
Astrocytes play an important role in the maintenance of the synaptic
micro-environment and in neuronal signal transmission. To
investigate potential changes in cellular gene expression associated
with HIV-1 infection of
astrocytes, we employed an efficient and sensitive rapid subtraction
hybridization approach, RaSH. Primary human astrocytes were isolated
from abortus brain tissue and low-passage cells were infected with
HIV-1. To identify genes
that display both early and late expression modifications after
HIV-1 infection and to
avoid cloning genes displaying normal cell cycle fluctuations in
astrocytes, RNAs were isolated and pooled from 6, 12, 24 h and 3 and
7 day uninfected and infected cells and used for RaSH. Temporal cDNA
libraries were prepared from double-stranded cDNAs that were
enzymatically digested into small fragments, ligated to adapters,
PCR amplified, and hybridized by incubation of tester and driver PCR
fragments. By subtracting temporal cDNAs derived from uninfected
astrocytes from temporal cDNAs made from HIV-1
infected cells, genes displaying elevated expression in virus
infected cells, termed astrocyte elevated genes (AEGs), were
identified. Both known and novel AEGs, not reported in current DNA
databases, are described that display early or late expression
kinetics following HIV-1
infection or treatment with recombinant HIV-1
envelope glycoprotein (gp120). For selected AEGs, expression of
their protein products was also tested by Western blotting and found
to display elevated expression following HIV-1
infection. The comparable pattern of regulation of the AEGs
following HIV-1 infection
or gp120 treatment suggest that HIV-1
exposure of astrocytes, even in the absence of productive infection,
can induce changes in cellular gene expression
Tarozzo G, Campanella M, Ghiani M, Bulfone A, Beltramo M
(2002) Expression of fractalkine and its receptor, CX3CR1, in
response to ischaemia-reperfusion brain injury in the rat.
Eur.J.Neurosci. 15:1663-1668
Abstract: Fractalkine is a
neuronally expressed chemokine that acts through its
G-protein-coupled receptor CX3CR1, localized on Microglial
and immune cells. Fractalkine might be involved in neuroinflammatory
processes secondary to neuronal damage, which normally occur in a
time frame of days after ischaemia. We evaluated by in situ
hybridization and immunohistochemistry the expression of fractalkine
and CX3CR1 in the rat brain, after a transient occlusion of the
middle cerebral artery. We found that at 12 h after ischaemia
neuronal fractalkine expression was transiently increased in
scattered necrotic neurons of the cortex and lost from the ischaemic
striatum. At 24 and 48 h after ischaemia, fractalkine
immunoreactivity was strongly increased in morphologically intact
cortical neurons of the ischaemic penumbra where also the
stress-inducible HSP-72 was strongly up-regulated. The intensity of
fractalkine immunoreactivity of neurons in the penumbra returned to
basal levels at 7 days after ischaemia. Fractalkine synthesis was
also induced in endothelial cells of the infarcted area, at 48 h and
7 days after ischaemia. CX3CR1 expression was detected in the
activated Microglial
cells of the ischaemic tissue 24 and 48 h after ischaemia, and
became strongly up-regulated in macrophages/phagocytic Microglia
inside the infarcted tissue 7 days after ischaemia. These data
suggest that fractalkine may participate in the activation and
chemoattraction of Microglia
into the infarcted tissue, and contribute to the control of
leucocyte trafficking from blood vessels into the injured area
Vilhardt F, Plastre O, Sawada M, Suzuki K, Wiznerowicz M,
Kiyokawa E, Trono D, Krause KH (2002) The HIV-1
Nef protein and phagocyte NADPH oxidase activation. J.Biol.Chem.
277:42136-42143
Abstract: Nef, a multifunctional HIV
protein, activates the Vav/Rac/p21-activated kinase (PAK) signaling
pathway. Given the potential role of this pathway in the activation
of the phagocyte NADPH oxidase, we have investigated the effect of
the HIV-1 Nef protein on
the phagocyte respiratory burst. Microglia
(cell line and primary culture) were transduced with lentiviral
expression vectors. Expression of Nef did not activate the NADPH
oxidase by itself but led to a massive enhancement of the responses
to a variety of stimuli (Ca(2+) ionophore, formyl peptide,
endotoxin). These effects were not caused by up-regulation of
phagocyte NADPH oxidase subunits. Nef mutants lacking motifs
involved in the interaction with Vav and PAK failed to reproduce the
effects of wild type Nef, suggesting a role for the Vav/Rac/PAK
signaling pathway. The following results suggest a key role for Rac
in the priming effect of Nef. (i) Inactivation of Rac by Clostridium
difficile toxin B abolished the Nef effect. (ii) The fraction of
activated Rac1 was increased in Nef-transduced cells, and (iii) the
dominant positive Rac1(V12) mutant mimicked the effect of Nef. These
results are to our knowledge the first analysis of the effect of Rac
activation on the NADPH oxidase in intact phagocytes. Rac activation
is not sufficient to stimulate the phagocyte NADPH oxidase; however,
it markedly enhances the NADPH oxidase response to other stimuli
Weiss RA (2002) HIV
receptors and cellular tropism. IUBMB.Life 53:201-205
Abstract:
Viruses use specific cell surface receptors to bind to and
subsequently gain entry into their host cells. Some retroviruses
such as HIV-1 and HIV-2
utilize one receptor for high-affinity binding (CD4), and a separate
coreceptor to mediate fusion of the viral envelope with the cell
membrane (CCR5 or CXCR4). The identification of these receptors
explains the cellular tropism of HIV,
and hence its pathogenesis leading to immune deficiency (T-helper
cell depletion), the wasting syndrome (macrophage infection), and
dementia (Microglia
infection). HIV can infect
cells by membrane fusion at the cell surface and by
receptor-mediated endocytosis. Knowledge of the HIV
receptors has led to practical developments such as inhibitory
drugs, reasons for genetic resistance to infection, and should
inform the judicious choice of candidate vaccines
Williams K, Schwartz A, Corey S, Orandle M, Kennedy W,
Thompson B, Alvarez X, Brown C, Gartner S, Lackner A (2002)
Proliferating cellular nuclear antigen expression as a marker of
perivascular macrophages in simian immunodeficiency virus
encephalitis. Am.J.Pathol. 161:575-585
Abstract: Brain
perivascular macrophages are a major target of simian
immunodeficiency virus (SIV) infection in rhesus macaques and HIV
infection in humans. Perivascular macrophages are distinct from
parenchymal Microglia
in their location, morphology, expression of myeloid markers, and
turnover in the CNS. In contrast to parenchymal Microglia,
perivascular macrophages are continuously repopulated by blood
monocytes, which undergo maturation to macrophages on entering the
central nervous system (CNS). We studied differences in
monocyte/macrophages in vivo that might account for preferential
infection of perivascular macrophages by SIV. In situ hybridization
for SIV and proliferating cellular nuclear antigen (PCNA)
immunohistochemistry demonstrated that SIV-infected and
PCNA-positive cells were predominantly found in perivascular cuffs
of viremic animals and in histopathological lesions that
characterize SIV encephalitis (SIVE) in animals with AIDS.
Multilabel techniques including double-label immunohistochemistry
and combined in situ hybridization and immunofluorescence confocal
microscopy revealed numerous infected perivascular macrophages that
were PCNA-positive. Outside the CNS, SIV-infected, PCNA-expressing
macrophage subpopulations were found in the small intestine and lung
of animals with AIDS. While
PCNA is used as a marker of cell proliferation it is also strongly
expressed in non-dividing cells undergoing DNA synthesis and repair.
Therefore, more specific markers for cell proliferation including
Ki-67, topoisomerase IIalpha, and bromodeoxyuridine (BrdU)
incorporation were used which indicated that PCNA-positive cells
within SIVE lesions were not proliferating. These observations are
consistent with perivascular macrophages as terminally
differentiated, non-dividing cells and underscores biological
differences that could potentially define mechanisms of
preferential, productive infection of perivascular macrophages in
the rhesus macaque model of neuroAIDS.
These studies suggest that within CNS and non-CNS tissues there
exist subpopulations of macrophages that are SIV-infected and
express PCNA
Williams KC, Hickey WF (2002) Central nervous system damage,
monocytes and macrophages, and neurological disorders in AIDS.
Annu.Rev.Neurosci. 25:537-562
Abstract: This review focuses on
the role of the extended macrophage/monocyte family in the central
nervous system during HIV
or SIV infection. The accumulated data, buttressed by recent
experimental results, suggest that these cells play a central,
pathogenic role in retroviral-associated CNS disease. While the
immune system is able to combat the underlying retroviral infection,
the accumulation and widespread activation of macrophages,
Microglia,
and perivascular cells in the CNS are held in check. However, with
the collapse of the immune system and the disappearance of the
CD4(+) T cell population, productive infection reemerges, especially
in CNS macrophages. These cells, as well as noninfected macrophages,
are stimulated to high levels of activation. When members of this
cell group become highly activated, they elaborate a wide spectrum
of deleterious substances into the neural parenchyma. In the final
phases of HIV or SIV
infection, this chronic, widespread, and dramatic level of
macrophage/monocyte/Microglial
activation constitutes a self-sustaining state of macrophage
dysregulation, which results in pathological alterations and the
emergence of various neurological problems
Albright AV, Martin J, O'Connor M, Gonzalez-Scarano F (2001)
Interactions between HIV-1
gp120, chemokines, and cultured adult Microglial
cells. J.Neurovirol. 7:196-207
Abstract: HIV
dementia (HIVD), a disease
that is apparently mediated by neurotoxins and viral proteins
secreted by HIV infected
Microglia,
is characterized neuropathologically by an increased number of
activated Microglia
in the brains of affected individuals. Consequently, the rational
design of potential therapeutic strategies should take into account
the mechanisms that lead to Microglial
activation and to their increased prominence in the adult brain. In
this regard, one leading hypothesis proposes that Microglia
are recruited to specific sites in the central nervous system (CNS)
as a result of interactions between Microglial
chemokine receptors and chemokines, or even the viral glycoprotein
gp120, which binds chemokine receptors in the process of cellular
entry. Adult Microglia
express the functional chemokine receptors CCR5 and CXCR4 molecules
that mediate chemotaxis in these and other cell types. We determined
that purified adult Microglial
cultures contain a heterogeneous population with respect to their
ability to respond to the alpha- and beta-chemokines, SDF1alpha, and
MIP-1beta. A mean of 14.6% of the Microglia
assayed responded to both alpha- and beta-chemokines
(CCR5(+)CXCR4(+) phenotype); 45.4% of Microglia
were phenotyped as CCR5(+)CXCR4(-); 12.9% of the Microglia
were CXCR4(+)CCR5(-); and 27.0% of Microglia
did not respond to either chemokine. No increase in intracellular
calcium levels was seen in the vast majority of Microglia
exposed to the soluble HIV
envelope protein, gp120, or to HIV
envelope (gp120/gp41) expressed on MLV virus pseudotypes. However,
exposure of Microglia
to soluble fractalkine or to other chemokines resulted in an
intracellular calcium flux. Our results raise the possibility of
Microglial
heterogeneity with respect to their response to chemokines, and
indicate that any effects due to gp120 are likely to be considerably
less robust than the response of Microglia
to the natural ligands of their chemokine receptors, for example
SDF1alpha and MIP-1beta
Allen NJ, Attwell D (2001) A chemokine-glutamate connection. Nat.Neurosci. 4:676-678
An SF, Osuntokun O, Groves M, Scaravilli F (2001) Expression
of CCR-5/CXCR-4 in spinal cord of patients with AIDS.
Acta Neuropathol.(Berl) 102:175-180
Abstract: The discovery that
chemokines and their receptors (in particular CXCR-4 and CCR-5) play
a role in HIV infection
challenges traditional views on the pathogenesis of HIV
infection in man and identifies new potential targets for
therapeutic intervention. Several groups as well as our pilot study
have found that increased numbers of CCR-5 positive
macrophage/Microglia
correlate with disease severity in brains of patients with AIDS.
Among HIV-related
disorders, vacuolar myelopathy (VM) is the most common spinal cord
disorder in patients with AIDS.
The purpose of this study was to investigate the possible
relationship between the expression of CCR-5/CXCR-4 and spinal cord
pathology in patients with AIDS.
Thirty-four spinal cords (forming two groups: without and with VM)
of patients with AIDS and 6
HIV-1-negative controls
were investigated by routine histological examination and
immunohistochemistry. Elevated expression of CXCR-4 was found in
most AIDS cases
with/without neuropathological disorders (8/17 and 13/16,
respectively). No CCR-5 expression was detected in HIV-1-negative
controls. Among 34 cases with AIDS,
expression of CCR-5 was detected in 1/16 HIV-1-positive
normal spinal cords and 5/18 with VM. Despite the lack of
statistical significance between the two groups (P=0.1019), our
results suggest that CCR-5/CXCR-4 are present in spinal cord of
patients with AIDS and that
CCR-5 is more frequently found in association with VM
Antinori A, Giancola ML, Alba L, Soldani F, Grisetti S (2001)
Cardiomyopathy and encephalopathy in AIDS.
Ann.N.Y.Acad.Sci. 946:121-129
Abstract: HIV
encephalopathy has been in the past years the most typical CNS
disorder in patients with AIDS.
Histologic abnormalities consist in astrocytosis, myelin pallor,
infiltration by infected macrophages, resident Microglia
and multinucleated giant cells, generally in absence of direct
infection of neurons. Mononuclear phagocytes in the brain are the
main target of HIV-1
infection and the site of productive viral replication, and viral
stimulation leads to the release of neurotoxic products causing
neurologic damage. Subclinical cardiac abnormalities are common in
HIV+ patients and several
studies suggested a role for cytokines and other inflammatory
products as mediators of cardiac abnormalities. The common pathway
for neurologic and cardiac manifestations supports the relationship
between neurologic disease and cardiac dysfunction in HIV
infection. Clinical observations suggest that cardiomyopathy could
be associated with encephalopathy in HIV+
patients and that it may affect survival. Antiretroviral therapy may
reduce impact of neurologic and cardiac abnormalities by suppressing
plasma HIV-1 viral load
Asensio VC, Maier J, Milner R, Boztug K, Kincaid C, Moulard
M, Phillipson C, Lindsley K, Krucker T, Fox HS, Campbell IL (2001)
Interferon-independent, human immunodeficiency virus type 1
gp120-mediated induction of CXCL10/IP-10 gene expression by
astrocytes in vivo and in vitro. J.Virol. 75:7067-7077
Abstract:
The CXC chemokine gamma interferon (IFN-gamma)-inducible protein
CXCL10/IP-10 is markedly elevated in cerebrospinal fluid and brain
of individuals infected with human immunodeficiency virus type 1
(HIV-1) and is implicated
in the pathogenesis of HIV-associated
dementia (HAD). To explore the possible role of CXCL10/IP-10 in HAD,
we examined the expression of this and other chemokines in the
central nervous system (CNS) of transgenic mice with
astrocyte-targeted expression of HIV
gp120 under the control of the glial fibrillary acidic protein
(GFAP) promoter, a murine model for HIV-1
encephalopathy. Compared with wild-type controls, CNS expression of
the CC chemokine gene CCL2/MCP-1 and the CXC chemokine genes
CXCL10/IP-10 and CXCL9/Mig was induced in the GFAP-HIV
gp120 mice. CXCL10/IP-10 RNA expression was increased most and
overlapped the expression of the transgene-encoded HIV
gp120 gene. Astrocytes and to a lesser extent Microglia
were identified as the major cellular sites for CXCL10/IP-10 gene
expression. There was no detectable expression of any class of IFN
or their responsive genes. In astrocyte cultures, soluble
recombinant HIV gp120
protein was capable of directly inducing CXCL10/IP-10 gene
expression a process that was independent of STAT1. These findings
highlight a novel IFN- and STAT1-independent mechanism for the
regulation of CXCL10/IP-10 expression and directly link expression
of HIV gp120 to the
induction of CXCL10/IP-10 that is found in HIV
infection of the CNS. Finally, one function of IP-10 expression may
be the recruitment of leukocytes to the CNS, since the brain of
GFAP-HIV gp120 mice had
increased numbers of CD3(+) T cells that were found in close
proximity to sites of CXCL10/IP-10 RNA expression
Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De Clercq
E, Vescovi A, Bagetta G, Kollias G, Meldolesi J, Volterra A (2001)
CXCR4-activated astrocyte glutamate release via TNFalpha:
amplification by Microglia
triggers neurotoxicity. Nat.Neurosci. 4:702-710
Abstract:
Astrocytes actively participate in synaptic integration by releasing
transmitter (glutamate) via a calcium-regulated, exocytosis-like
process. Here we show that this process follows activation of the
receptor CXCR4 by the chemokine stromal cell-derived factor 1
(SDF-1). An extraordinary feature of the ensuing signaling cascade
is the rapid extracellular release of tumor necrosis factor-alpha
(TNFalpha). Autocrine/paracrine TNFalpha-dependent signaling leading
to prostaglandin (PG) formation not only controls glutamate release
and astrocyte communication, but also causes their derangement when
activated Microglia
cooperate to dramatically enhance release of the cytokine in
response to CXCR4 stimulation. We demonstrate that altered glial
communication has direct neuropathological consequences and that
agents interfering with CXCR4-dependent astrocyte-Microglia
signaling prevent neuronal apoptosis induced by the HIV-1
coat glycoprotein, gp120IIIB. Our results identify a new pathway for
glia-glia and glia-neuron communication that is relevant to both
normal brain function and neurodegenerative diseases
Bruce-Keller AJ, Barger SW, Moss NI, Pham JT, Keller JN, Nath
A (2001) Pro-inflammatory and pro-oxidant properties of the HIV
protein Tat in a Microglial
cell line: attenuation by 17 beta-estradiol. J.Neurochem.
78:1315-1324
Abstract: Microglia
are activated in humans following infection with human
immunodeficiency virus (HIV),
and brain inflammation is thought to be involved in neuronal injury
and dysfunction during HIV
infection. Numerous studies indicate a role for the HIV
regulatory protein Tat in HIV-related
inflammatory and neurodegenerative processes, although the specific
effects of Tat on Microglial
activation, and the signal transduction mechanisms thereof, have not
been elucidated. In the present study, we document the effects of
Tat on Microglial
activation and characterize the signal transduction pathways
responsible for Tat's pro-inflammatory effects. Application of Tat
to N9 Microglial
cells increased multiple parameters of Microglial
activation, including superoxide production, phagocytosis, nitric
oxide release and TNF alpha release. Tat also caused activation of
both p42/p44 mitogen activated protein kinase (MAPK) and NF kappa B
pathways. Inhibitor studies revealed that Tat-induced NF kappa B
activation was responsible for increased nitrite release, while MAPK
activation mediated superoxide release, TNF alpha release, and
phagocytosis. Lastly, pre-treatment of Microglial
cells with physiological concentrations of 17 beta-estradiol
suppressed Tat-mediated Microglial
activation by interfering with Tat-induced MAPK activation.
Together, these data elucidate specific components of the Microglial
response to Tat and suggest that Tat could contribute to the
neuropathology associated with HIV
infection through Microglial
promulgation of oxidative stress
Cambien B, Pomeranz M, Schmid-Antomarchi H, Millet MA,
Breittmayer V, Rossi B, Schmid-Alliana A (2001) Signal transduction
pathways involved in soluble fractalkine-induced monocytic cell
adhesion. Blood 97:2031-2037
Abstract: Fractalkine displays
features that distinguishes it from the other chemokines. In
particular, besides its chemoattractant action it promotes, under
physiologic flow, the rapid capture and the firm adhesion of a
subset of leukocytes or intervenes in the neuron/Microglia
interaction. This study verified that indeed the human monocytic
MonoMac6 cell line adheres to fibronectin-coated filters in response
to soluble fractalkine (s-FKN). s-FKN stimulates, with distinct time
courses, extracellular signal-related kinases (ERK1 and ERK2) and
stress-activated protein kinases (SAPK1/JNK1 and SAPK2/p38). Both
p60 Src and p72 Syk were activated under s-FKN stimulation with a
rapid kinetic profile compatible with a downstream regulation on the
mitogen-activated protein kinase (MAPK) congeners. The use of
specific tyrosine kinase inhibitors revealed that the ERK pathway is
strictly controlled by Syk, whereas c-Src up-regulated the
downstream SAPK2/p38. In contrast, the SAPK1/JNK1 pathway was not
regulated by any of these nonreceptor tyrosine kinases. The
s-FKN-mediated increased adherence of MonoMac6 cells was partially
inhibited by SB202190, a broad SAPKs inhibitor, PD98059, an MEK
inhibitor, LY294002, a phosphatidyl inositol 3-kinase inhibitor, and
a pertussis toxin-sensitive G protein. These data highlight that the
integration of a complex array of signal transduction pathways is
necessary to complete the full s-FNK-dependent adherence of human
monocytic cells to fibronectin. (Blood. 2001;97:2031-2037)
Corasaniti MT, Maccarrone M, Nistico R, Malorni W, Rotiroti
D, Bagetta G (2001) Exploitation of the HIV-1
coat glycoprotein, gp120, in neurodegenerative studies in vivo.
J.Neurochem. 79:1-8
Abstract: Neuronal loss has often been
described at post-mortem in the brain neocortex of patients
suffering from AIDS.
Neuroinvasive strains of HIV
infect macrophages, Microglial
cells and multinucleated giant cells, but not neurones. Processing
of the virus by cells of the myelomonocytic lineage yields viral
products that, in conjunction with potentially neurotoxic molecules
generated by the host, might initiate a complex network of events
which lead neurones to death. In particular, the HIV-1
coat glycoprotein, gp120, has been proposed as a likely aetiologic
agent of the described neuronal loss because it causes death of
neurones in culture. More recently, it has been shown that brain
neocortical cell death is caused in rat by intracerebroventricular
injection of a recombinant gp120 coat protein, and that this occurs
via apoptosis. The latter observation broadens our knowledge in the
pathophysiology of the reported neuronal cell loss and opens a new
lane of experimental research for the development of novel
therapeutic strategies to limit damage to the brain of patients
suffering from HIV-associated
dementia
Corasaniti MT, Piccirilli S, Paoletti A, Nistico R, Stringaro
A, Malorni W, Finazzi-Agro A, Bagetta G (2001) Evidence that the
HIV-1 coat protein gp120
causes neuronal apoptosis in the neocortex of rat via a mechanism
involving CXCR4 chemokine receptor. Neurosci.Lett.
312:67-70
Abstract: The HIV-1
coat protein, gp120 (100 ng given intracerebroventricularly (i.c.v.)
daily for seven consecutive days) causes DNA fragmentation in the
brain neocortex of rat. In neocortical cells bearing ultrastructural
features typical of apoptosis, electron microscopy revealed specific
immunopositivity for neurofilament cytoskeletal proteins, suggesting
the neuronal nature of dying cells. Neuronal apoptosis by gp120
implicates CXCR4 chemokine receptors; in fact, in rats receiving a
single daily, non-neurotoxic, dose of SDF-1alpha (0.25 pmoles given
i.c.v. for 7 days before gp120), the natural ligand of CXCR4
receptor, apoptosis was significantly hindered. The mechanism of
SDF-1alpha protection involves inhibition of gp120-enhanced
expression of IL-1beta, a cytokine implicated in the mechanisms of
apoptosis induced by the viral protein in the neocortex of rat
Cross AK, Woodroofe MN (2001) Immunoregulation of Microglial
functional properties. Microsc.Res.Tech. 54:10-17
Abstract:
Microglia
are the resident tissue macrophages of the central nervous system
(CNS) parenchyma and are key players in the initiation of an
inflammatory response. Microglia
rapidly transform from a resting to an activated morphology in
response to a variety of disease states. However, they can also be
the target of infections, as in the case of HIV.
Many of the effector properties of Microglia
can be attributed to the array of substances they secrete in
response to stimuli such as bacterial lipopolysaccharide, cytokines,
and chemokines. The products of activated Microglia
include: cytokines (pro- and anti-inflammatory), chemokines, nitric
oxide, superoxide radicals, and proteases. Furthermore, Microglia
have the ability to present antigen to T cells, migrate in response
to chemotactic stimuli, and phagocytose cell debris. This report
focuses on the immunomodulatory functions of Microglia,
with particular attention to chemokines, and highlights their
pivotal role in the CNS
Dugas N, Lacroix C, Kilchherr E, Delfraissy JF, Tardieu M
(2001) Role of CD23 in astrocytes inflammatory reaction during HIV-1
related encephalitis. Cytokine 15:96-107
Abstract: Soluble
factors released by intra-cerebral activated cells are implicated in
neuronal alterations during central nervous system inflammatory
diseases. In this study, the role of the CD23 pathway in astrocyte
activation and its participation in human immunodeficiency virus-1
(HIV-1)-induced
neuropathology were evaluated. In human primary astrocytes, CD23
protein membrane expression was dose-dependently upregulated by
gp120. It was also upregulated by gamma-interferon (gamma-IFN) and
modulated by interleukin-1-beta (IL-1beta) whereas Microglial
cells in these stimulation conditions did not express CD23. Cell
surface stimulation of CD23 expressed by astrocytes induced
production of nitric oxide (NO) and IL-1beta which was inhibited by
a specific inducible NO-synthase (iNOS) inhibitor (aminoguanidine),
indicating the implication of this receptor in the astrocyte
inflammatory reaction. On brain tissues from five out of five
patients with HIV-1-related
encephalitis, CD23 was expressed by astrocytes and by some
Microglial
cells, whereas it was not detectable on brain tissue from five of
five HIV-1-infected
patients without central nervous system (CNS) disease or from two of
two control subjects. In addition, CD23 antigen was co-localized
with iNOS and nitrotyrosine on brain tissue from patients with
HIV1-related encephalitis,
suggesting that CD23 participates in iNOS activation of astrocytes
in vivo. In conclusion, CD23 ligation is an alternative pathway in
the induction of inflammatory product synthesis by astrocytes and
participates in CNS inflammation
Fischer-Smith T, Croul S, Sverstiuk AE, Capini C, L'Heureux
D, Regulier EG, Richardson MW, Amini S, Morgello S, Khalili K,
Rappaport J (2001) CNS invasion by CD14+/CD16+ peripheral
blood-derived monocytes in HIV
dementia: perivascular accumulation and reservoir of HIV
infection. J.Neurovirol. 7:528-541
Abstract: Increases in
circulating CD14+/CD16+ monocytes have been associated with HIV
dementia; trafficking of these cells into the CNS has been proposed
to play an important role in the pathogenesis of HIV-induced
neurological disorders. This model suggests that events outside the
CNS leading to monocyte activation initiate the process leading to
HIV dementia. To
investigate the role of this activated monocyte subset in the
pathogenesis of HIV
dementia, we examined brain specimens from patients with HIV
encephalopathy (HIVE), HIV
without encephalopathy, and seronegative controls. An accumulation
of perivascular macrophages was observed in HIVE.
The majority of these cells identified in Microglial
nodules and in the perivascular infiltrate were CD14+/CD16+. P24
antigen colocalized with both CD14 and CD16 suggesting that the
CD14+/CD16+ macrophage is a major reservoir of HIV-1
infection in CNS. Using CD45/LCA staining, the perivascular
macrophage was distinguished from resident Microglia.
In addition to perivascular and nodular localizations, CD16 also
stained ramified cells throughout the white matter. These cells were
more ramified and abundant than cells positive for CD14 in white
matter. Double staining for p24 and CD16 suggests that these cells
were often infected with HIV-1.
The prominent distribution of CD14+ cells in HIVE
prompted our analysis of soluble CD14 levels in cerebrospinal fluid.
Higher levels of soluble CD14 (sCD14) were observed in patients with
moderate-to-severe HIV
dementia, suggesting the utility of sCD14 as a surrogate marker.
CD14+/CD16+ monocytes may play a role in other neurological
disorders and sCD14 may be useful for evaluating these conditions
Giralt M, Carrasco J, Penkowa M, Morcillo MA, Santamaria J,
Campbell IL, Hidalgo J (2001) Astrocyte-targeted expression of
interleukin-3 and interferon-alpha causes region-specific changes in
metallothionein expression in the brain. Exp.Neurol.
168:334-346
Abstract: Transgenic mice expressing IL-3 and
IFN-alpha under the regulatory control of the GFAP gene promoter
(GFAP-IL3 and GFAP-IFNalpha mice) exhibit a cytokine-specific,
late-onset chronic-progressive neurological disorder which resemble
many of the features of human diseases such as multiple sclerosis,
Aicardi-Goutieres syndrome, and some viral encephalopathies
including HIV
leukoencephalopathy. In this report we show that the
metallothionein-I+II (MT-I+II) isoforms were upregulated in the
brain of both GFAP-IL3 and GFAP-IFNalpha mice in accordance with the
site and amount of expression of the cytokines. In the GFAP-IL3
mice, in situ hybridization analysis for MT-I RNA and
radioimmunoassay results for MT-I+II protein revealed that a
significant upregulation was observed in the cerebellum and medulla
plus pons at the two ages studied, 1-3 and 6-10 months. Increased
MT-I RNA levels occurred in the Purkinje and granular layers of the
cerebellum, as well as in its white matter tracts. In contrast to
the cerebellum and brain stem, MT-I+II were downregulated by IL-3 in
the hippocampus and the remaining brain in the older mice. In situ
hybridization for MT-III RNA revealed a modest increase in the
cerebellum, which was confirmed by immunohistochemistry. MT-III
immunoreactivity was present in cells that were mainly round or
amoeboid monocytes/macrophages and in astrocytes. MT-I+II induction
was more generalized in the GFAP-IFNalpha (GIFN12 and GIFN39 lines)
mice, with significant increases in the cerebellum, thalamus,
hippocampus, and cortex. In the high expressor line GIFN39, MT-III
RNA levels were significantly increased in the cerebellum (Purkinje,
granular, and molecular layers), thalamus, and hippocampus (CA2/CA3
and especially lacunosum molecular layers). Reactive astrocytes,
activated rod-like Microglia,
and macrophages, but not the perivenular infiltrating cells, were
identified as the cellular sources of the MT-I+II and MT-III
proteins. The pattern of expression of the different MT isoforms in
these transgenic mice differed substantially, demonstrating unique
effects associated with the expression of each cytokine. The results
indicate that the MT expression in the CNS is significantly affected
by the cytokine-induced inflammatory response and support a major
role of these proteins during CNS injury
Gorry PR, Bristol G, Zack JA, Ritola K, Swanstrom R, Birch
CJ, Bell JE, Bannert N, Crawford K, Wang H, Schols D, De Clercq E,
Kunstman K, Wolinsky SM, Gabuzda D (2001) Macrophage tropism of
human immunodeficiency virus type 1 isolates from brain and lymphoid
tissues predicts neurotropism independent of coreceptor specificity.
J.Virol. 75:10073-10089
Abstract: The viral determinants that
underlie human immunodeficiency virus type 1 (HIV-1)
neurotropism are unknown, due in part to limited studies on viruses
isolated from brain. Previous studies suggest that brain-derived
viruses are macrophage tropic (M-tropic) and principally use CCR5
for virus entry. To better understand HIV-1
neurotropism, we isolated primary viruses from autopsy brain,
cerebral spinal fluid, blood, spleen, and lymph node samples from
AIDS patients with dementia
and HIV-1 encephalitis.
Isolates were characterized to determine coreceptor usage and
replication capacity in peripheral blood mononuclear cells (PBMC),
monocyte-derived macrophages (MDM), and Microglia.
Env V1/V2 and V3 heteroduplex tracking assay and sequence analyses
were performed to characterize distinct variants in viral
quasispecies. Viruses isolated from brain, which consisted of
variants that were distinct from those in lymphoid tissues, used
CCR5 (R5), CXCR4 (X4), or both coreceptors (R5X4). Minor usage of
CCR2b, CCR3, CCR8, and Apj was also observed. Primary brain and
lymphoid isolates that replicated to high levels in MDM showed a
similar capacity to replicate in Microglia.
Six of 11 R5 isolates that replicated efficiently in PBMC could not
replicate in MDM or Microglia
due to a block in virus entry. CD4 overexpression in Microglia
transduced with retroviral vectors had no effect on the restricted
replication of these virus strains. Furthermore, infection of
transfected cells expressing different amounts of CD4 or CCR5 with
M-tropic and non-M-tropic R5 isolates revealed a similar dependence
on CD4 and CCR5 levels for entry, suggesting that the entry block
was not due to low levels of either receptor. Studies using TAK-779
and AMD3100 showed that two highly M-tropic isolates entered
Microglia
primarily via CXCR4. These results suggest that HIV-1
tropism for macrophages and Microglia
is restricted at the entry level by a mechanism independent of
coreceptor specificity. These findings provide evidence that
M-tropism rather than CCR5 usage predicts HIV-1
neurotropism
Gray F, Adle-Biassette H, Chretien F, Lorin dlG, Force G,
Keohane C (2001) Neuropathology and neurodegeneration in human
immunodeficiency virus infection. Pathogenesis of HIV-induced
lesions of the brain, correlations with HIV-associated
disorders and modifications according to treatments.
Clin.Neuropathol. 20:146-155
Abstract: A variety of HIV-induced
lesions of the central nervous system (CNS) have been described,
including HIV encephalitis,
HIV leukoencephalopathy,
axonal damage, and diffuse poliodystrophy with neuronal loss of
variable severity resulting, at least partly, from an apoptotic
process. However, no correlation could be established between these
changes and HIV dementia
(HIVD). From our study of
HIV infected patients, it
appeared that neuronal apoptosis is probably not related to a single
cause. Microglial
and glial activation, directly or indirectly related to HIV
infection, plays a major role in neuronal apoptosis possibly through
the mediation of oxidative stress. In our patients with full-blown
AIDS, this mechanism
predominated in the basal ganglia and correlated well with HIVD.
Axonal damage, either secondary to Microglial
activation, or to systemic factors also contributes to neuronal
apoptosis. Although massive neuronal loss may be responsible for
HIVD in occasional cases,
we conclude that neuronal apoptosis is a late event and does not
represent the main pathological substrate of HIVD.
The dementia more likely reflects a specific neuronal dysfunction
resulting from the combined effects of several mechanisms, some of
which may be reversible. Introduction of highly active
antiretroviral therapy dramatically improved patient survival,
however, its impact on the incidence and course of HIVD
remains debatable. In our series, the incidence of HIVE
has dramatically decreased since the introduction of multitherapies,
but a number of cases remain whose cognitive disorders persist,
despite HAART. The poor CNS penetration of many antiretroviral
agents is a possible explanation, but irreversible "burnt out"
HIV-induced CNS changes may
also be responsible
Herzberg U, Sagen J (2001) Peripheral nerve exposure to HIV
viral envelope protein gp120 induces neuropathic pain and spinal
gliosis. J.Neuroimmunol. 116:29-39
Abstract: Painful sensory
neuropathy is a common and debilitating consequence of human
immunodeficiency virus (HIV).
The underlying causes of neuropathic pain are most likely not due to
direct infection of the nervous system by active virus. The goal of
this study was to determine whether epineural exposure to the HIV-1
envelope protein gp120 could lead to chronic painful peripheral
neuropathy. Two doses of gp120 or BSA control were transiently
delivered epineurally via oxidized cellulose wrapped around the rat
sciatic nerve. Animals were assessed for neuropathic pain behaviors
at several intervals from 1-30 days following nerve surgery.
Allodynia and hyperalgesia were observed within 1-3 days following
gp120 and sustained throughout the testing period. The gp120-exposed
sciatic nerve exhibited early but transient pathology, notably
axonal swelling and increased tumor necrosis factor alpha
(TNF-alpha) within the nerve trunk. In contrast, intense astrocytic
and Microglial
activation was observed in the spinal cord, and this gliosis
persisted for at least 30 days following epineural gp120, in
parallel with neuropathic pain behaviors. These findings demonstrate
that limited peripheral nerve exposure to HIV
protein can induce persistent painful sensory neuropathy that may be
sustained and magnified by long-term spinal neuropathology
Heyes MP, Ellis RJ, Ryan L, Childers ME, Grant I, Wolfson T,
Archibald S, Jernigan TL (2001) Elevated cerebrospinal fluid
quinolinic acid levels are associated with region-specific cerebral
volume loss in HIV
infection. Brain 124:1033-1042
Abstract: Neuronal injury,
dendritic loss and brain atrophy are frequent complications of
infection with human immunodeficiency virus (HIV)
type 1. Activated brain macrophages and Microglia
can release quinolinic acid, a neurotoxin and NMDA
(N-methyl-D-aspartate) receptor agonist, which we hypothesize
contributes to neuronal injury and cerebral volume loss. In the
present cross-sectional study of 94 HIV-1-infected
patients, elevated CSF quinolinic acid concentrations correlated
with worsening brain atrophy, quantified by MRI, in regions
vulnerable to excitotoxic injury (the striatum and limbic cortex)
but not in regions relatively resistant to excitotoxicity (the
non-limbic cortex, thalamus and white matter). Increased CSF
quinolinic acid concentrations also correlated with higher CSF HIV-1
RNA levels. In support of the specificity of these associations,
blood levels of quinolinic acid were unrelated to striatal and
limbic volumes, and CSF levels of beta(2)-microglobulin, a
non-specific and non-excitotoxic marker of immune activation, were
unrelated to regional brain volume loss. These results are
consistent with the hypothesis that quinolinic acid accumulation in
brain tissue contributes to atrophy in vulnerable brain regions in
HIV infection and that
virus replication is a significant driver of local quinolinic acid
biosynthesis
Kaul M, Garden GA, Lipton SA (2001) Pathways to neuronal
injury and apoptosis in HIV-associated
dementia. Nature 410:988-994
Abstract: Human immunodeficiency
virus-1 (HIV-1) can induce
dementia with alarming occurrence worldwide. The mechanism remains
poorly understood, but discovery in brain of HIV-1-binding
sites (chemokine receptors) provides new insights. HIV-1
infects macrophages and Microglia,
but not neurons, although neurons are injured and die by apoptosis.
The predominant pathway to neuronal injury is indirect through
release of macrophage, Microglial
and astrocyte toxins, although direct injury by viral proteins might
also contribute. These toxins overstimulate neurons, resulting in
the formation of free radicals and excitotoxicity, similar to other
neurodegenerative diseases. Recent advances in understanding the
signalling pathways mediating these events offer hope for
therapeutic intervention
Langford D, Masliah E (2001) Crosstalk between components of
the blood brain barrier and cells of the CNS in Microglial
activation in AIDS. Brain
Pathol. 11:306-312
Abstract: During the progression of AIDS,
a majority of patients develop cognitive disorders such as HIV
encephalitis (HIVE) and
AIDS dementia complex
(ADC), which correlate closely with macrophage infiltration into the
brain and Microglial
activation. Microglial
activation occurs in response to infection, inflammation and
neurological disorders including HIVE,
Alzheimer's disease, Parkinson's disease and multiple sclerosis.
Microglia
can be activated by immunoreactive cells independent of, but
enhanced by HIV infection,
from at least two routes. Activation may occur from signals
originating from activated monocytes and lymphocytes in the blood
stream, which initiate a cascade of stimuli that ultimately reach
Microglia
in the brain or from activated macrophages/Microglia/astrocytes
within the brain. Effects of Microglial
activation stemming from both systemic and CNS HIV
infection act together to commence signaling feedback, leading to
HIVE and increased
neurodegeneration. Most recent data indicate that in AIDS
patients, Microglial
activation in the brain with subsequent release of excitotoxins,
cytokines and chemokines leads to neurodegeneration and cognitive
impairment. Since the presence of HIV
in the brain results from migration of infected monocytes and
lymphocytes across the vascular boundary, the development of novel
therapies aimed at protecting the integrity of the blood brain
barrier (BBB) upon systemic HIV
infection is critical for controlling CNS infection
Levin MC, Rosenblum MK, Fox CH, Jacobson S (2001)
Localization of retrovirus in the central nervous system of a
patient co-infected with HTLV-1 and HIV
with HAM/TSP and HIV-associated
dementia. J.Neurovirol. 7:61-65
Abstract: Persons co-infected
with HTLV-1 and HIV are at
increased risk for neurologic disease. These patients may develop
HAM/TSP and/or HIV-associated
dementia. In this study, we localized cells infected with retrovirus
in the central nervous system (CNS) of a patient with both HAM/TSP
and HIV-associated
dementia. HTLV-1 was localized to astrocytes and HIV
to macrophage/Microglia.
There was no co-infection of a single cell phenotype in this
patient. These data suggest that mechanisms other than co-infection
of the same CNS cell may play a role in the development of
neurologic disease in patients dual infected with HTLV-1 and HIV
Martin J, LaBranche CC, Gonzalez-Scarano F (2001)
Differential CD4/CCR5 utilization, gp120 conformation, and
neutralization sensitivity between envelopes from a
Microglia-adapted
human immunodeficiency virus type 1 and its parental isolate.
J.Virol. 75:3568-3580
Abstract: Human immunodeficiency virus type
1 (HIV-1) infects and
induces syncytium formation in Microglial
cells from the central nervous system (CNS). A primary isolate
(HIV-1(BORI)) was
sequentially passaged in cultured Microglia,
and the isolate recovered (HIV-1(BORI-15))
showed high levels of fusion and replicated more efficiently in
Microglia
(J. M. Strizki, A. V. Albright, H. Sheng, M. O'Connor, L. Perrin,
and F. Gonzalez-Scarano, J. Virol. 70:7654-7662, 1996). The parent
and adapted viruses used CCR5 as coreceptor. Recombinant viruses
demonstrated that the syncytium-inducing phenotype was associated
with four amino acid differences in the V1/V2 region of the viral
gp120 (J. T. C. Shieh, J. Martin, G. Baltuch, M. H. Malim, and F.
Gonzalez-Scarano, J. Virol. 74:693-701, 2000). We produced
luciferase-reporter, env-pseudotyped viruses using plasmids
containing env sequences from HIV-1(BORI),
HIV-1(BORI-15), and the
V1/V2 region of HIV-1(BORI-15)
in the context of HIV-1(BORI)
env (named rBORI, rB15, and rV1V2, respectively). The pseudotypes
were used to infect cells expressing various amounts of CD4 and CCR5
on the surface. In contrast to the parent recombinant, the rB15 and
rV1V2 pseudotypes retained their infectability in cells expressing
low levels of CD4 independent of the levels of CCR5, and they
infected cells expressing CD4 with a chimeric coreceptor containing
the third extracellular loop of CCR2b in the context of CCR5 or a
CCR5 Delta4 amino-terminal deletion mutant. The VH-rB15 and VH-rV1V2
recombinant viruses were more sensitive to neutralization by a panel
of HIV-positive sera than
was VH-rBORI. Interestingly, the CD4-induced 17b epitope on gp120
was more accessible in the rB15 and rV1V2 pseudotypes than in rBORI,
even before CD4 binding, and concomitantly, the rB15 and rV1V2
pseudotypes were more sensitive to neutralization with the human 17b
monoclonal antibody. Adaptation to growth in Microglia--cells
that have reduced expression of CD4 in comparison with other cell
types--appears to be associated with changes in gp120 that modify
its ability to utilize CD4 and CCR5. Changes in the availability of
the 17b epitope indicate that these affect conformation. These
results imply that the process of adaptation to certain tissue types
such as the CNS directly affects the interaction of HIV-1
envelope glycoproteins with cell surface components and with humoral
immune responses
Milligan ED, O'Connor KA, Nguyen KT, Armstrong CB, Twining C,
Gaykema RP, Holguin A, Martin D, Maier SF, Watkins LR (2001)
Intrathecal HIV-1 envelope
glycoprotein gp120 induces enhanced pain states mediated by spinal
cord proinflammatory cytokines. J.Neurosci. 21:2808-2819
Abstract:
Perispinal (intrathecal) injection of the human immunodeficiency
virus-1 (HIV-1) envelope
glycoprotein gp120 creates exaggerated pain states. Decreases in
response thresholds to both heat stimuli (thermal hyperalgesia) and
light tactile stimuli (mechanical allodynia) are rapidly induced
after gp120 administration. gp120 is the portion of HIV-1
that binds to and activates Microglia
and astrocytes. These glial cells have been proposed to be key
mediators of gp120-induced hyperalgesia and allodynia because these
pain changes are blocked by drugs thought to affect glial function
preferentially. The aim of the present series of studies was to
determine whether gp120-induced pain changes involve proinflammatory
cytokines [interleukin-1beta (IL-1) and tumor necrosis factor-alpha
(TNF-alpha)], substances released from activated glia. IL-1 and TNF
antagonists each prevented gp120-induced pain changes. Intrathecal
gp120 produced time-dependent, site-specific increases in TNF and
IL-1 protein release into lumbosacral CSF; parallel cytokine
increases in lumbar dorsal spinal cord were also observed.
Intrathecal administration of fluorocitrate (a glial metabolic
inhibitor), TNF antagonist, and IL-1 antagonist each blocked
gp120-induced increases in spinal IL-1 protein. These results
support the concept that activated glia in dorsal spinal cord can
create exaggerated pain states via the release of proinflammatory
cytokines
Mitchell W (2001) Neurological and developmental effects of
HIV and AIDS
in children and adolescents. Ment.Retard.Dev.Disabil.Res.Rev.
7:211-216
Abstract: HIV-related
encephalopathy is an important problem in vertically infected
children with HIV. Infected
infants may manifest early, catastrophic encephalopathy, with loss
of brain growth, motor abnormalities, and cognitive dysfunction.
Even without evidence of AIDS,
infected infants score lower than serorevertors on developmental
measures, particularly language acquisition. Children with perinatal
or later transfusion-related infection generally are roughly
comparable developmentally to their peers until late in their
course. Symptoms similar to adult AIDS
dementia complex are occasionally seen in adolescents with advanced
AIDS, including dementia,
bradykinesia, and spasticity. Opportunistic CNS infections such as
toxoplasmosis and progressive multifocal leukoencephalopathy are
less common in children and adolescents than in adults. Increasing
evidence suggests that aggressive antiretroviral treatment may halt
or even reverse encephalopathy. Neuroimaging changes may precede or
follow clinical manifestations, and include early lenticulostriate
vessel echogenicity on cranial ultrasound, calcifying
microangiopathy on CT scan, and/or white matter lesions and central
atrophy on MRI. Differential diagnosis of neurological dysfunction
in an HIV-infected infant
includes the effects of maternal substance abuse, other CNS
congenital infections, and other causes of early static
encephalopathy. Initial entry of HIV
into the nervous system occurs very early in infection. The risk of
clinical HIV encephalopathy
increases with very early age of infection and with high viral
loads. Virus is found in Microglia
and brain derived macrophages, not neurons. The neuronal effect of
HIV is probably indirect,
with various cytokines implicated. Apoptosis is the presumed
mechanism of damage to neurons by HIV
Mrak RE, Griffinbc WS (2001) The role of activated astrocytes
and of the neurotrophic cytokine S100B in the pathogenesis of
Alzheimer's disease. Neurobiol.Aging 22:915-922
Abstract:
Activated astrocytes, overexpressing the neurotrophic signaling
molecule S100beta, are invariant components of the Abeta plaques of
Alzheimer's disease. Even early, nonfibrillar amyloid deposits in
Alzheimer's disease contain such astrocytes, and the numbers and
degree of activation of these wax and wane with the subsequent
neuritic pathology of plaque evolution. Astrocytic overexpression of
S100B in the neuritic plaques of Alzheimer's disease correlates with
the degree of neuritic pathology in Abeta plaques in this disease,
suggesting a pathogenic role for S100B's neurotrophic properties in
the evolution of these lesions. Astrocytic overexpression of S100B,
in turn, is promoted by high levels of interleukin-1 (IL-1),
originating from activated Microglia
that are also constant components of Abeta plaques in Alzheimer's
disease. Similar patterns of astrocyte activation, S100B
overexpression, Microglial
activation, and IL-1 overexpression are seen in conditions that
confer risk for Alzheimer's disease (aging, head trauma, Down's
syndrome), in conditions that predispose to accelerated appearance
of Alzheimer-like neuropathologic changes (chronic epilepsy, HIV
infection), and in animal models of Alzheimer's disease. These cells
and molecules are an important components of a cytokine cycle of
molecular and cellular cascades that may drive disease progression
in Alzheimer's disease
Nebuloni M, Pellegrinelli A, Ferri A, Bonetto S, Boldorini R,
Vago L, Grassi MP, Costanzi G (2001) Beta amyloid precursor protein
and patterns of HIV p24
immunohistochemistry in different brain areas of AIDS
patients. AIDS
15:571-575
Abstract: OBJECTIVES: To evaluate the correlation
between immunohistochemical positive patterns (globular and
filamentous structures) of beta-amyloid precursor protein
(beta-APP), used as a marker of axonal damage, and the different
distribution of HIV p24
antigens, in three different brain areas of AIDS
patients. METHODS: Eighteen AIDS
patients with HIV-related
brain lesions were included in the study. Forty-nine sections from
basal ganglia, frontal cortex and hippocampus were selected. After
microwave oven pre-treatment, the sections were incubated with
anti-HIV p24 and
anti-beta-APP monoclonal antibodies; the reactions were developed
with peroxidase/3,3'diaminobenzidine. The positivity was graded by
semi-quantitative scores. Double immunohistochemical staining was
used to evaluate the co-localization of the antigens. RESULTS: HIV
p24 immunohistochemistry was positive in 44 of 49 sections (89%),
with a prevalence of interstitial positive cells and positive
Microglial
nodules in 27 and 13 sections respectively. beta-APP-positive
structures were demonstrated in 23 of 44 sections (52%) with
HIV-related lesions, and
were absent from the five sections without viral expression.
Globular and filamentous lesions were observed in 21 of 23 sections
and 10 of 23 lesions respectively. Moreover, a high grade of
globular type lesion was related to an elevated presence of diffuse
interstitial HIV
p24-positive cells in basal ganglia; double immunohistochemical
reactions demonstrated the co-localization of beta-APP globules and
HIV p24 antigens.
CONCLUSIONS: The data obtained confirm the coexpression of beta-APP
and viral antigens in particular areas of the brain with HIV-related
lesions; there is a strict correlation between beta-APP globules
(indicating chronic cerebral damage) and the interstitial pattern of
HIV p24
immunohistochemistry
Orenstein JM (2001) The macrophage in HIV
infection. Immunobiology 204:598-602
Abstract: Macrophages play a
key role in several critical aspects of HIV
disease. They appear to be the first cells infected by HIV
and perhaps the very source of HIV
production when CD4+ cells are markedly depleted in the patient.
Macrophages and Microglial
cells are the cells infected by HIV
in the CNS. In tonsils and adenoids of HIV-infected
patients, macrophages fuse into multinucleated giant cells that
produce copious amounts of virus. Finally, opportunistic pathogens
can cause an upregulation of HIV
production by macrophages, often in the multinucleated form
Patrizio M, Colucci M, Levi G (2001) Human immunodeficiency
virus type 1 Tat protein decreases cyclic AMP synthesis in rat
Microglia
cultures. J.Neurochem. 77:399-407
Abstract: We have studied the
modulation of cyclic AMP (cAMP) accumulation by the human
immunodeficiency virus type 1 (HIV
1) protein Tat in Microglia
and astrocyte cultures obtained from neonatal rat brain.
Pretreatment of Microglia
with recombinant Tat resulted in a dose- and time-dependent decrease
of cAMP accumulation induced by subsequent exposure to isoproterenol
(1 microM). The inhibitory action of 100 ng/mL Tat approached 50%
after 4 h of preincubation and reached a maximum of 70% after 24 h.
The Tat-induced time- and dose-dependent decrease of cAMP
accumulation was observed also when Microglial
cultures were stimulated with the adenylyl cyclase activator
forskolin (100 microM). In both cases, Tat inhibitory action was 70%
reverted by a specific monoclonal anti-Tat antibody, but was not
prevented either by the phosphodiesterase inhibitor
3-isobutyl-1-methyl-xantine (100 microM) or by a 16-h pretreatment
of Microglial
cultures with the Gi protein inhibitor pertussis toxin (10 ng/mL).
All these results suggested that the viral protein acts at a step of
the cAMP transduction pathway other than receptors, G proteins and
phosphodiesterases. The target of Tat appeared to be adenylyl
cyclase, whose activity was markedly reduced (up to 60%) in
membranes prepared from Tat-treated Microglial
cells, both in basal conditions and after stimulation with
isoproterenol and forskolin. The inability of the competitive
inhibitor of nitric oxide synthase N(G)-monometyl- L-arginine (20
and 200 microM) to revert Tat action on forskolin-induced cAMP
accumulation, and of two potent nitric oxide donors, PAPA and DETA
(0.1-2 m M), to alter forskolin-induced cAMP accumulation, excluded
an involvement of nitric oxide in Tat-induced adenylyl cyclase
inhibition. On the contrary, two inhibitors of nuclear factor kappaB
activation, N-tosyl-( L)-phenylalanine chloromethyl ketone (10
microM) and SN50 (25 microM), markedly prevented the reduction of
forskolin-evoked cAMP accumulation by Tat, suggesting a possible
role for this nuclear transcriptional factor in the regulation of
adenylyl cyclase by Tat in Microglia.
This assumption was strengthened by the ability of
lipopolysaccharide (100 ng/mL, 4 h) to mimic the inhibitory effect
of the viral protein. Conversely, astrocyte cAMP accumulation was
unaffected by the viral protein, as tested at various concentrations
and time points. Finally, Tat inhibition of Microglial
adenylyl cyclase was not due to non-specific cytotoxicity. As cAMP
has been reported to exert a neuroprotective role in several in vivo
and in vitro models of brain pathologies, and Microglia
is believed to mediate Tat-induced neurotoxicity, these results
suggest that the ability of Tat to inhibit cAMP synthesis in
Microglia
may contribute to neuronal degeneration and cell death associated
with HIV infection
Peterson KE, Robertson SJ, Portis JL, Chesebro B (2001)
Differences in cytokine and chemokine responses during neurological
disease induced by polytropic murine retroviruses Map to separate
regions of the viral envelope gene. J.Virol. 75:2848-2856
Abstract:
Infection of the central nervous system (CNS) by several viruses can
lead to upregulation of proinflammatory cytokines and chemokines. In
immunocompetent adults, these molecules induce prominent
inflammatory infiltrates. However, with immunosuppressive
retroviruses, such as human immunodeficiency virus (HIV),
little CNS inflammation is observed yet proinflammatory cytokines
and chemokines are still upregulated in some patients and may
mediate pathogenesis. The present study examined expression of
cytokines and chemokines in brain tissue of neonatal mice infected
with virulent (Fr98) and avirulent (Fr54) polytropic murine
retroviruses. While both viruses infect Microglia
and endothelia primarily in the white matter areas of the CNS, only
Fr98 induces clinical CNS disease. The pathology consists of gliosis
with minimal morphological changes and no inflammation, similar to
HIV. In the present
experiments, mice infected with Fr98 had increased cerebellar mRNA
levels of proinflammatory cytokines tumor necrosis factor alpha
(TNF-alpha), TNF-beta, and interleukin-1 alpha and chemokines
macrophage inflammatory protein-1 alpha (MIP-1 alpha), MIP-1 beta,
monocyte chemoattractant protein 1 (MCP-1),
gamma-interferon-inducible protein 10 (IP-10), and RANTES compared
to mice infected with Fr54 or mock-infected controls. The increased
expression of these genes occurred prior to the development of
clinical symptoms, suggesting that these cytokines and chemokines
might be involved in induction of neuropathogenesis. Two separate
regions of the Fr98 envelope gene are associated with
neurovirulence. CNS disease associated with the N-terminal portion
of the Fr98 env gene was preceded by upregulation of cytokines and
chemokines. In contrast, disease associated with the central region
of the Fr98 env gene showed no upregulation of cytokines or
chemokines and thus did not require increased expression of these
genes for disease induction
Petito CK, Roberts B, Cantando JD, Rabinstein A, Duncan R
(2001) Hippocampal injury and alterations in neuronal chemokine
co-receptor expression in patients with AIDS.
J.Neuropathol.Exp.Neurol. 60:377-385
Abstract: Hippocampal
neurons express high levels of HIV
chemokine co-receptors, activation of which causes injury or death
in vitro. To determine if their in vivo expression correlates with
injury, we evaluated neuronal CXCR4 and CCR5 immunoreactivity and
reactive gliosis in autopsy hippocampus of 10 control cases, 11 AIDS
cases without HIV
encephalitis (HIVnE) or
opportunistic infections/lymphomas (OI/L), and 11 AIDS
cases with HIV encephalitis
(HIVE). All groups had
higher CXCR4 and CCR5 expression in CA3 and CA4 neurons than CA1
neurons (p < 0.05). HIVE
cases had increased neuronal CXCR4 and decreased neuronal CCR5
expression as well as increased numbers of hippocampal GFAP-positive
astrocytes and LN3-positive Microglia.
Changes were most severe in CA3 and CA4 and lowest in CA1 regions.
These findings also were noted in the 4 HIVE
cases with neither hippocampal HIVE
nor brain OI/L and in the HIVnE
groups. This study quantitates the regional distribution of
hippocampal neuronal CXCR4 and CCR5 and shows their respective
increase and decrease in AIDS.
It suggests a relationship between neuronal loss and gliosis with
intensity of neuronal chemokine expression and raises the
possibility of a selective vulnerability of hippocampal neurons to
AIDS-related injury
Power C, Johnson RT (2001) Neuroimmune and neurovirological
aspects of human immunodeficiency virus infection. Adv.Virus Res.
56:389-433
Abstract: Like most lentiviruses, HIV-1
causes both immune suppression and neurological disease.
Neurological disease may occur at any stage of HIV
infection but is most apparent with severe immune suppression.
Cognitive impairment, reflected strikingly by HIV-associated
dementia, has attracted intense interest since the outset of the HIV
epidemic, and understanding of its pathogenesis has been spurred on
by the emergence of several hypotheses outlining potential
pathogenic mechanisms. The release of inflammatory molecules by
HIV-infected Microglia
and macrophages and the concurrent neuronal damage play central
roles in the conceptualization of HIV
neuropathogenesis. Many inflammatory molecules appear to contribute
to the pathogenic cascade and their individual roles remain
undefined. At the same time, the abundance of virus in the brain and
the type or strain of virus found in the brain may also be important
codeterminants of neurological disease, as shown for other
neurotropic viruses. Coreceptor use by HIV
found in the brain appears to closely mirror what has been reported
in systemic macrophages. The impact of HAART on viral genotype and
phenotype found in the brain, and its relationship to clinical
disease, remain uncertain. Several interesting animal models have
been developed, using other lentiviruses, transgenic animals, and
HIV-infected SCID mice,
that may prove useful in future pathogenesis and therapeutic
studies. Despite the progress in the understanding of HIV
neuropathogenesis, many questions remain unanswered
Pulliam L, Irwin I, Kusdra L, Rempel H, Flitter WD, Garland
WA (2001) CPI-1189 attenuates effects of suspected neurotoxins
associated with AIDS
dementia: a possible role for ERK activation. Brain Res.
893:95-103
Abstract: Individuals infected with the human
immunodeficiency virus (HIV)
often experience a dementia characterized by mental slowing and
memory loss. Motor dysfunction may also accompany this condition.
The pathogenesis of the dementia is not known, but microscopic
examination of brain tissue from those afflicted shows evidence of
chronic inflammation, reactive gliosis and cell death. Neurotoxic
factors produced from activated macrophage or Microglial
cells such as tumor necrosis factor-alpha (TNFalpha), gp120 and
quinolinic acid have been implicated as agents for the cell death
which often appears to occur by an apoptotic mechanism. CPI-1189, a
drug currently undergoing clinical evaluation as a treatment for the
dementia associated with AIDS,
is shown in this paper to mitigate apoptosis induced by TNFalpha,
gp120, and necrosis induced by quinolinic acid. In addition,
CPI-1189 mitigates the cell death produced by supernatants from
cultured macrophages obtained from patients with AIDS
dementia. The exact mechanism by which CPI-1189 prevents
neurotoxicity is not known; however, protection from TNFalpha and
supernatant-induced toxicity does not appear to involve NFkappaB
translocation, and appears to be associated with an increase in
activated ERK-MAP kinase. These findings may have implications for
other neurological diseases where apoptotic cell death contributes
to neurodegeneration
Ruff MR, Melendez-Guerrero LM, Yang QE, Ho WZ, Mikovits JW,
Pert CB, Ruscetti FA (2001) Peptide T inhibits HIV-1
infection mediated by the chemokine receptor-5 (CCR5). Antiviral
Res. 52:63-75
Abstract: Peptide T, which is derived from the V2
region of HIV-1, inhibits
replication of R5 and dual-tropic (R5/X4) HIV-1
strains in monocyte-derived macrophages (MDMs), Microglia,
and primary CD4(+)T cells. Little to no inhibition by peptide T was
observed with lab adapted X4 viruses such as IIIB, MN, or NL4-3
propagated in CD4(+) T cells or in the MAGI entry assay. The more
clinically relevant R5/X4 early passage patient isolates were
inhibited via either the X4 or R5 chemokine receptors, although
inhibition was greater with R5 compared to X4 receptors. Virus
inhibition ranged from 60 to 99%, depending on the assay, receptor
target, viral isolate and amount of added virus. Peak inhibitory
effects were detected at concentrations from 10(-12) to 10(-9) M.
Peptide T acted to block viral entry as it inhibited in the MAGI
cell assay and blocked infection in the luciferase reporter assay
using HIV virions
pseudotyped with ADA envelope. These results using early passage
virus grown in primary cells, together with two different entry
reporter assays, show that peptide T selectively inhibits HIV
replication using chemokine receptor CCR5 compared to CXC4,
explaining past inconsistencies of in vitro antiviral effects
Wang TH, Donaldson YK, Brettle RP, Bell JE, Simmonds P (2001)
Identification of shared populations of human immunodeficiency virus
type 1 infecting Microglia
and tissue macrophages outside the central nervous system. J.Virol.
75:11686-11699
Abstract: Infection of Microglia
and other cells of the macrophage/monocyte lineage in the central
nervous system (CNS) by human immunodeficiency virus type I (HIV-1)
underlies the development of giant cell encephalitis (GCE). It is
currently unknown whether GCE depends on the emergence of virus
populations specifically adapted to replicate in cells of the
monocyte/macrophage lineage and whether this also leads to the
specific targeting of macrophages in other nonlymphoid tissues.
Autopsy samples from lymph node, brain (frontal region), lung, and
full-thickness colon sections were obtained from nine study subjects
with GCE and from nine without. The two groups showed no significant
differences in CD4 counts, disease progression, or treatment history
before death. Genetic relatedness between variants recovered from
lymph node and nonlymphoid tissues was assessed by sequence
comparison of V3 and p17(gag) regions using a newly developed method
that scores the sample composition at successive nodes in a
neighbor-joining tree. The association index enabled objective,
numerical comparisons on the degree of tissue compartmentalization
to be made. High proviral loads and p24 antigen expression in the
brain were confined to the nine individuals with GCE. GCE was also
associated with significantly higher proviral loads in colon samples
(median of the GCE(+) group: 1,010 copies/10(6) cells; median of
GCE(-) group, 10/10(6) cells; P = 0.006). In contrast, there were no
significant differences in proviral load between the GCE(+) and
GCE(-) groups in lymph node or lung samples, where HIV
infection was manifested predominantly by infiltrates of lymphoid
cells. V3 sequences from brain samples of individuals with GCE
showed the greatest compartmentalization from those of lymph node,
although samples from other tissues, particularly the colon,
frequently contained variants phylogenetically related to those
found in brain. The existence of shared, distinct populations of HIV
specifically distributed in cells of the monocyte/macrophage lineage
was further indicated by immunocytochemical detection of CD68(+),
multinucleated giant cells expressing p24 antigen in samples of lung
and colon in two individuals with GCE. This study provides the basis
for future investigation of possible phenotypic similarities that
underline the shared distributions of HIV
variants infecting Microglia
and tissue macrophages outside the CNS
Wesselingh SL, Thompson KA (2001) Immunopathogenesis of
HIV-associated dementia.
Curr.Opin.Neurol. 14:375-379
Abstract: This review provides a
subjective analysis of the advances in our understanding of the
immunopathogenesis of HIV-associated
dementia that have occurred over the past 12 months. The review will
focus on the following areas: (i) the role of chemokines and
cytokines; (ii) the role of astrocytes, astrocyte cell death and
non-productive infection of astrocytes; (iii) a model of the
neuropathogenesis of HIV-associated
dementia and its impact on treatment paradigms and future research.
The requirements for the development of HIV-associated
dementia are immunosuppression, the loss of macrophage regulation,
central nervous system HIV
infection of Microglia
and macrophages with a neurovirulent HIV
strain, restricted HIV
infection of astrocytes, and astrocyte cell death, all of which lead
to an intracellular milieu that is neurotoxic. This cascade can be
prevented and probably reversed by the use of highly active
antiretroviral therapy, which controls viral replication both
systemically and centrally. However, for those patients who have
resistant virus and persistently high levels of replication, or who
develop resistance or toxicity, other treatment strategies need to
be developed. The control of excessive Microglial
and macrophage activation or a diminution of astrocyte and neuronal
apoptosis could have benefits in terms of cognitive function. We
therefore need to develop further our understanding of the
immunopathogenesis of HIV-associated
dementia so that we can control a number of other steps in the
cascade rather than simply controlling the viral replication
Williams K, Alvarez X, Lackner AA (2001) Central nervous
system perivascular cells are immunoregulatory cells that connect
the CNS with the peripheral immune system. Glia 36:156-164
Abstract:
Perivascular cells are a heterogeneous population found in the
central nervous system (CNS) and the peripheral nervous system
(PNS). Several terms are used for these cells, including
perivascular cells, perivascular macrophages, perivascular
Microglia,
fluorescent granular perithelial cells (FGP), or Mato cells.
Different terminology used may reflect subpopulations of
perivascular cells within different anatomic regions and
experimental paradigms, neuropathological conditions, and species
studied. Different terminology also points to the lack of clear
consensus of what cells are perivascular cells in different disease
states and models, especially with breakdown of the blood-brain
barrier (BBB). Despite this, there is consensus that perivascular
cells, although a minor component of the CNS, are important
immunoregulatory cells. Perivascular cells are bone marrow derived,
continuously turn over in the CNS, and are found adjacent to CNS
vessels. Thus, they are potential sensors of CNS and peripheral
immune system perturbations; are activated in models of CNS
inflammation, autoimmune disease, neuronal injury and death; and are
implicated as phagocytic and pinocytotic cells in models of stroke
and hypertension. Recent evidence from our laboratory implicate
perivascular cells as primary targets of human immunodeficiency
virus (HIV) and simian
immunodeficiency virus (SIV) infection in the CNS of humans and
macaques. This article reviews current knowledge of perivascular
cells, including anatomic location and nomenclature and putative
immunoregulatory roles, and discusses new data on the infection of
these cells by SIV, their accumulation after SIV infection, and a
possible role of the immune system in SIV encephalitis
Williams KC, Corey S, Westmoreland SV, Pauley D, Knight H,
deBakker C, Alvarez X, Lackner AA (2001) Perivascular macrophages
are the primary cell type productively infected by simian
immunodeficiency virus in the brains of macaques: implications for
the neuropathogenesis of AIDS.
J.Exp.Med. 193:905-915
Abstract: The macrophage is well
established as a target of HIV
and simian immunodeficiency virus (SIV) infection and a major
contributor to the neuropathogenesis of AIDS.
However, the identification of distinct subpopulations of
monocyte/macrophages that carry virus to the brain and that sustain
infection within the central nervous system (CNS) has not been
examined. We demonstrate that the perivascular macrophage and not
the parenchymal Microglia
is the primary cell productively infected by SIV. We further
demonstrate that although productive viral infection of the CNS
occurs early, thereafter it is not easily detectable until terminal
AIDS. The biology of
perivascular macrophages, including their rate of turnover and
replacement by peripheral blood monocytes, may explain the timing of
neuroinvasion, disappearance, and reappearance of virus in the CNS,
and questions the ability of the brain to function as a reservoir
for productive infection by HIV/SIV
Zhao ML, Kim MO, Morgello S, Lee SC (2001) Expression of
inducible nitric oxide synthase, interleukin-1 and caspase-1 in
HIV-1 encephalitis.
J.Neuroimmunol. 115:182-191
Abstract: Inflammatory cytokines and
enzymes such as IL-1 and inducible nitric oxide synthase (iNOS) may
play an important role in the pathogenesis of AIDS
dementia, a condition associated with infection of the CNS cells by
the HIV-1. In this report,
we investigated the expression of iNOS, IL-1, and caspase-1
(interleukin-1 converting enzyme) in HIV-1
encephalitis (HIVE) by
immunocytochemistry and analyzed their expression with respect to
HIV-1 infection and glial
activation. In HIVE, all
three molecules were expressed at high levels in areas of HIV-1
infection (Microglial
nodules with HIV-1 p24
immunoreactivity) and in areas of diffuse white matter gliosis.
Expression was cell-type specific, with IL-1 and caspase-1 being
expressed in macrophages and Microglia,
and iNOS in activated astrocytes. Multinucleated giant cells, a
hallmark of virally infected cells, showed intense staining for both
IL-1 and caspase-1, suggesting induction of these molecules by
HIV-1. Double
immunocytochemistry demonstrated a regional co-localization of
astrocyte iNOS and Microglial
IL-1 and caspase-1. These results support the notion that autocrine
and paracrine interactions between HIV-1
infected macrophages and Microglia,
activated Microglia,
and astrocytes lead to expression of proinflammatory and neurotoxic
molecules. iNOS and caspase-1 may provide additional therapeutic
targets for HIVE
Zink MC, Coleman GD, Mankowski JL, Adams RJ, Tarwater PM, Fox
K, Clements JE (2001) Increased macrophage chemoattractant protein-1
in cerebrospinal fluid precedes and predicts simian immunodeficiency
virus encephalitis. J.Infect.Dis. 184:1015-1021
Abstract:
Macrophage chemoattractant protein-1 (MCP-1) may be a key trigger
for the influx of macrophages into the brain in human
immunodeficiency virus (HIV)
encephalitis. In this study, simian immunodeficiency virus-infected
macaques that developed moderate-to-severe encephalitis had
significantly higher MCP-1 levels in cerebrospinal fluid (CSF) than
in plasma as early as 28 days after inoculation, which was before
the development of brain lesions. In contrast, CSF:plasma MCP-1
ratios remained constant at preinoculation levels in macaques that
developed minimal or no encephalitis. Abundant MCP-1 protein and
mRNA were detected in both macrophages and astrocytes in the brain.
Macaques with increased MCP-1 in CSF had significantly greater
expression of markers of macrophage and Microglia
activation and infiltration (CD68; P= .003) and astrocyte activation
(glial fibrillary acidic protein; P= .019 and P= .031 in white and
gray matter, respectively). The results suggest that the CSF:plasma
MCP-1 ratio may be a valuable prognostic marker for the development
of HIV-induced central
nervous system disease
Albright AV, Shieh JT, O'Connor MJ, Gonzalez-Scarano F (2000)
Characterization of cultured Microglia
that can be infected by HIV-1.
J.Neurovirol. 6 Suppl 1:S53-S60
Abstract: Parenchymal Microglia
are targets of HIV
infection. We, as well as others, have used in vitro Microglia
culture systems to study the tropism and replication of HIV.
Characterization of perivascular and parenchymal Microglia
surface markers in vivo, in vitro, and ex vivo, has led to the
understanding that these cell populations are different, and data
from both the HIV and SIV
models support the hypothesis that they may play different roles in
infection of the CNS. We determined that human adult parenchymal
Microglia
cultured from temporal lobe tissue for use in HIV
replication studies, were CD11c+, CD45+, CD68+,
Albright AV, Erickson-Viitanen S, O'Connor M, Frank I, Rayner
MM, Gonzalez-Scarano F (2000) Efavirenz is a potent nonnucleoside
reverse transcriptase inhibitor of HIV
type 1 replication in Microglia
in vitro. AIDS
Res.Hum.Retroviruses 16:1527-1537
Abstract: The objective of this
study was to determine whether reverse transcriptase inhibitors
(RTIs) could decrease viral replication in Microglia.
Human Microglia
obtained from individuals undergoing temporal lobectomy were
cultured and infected with HIV-1
isolates from the central nervous system (CNS) as previously
described (Strizki JM, et al. J Virol 1996;70:7654-7662). These
Microglial
cultures were treated with one of three nucleoside RTIs (NRTIs) or
with efavirenz, a nonnucleoside RTI (NNRTI), at various time points
before and during HIV-1
infection. The drug levels sufficient to provide > 90% inhibition
of Microglial
HIV replication (IC90) were
determined by comparison of p24(gag) release in the cultures among
treated and untreated Microglia.
Infectious virus released from the infected cultures was also
measured with U373-MAGI-CCR5 cells. Efavirenz, an NNRTI, blocked
HIV-1(DS-br) infection of
Microglia
with an IC(90) of 0.7-7 nM. This value is similar to the efavirenz
IC(90) values for inhibition of laboratory and clinical isolates in
lymphocytes, is 2-3 logs lower than the IC90 values of AZT and d4T,
and is 1-2 logs lower than that of ddC in Microglia.
Efavirenz also inhibited infection with other neurotropic isolates,
and with viruses isolated from other compartments that also
replicated well in Microglia.
Thus, efavirenz is a potent inhibitor of HIV-1
infection in Microglia.
Furthermore, efavirenz IC(90) drug levels are present in the
cerebrospinal fluid (CSF) of patients taking this once daily NNRTI
Boutet A, Altmeyer R, Hery C, Tardieu M (2000) Direct role of
plasma membrane-expressed gp120/41 in toxicity to human astrocytes
induced by HIV-1-infected
macrophages. AIDS
14:2687-2697
Abstract: OBJECTIVE: To compare astrocyte toxicity
induced by plasma membrane-expressed gp120/41 and soluble gp120.
DESIGN: Analysis of morphological alterations and lactate
dehydrogenase (LDH) release from astrocytes in culture with
monocytes infected with HIV-1,
Microglia
expressing Env of a macrophage-tropic HIV-1
isolate or soluble Env. METHODS: Primary human embryonic astrocytes
were cultured with: monocytes infected with two M-tropic HIV-1
isolates (HIV-1(9533),
HIV-1(BX08)); human
Microglia
infected with the defective Semliki Forest virus (SFV) vector coding
for the env gene of HIV-1(BX08)
isolate (SFVenvBX08); and soluble gp140 purified from baby hamster
kidney cells transfected with the env gene of HIV-1(BX08)
lacking the intracytoplasmic region of gp41 (SFVdelta envBX08).
Gp120 mRNA levels were assessed by quantitative reverse
transcriptase-polymerase chain reaction and the protein was detected
by immunofluorescence in infected monocytes or Microglia.
RESULTS: Contact of HIV-infected
monocytes induced morphological changes in astrocytes and a 137%
increase in LDH release at day 2 of co-culture compared with
controls (uninfected monocytes). Gp120/41(BX08)-expressing Microglia
induced a 170% increase in LDH release (relative to SFVLacZ-infected
Microglia).
Pretreatment of co-cultures with an anti-gp120 monoclonal antibody
(mAb; NEA-9305) directed against the V3 loop inhibited LDH release.
Soluble purified gp140 from BX08 isolate induced only a weak LDH
release (104%). Finally, cytotoxicity was not blocked by treatment
of the co-culture with Bordetella pertussis toxin, an inhibitor of
Gi alpha protein-dependent receptors. CONCLUSION: HIV
envelope glycoprotein expressed at the plasma membrane induced
astrocyte damage more efficiently than its soluble counterpart. The
V3 loop was involved in toxicity induction through a pathway
independent of the Gi alpha protein-coupled receptor
Buch S, Pinson D, Hou Y, Adany I, Li Z, Mukherjee S, Jia F,
Mackay G, Silverstein P, Kumar A, Narayan O (2000) Neuropathogenesis
of chimeric simian human immunodeficiency virus infection in rhesus
macaques. J.Med.Primatol. 29:96-106
Abstract: Comparative studies
were performed to determine the neuropathogenesis of infection in
macaques with simian human immunodeficiency virus (SHIV)89.6P
and SHIV(KU). Both viruses
utilize the CD4 receptor and CXCR4 co-receptor. However, in
addition, SHIV89.6P uses
the CCR5 co-receptor. Both agents are dual tropic for CD4+ T cells
and blood-derived macrophages of rhesus macaques. Following
inoculation into macaques, both caused rapid elimination of CD4+ T
cells but they varied greatly in mechanisms of neuropathogenesis.
Two animals infected with SHIV89.6P
developed typical lentiviral encephalitis in which multinucleated
giant cell formation, nodular accumulations of Microglial
cells, activated macrophages and astrocytes, and perivascular
accumulations of mononuclear cells were present in the brain. Many
of the macrophages in these lesions contained viral RNA. Three
macaques infected with SHIV(KU)
and killed on days 6, 11 and 18, respectively, developed a slowly
progressive infection in the CNS but macrophages were not
productively infected and there were no pathological changes in the
brain. Two other animals infected with this virus and killed several
months later showed minimal infection in the brain even though one
of the two developed encephalitis of unknown etiology. The basic
difference in the mechanisms of neuropathogenesis by the two viruses
may be related to co-receptor usage. SHIV89.6P,
in utilizing the CCR5 co-receptor, caused neuropathogenic effects
that are similar to other neurovirulent primate lentiviruses
Chao CC, Hu S, Gekker G, Lokensgard JR, Heyes MP, Peterson PK
(2000) U50,488 protection against HIV-1-related
neurotoxicity: involvement of quinolinic acid suppression.
Neuropharmacology 39:150-160
Abstract: The pathogenesis of human
immunodeficiency virus type 1 (HIV-1)
encephalopathy has been associated with multiple factors including
the neurotoxin quinolinate (an endogenous N-methyl-D-aspartate
[NMDA] receptor ligand) and viral proteins. The kappa opioid
receptor (KOR) agonist U50,488 recently has been shown to inhibit
HIV-1 p24 antigen
production in acutely infected Microglial
cell cultures. Using primary human brain cell cultures in the
present study, we found that U50,488 also suppressed in a
dose-dependent manner the neurotoxicity mediated by supernatants
derived from HIV-1-infected
Microglia.
This neuroprotective effect of U50,488 was blocked by the KOR
selective antagonist nor-binaltorphimine. The neurotoxic activity of
the supernatants from HIV-1-infected
Microglia
was blocked by the NMDA receptor antagonists
2-amino-5-phosphonovalerate and MK-801. HIV-1
infection of Microglial
cell cultures induced the release of quinolinate, and U50,488
dose-dependently suppressed quinolinate release by infected
Microglial
cell cultures with a corresponding inhibition of HIV-1
p24 antigen levels. These findings suggest that the kappa opioid
ligand U50,488 may have therapeutic potential in HIV-1
encephalopathy by attenuating Microglial
cell production of the neurotoxin quinolinate and viral proteins
Choe W, Albright A, Sulcove J, Jaffer S, Hesselgesser J, Lavi
E, Crino P, Kolson DL (2000) Functional expression of the
seven-transmembrane HIV-1
co-receptor APJ in neural cells. J.Neurovirol. 6 Suppl
1:S61-S69
Abstract: APJ is a recently described
seven-transmembrane (7TM) receptor that is abundantly expressed in
the central nervous system (CNS). This suggests an important role
for APJ in neural development and/or function, but neither its
cellular distribution nor its function have been defined. APJ can
also serve as a co-receptor with CD4 for fusion and infection by
some strains of human immunodeficiency virus (HIV-1)
in vitro, suggesting a role in HIV
neuropathogenesis if it were expressed on CD4-positive CNS cells. To
address this, we examined APJ expression in cultured neurons,
astrocytes, oligodendrocytes, Microglia
and monocyte-derived macrophages utilizing both immunocytochemical
staining with a polyclonal anti-APJ antibody and RT - PCR. We also
analyzed the ability of a recently identified APJ peptide ligand,
apelin, to induce calcium elevations in cultured neural cells. APJ
was expressed at a high level in neurons and oligodendrocytes, and
at lower levels in astrocytes. In contrast, APJ was not expressed in
either primary Microglia
or monocyte-derived macrophages. Several forms of the APJ peptide
ligand induced calcium elevations in neurons. Thus, APJ is
selectively expressed in certain CNS cell types and mediates
intracellular signals in neurons, suggesting that APJ may normally
play a role in signaling in the CNS. However, the absence of APJ
expression in Microglia
and macrophages, the prinicpal CD4-positive cell types in the brain,
indicates that APJ is unlikely to mediate HIV-1
infection in the CNS
Cota M, Kleinschmidt A, Ceccherini-Silberstein F, Aloisi F,
Mengozzi M, Mantovani A, Brack-Werner R, Poli G (2000) Upregulated
expression of interleukin-8, RANTES and chemokine receptors in human
astrocytic cells infected with HIV-1.
J.Neurovirol. 6:75-83
Abstract: Human immunodeficiency virus
(HIV) infection of the
central nervous system (CNS) affects primarily Microglial
cells and astrocytes. Infection of these latter cells occurs
independently of CD4 and is characterised by preferential
accumulation of 2 Kb mRNA, encoding mostly Nef, and by low levels of
4.5 and 9 Kb RNAs. We have investigated the potential role of
chronic HIV infection of
human astrocytic cells on the expression of pro-inflammatory
cytokines, chemokines and their receptors by comparing the infected
TH4-7-5 with its parental uninfected 85HG66 cell lines. Upregulated
levels of tumour necrosis factor-alpha (TNF-alpha) and of certain
chemokines, namely interleukin-8 (IL-8) and regulated upon
activation normal T cell expressed and secreted (RANTES), were
observed in the infected versus uninfected cells, whereas monocyte
chemotactic protein-1 (MCP-1) was comparably expressed in both cell
lines. This pattern of expression was confirmed in primary foetal
astrocytes transiently transfected with HIV.
In addition, CXCR1, CXCR2 and CCR2b, receptors for IL-8 and MCP-1,
respectively, were also found to be upregulated in TH4-7-5 versus
85HG66. CXCR4, the receptor of stromal cell derived factor-1 (SDF-1)
and co-receptor for syncytium inducing HIVs,
was comparably expressed in infected and uninfected astrocytic
cells, whereas CCR5 was not detected in either cell line.
Furthermore, treatment of TH4-7-5 cells with TNF-alpha or IL-1beta
stimulated RNA and protein secretion of IL-8, MCP-1, and RANTES as
well as HIV expression.
Thus, our findings suggest that HIV
infection of astrocytic cells can contribute to the establishment of
a chronic inflammatory state in the CNS, eventually resulting in HIV
encephalitis, by increasing the secretion of pro-inflammatory
cytokines, such as TNF-alpha and several chemokines. Overexpression
of chemokine receptors including CCR2b, CXCR1 and CXCR2 in infected
astrocytic cells may contribute to HIV-induced
damage of the CNS via autocrine/paracrine activation of astrocytes
Gabuzda D, Wang J (2000) Chemokine receptors and mechanisms
of cell death in HIV
neuropathogenesis. J.Neurovirol. 6 Suppl 1:S24-S32
Abstract:
Several chemokine receptors are used as coreceptors for HIV-1
entry in the central nervous system (CNS). CCR5 is the major
coreceptor together with CD4 for HIV-1
infection of Microglia,
the major target cells for HIV-1
infection in the CNS. CXCR4 and CCR3 are also expressed on Microglia
and can mediate infection by certain HIV-1
isolates but at lower efficiency than CCR5. Additional chemokine
coreceptors are expressed in the brain, but their role in HIV-1
neuropathogenesis has not been defined. The expression of CXCR4, and
possibly other chemokine receptors, on subpopulations of neurons and
glial cells may render neurons vulnerable to mechanisms of CNS
injury induced by the HIV-1
gp120 Env protein. HIV-1
viruses which use CXCR4 and emerge during the late stages of HIV-1
infection may impact disease progression in the CNS by inducing
apoptosis of neurons and other cell types. The neurodegenerative
mechanisms may involve infection of Microglia
by certain CXCR4 tropic viruses in addition to cellular dysfunction
and apoptosis induced by HIV-1
gp120 binding to CXCR4. Understanding the role of CXCR4 and other
chemokine receptors in HIV-1
neuropathogenesis will help to advance the development of new
therapeutic strategies for the prevention and treatment of
neurologic disorders associated with HIV-1
infection
Gray F, Adle-Biassette H, Brion F, Ereau T, le M, I, Levy V,
Corcket G (2000) Neuronal apoptosis in human immunodeficiency virus
infection. J.Neurovirol. 6 Suppl 1:S38-S43
Abstract: Neuronal
apoptosis has been shown to occur in HIV
infection by a number of in vivo and in vitro studies, however, the
cause of neuronal damage in AIDS
is still unclear and its relationships with the cognitive disorders
characteristic of HIV
dementia remain a matter of debate. In this review, based on our
experience, we analyse the techniques used to identify neuronal
apoptosis on post-mortem AIDS
brains and describe the relationships of neuronal apoptosis with the
stage of disease, a history of HIV-dementia,
the degree of productive HIV
infection, Microglial
activation, blood-brain barrier involvement and axonal damage. We
conclude that the severity of neuronal apoptosis in the cerebral
cortex correlates with the presence of cerebral atrophy, but not
with the cognitive disorders. There is no global quantitative
correlation between neuronal apoptosis and HIV
encephalitis, Microglial
activation or axonal damage. However we found some topographical
correlation between these changes. We conclude that neuronal
apoptosis and consequent neuronal loss, in HIV
infected patients, are probably not related to a single cause. It
seems likely that Microglial
activation, directly or indirectly related to HIV
infection of the CNS, plays a major role in its causation possibly
through the mediation of oxidative stress. Axonal damage, either
secondary to Microglial
activation, or to the intervention of systemic factors may also
contribute to neuronal apoptosis
Grulich AE, Dore GJ, Brew BJ (2000) Human Herpesvirus 8 and
Protection from AIDS
Dementia Complex. Herpes. 7:38-40
Abstract: Infection with human
herpesvirus 8 (HHV-8) has been associated with the development of
three distinct conditions: Kaposi's sarcoma, body cavitybased
lymphoma and Castleman's disease. HHV-8 produces chemokinelike
proteins including viral macrophage inflammatory protein II, which
has been shown to block human immunodeficiency virus 1 (HIV-1)
infection of CD4-positive cells expressing CCR-3. As CCR-3 is a
receptor for HIV-1 into
Microglial
cells, it has been hypothesized that HHV-8 infection may inhibit
HIV-1 infection of the
brain, thereby decreasing the incidence of AIDS
dementia complex. We reviewed published studies of the incidence of
AIDS dementia complex in
individuals with and without Kaposi's sarcoma. The data are
consistent in showing a negative association between Kaposi's
sarcoma and AIDS dementia
complex and, although sparse, support the hypothesis that productive
HHV-8 infection decreases HIV-1
infection of the brain sufficiently to decrease the incidence of
AIDS dementia complex. This
negative association should be examined in further cohorts of
HIV-1-infected subjects, to
exclude alternative explanations
Guillemin GJ, Smith DG, Kerr SJ, Smythe GA, Kapoor V, Armati
PJ, Brew BJ (2000) Characterisation of kynurenine pathway metabolism
in human astrocytes and implications in neuropathogenesis.
Redox.Rep. 5:108-111
Abstract: The role of astrocytes in the
production of the neurotoxin quinolinic acid (QUIN) and other
products of the kynurenine pathway (KP) is controversial. Using
cytokine-stimulated human astrocytes, we assayed key enzymes and
products of the KP. We found that astrocytes lack
kynurenine-hydroxylase so that large amounts of kynurenine (KYN) and
kynurenic acid (KYNA) were produced, while minor amounts of QUIN
were synthesised that were completely degraded. We then showed that
kynurenine added to macrophages led to significant production of
QUIN. These results suggest that astrocytes alone are
neuroprotective by minimising QUIN production and maximising
synthesis of KYNA. However, it is likely that, in the presence of
macrophages and/or Microglia,
astrocytes are neurotoxic by producing large concentrations of KYN
that can be metabolised by neighbouring monocytic cells to QUIN
Hegg CC, Hu S, Peterson PK, Thayer SA (2000) Beta-chemokines
and human immunodeficiency virus type-1 proteins evoke intracellular
calcium increases in human Microglia.
Neuroscience 98:191-199
Abstract: Activation of beta-chemokine
receptors, co-receptors for human immunodeficiency virus type-1
(HIV-1), stimulates
movement and secretion in Microglia,
possibly through a Ca(2+)-dependent mechanism. We studied chemokine
activation of Ca(2+) signaling processes in Microglia.
Human fetal Microglia
were grown in primary culture and chemokine-induced increases in
intracellular calcium concentration ([Ca(2+)](i)) were measured in
single cells using indo-1-based microfluorimetry. Application of 50
ng/ml regulated on activation, normal T expressed and secreted
(RANTES; 120 s) evoked responses in 26% of the Microglia
(187/719 cells). [Ca(2+)](i) increased from a basal level of 66+/-6
nM to peak at 268+/-23 nM (n=187). Chemokine-evoked responses
rapidly desensitized as indicated by the rapid return to basal
[Ca(2+)](i) levels in the maintained presence of RANTES. The removal
of extracellular Ca(2+) or stimulation in the presence of Ni(2+)
(2mM) or La(3+) (100 microM) blocked the RANTES-elicited [Ca(2+)](i)
increase. The L-type calcium channel antagonist nimodipine (10
microM) inhibited the RANTES-mediated increase in [Ca(2+)](i) by
80+/-16%. Thus, the RANTES-evoked calcium transient appears to
result from Ca(2+) influx with little if any release from
intracellular stores. Application of gp120(clade) (E) and
gp120(CM235) (50 ng/ml) neither mimicked nor antagonized the
RANTES-evoked response. Application of 50 ng/ml eotaxin (120 s)
evoked an increase in [Ca(2+)](i) in 13% of the human Microglia
in culture (61/469 cells). The HIV-1
regulatory protein Tat (50 ng/ml) increased the [Ca(2+)](i) in a
subset of eotaxin-responsive cells (16/30). The L-type calcium
channel antagonist nimodipine (3 microM) inhibited eotaxin- and
Tat-mediated increases in [Ca(2+)](i) by 88+/-6% and 93+/-6%,
respectively. Thus, activation of CCR3 appears to evoke Ca(2+)
influx through L-type Ca(2+) channels.These results indicate that
beta-chemokines, RANTES and eotaxin, activate a nimodipine sensitive
Ca(2+) influx pathway in human fetal Microglia.
HIV-1 Tat protein mimicked
chemokine-mediated Ca(2+) signaling and may modulate the migratory
and secretory responses of Microglia
Hein A, Martin JP, Koehren F, Bingen A, Dorries R (2000) In
vivo infection of ramified Microglia
from adult cat central nervous system by feline immunodeficiency
virus. Virology 268:420-429
Abstract: Infection of Microglial
cells by the human immunodeficiency virus (HIV)
is supposed to play an important role in the pathogenesis of
AIDS-related central
nervous system (CNS) complications. So far, however, experimental
data about interactions between HIV
and ramified Microglia
from the adult CNS were only occasionally reported, making it
difficult to understand the exact nature of pathogenic events
contributing to HIV-encephalopathy.
Therefore, we used the animal model of feline immunodeficiency virus
(FIV) infection of domestic cats to establish an experimental system
which is suitable for studying the relationships between an
immunodeficiency virus and the mature ramified Microglia
of the central nervous system. By means of density gradient
centrifugation approximately 95% pure Microglial
cells could be isolated from adult feline brain that were
characterized by their CD45(low) phenotype. Resident Microglia
extracted from the CNS of experimentally infected cats harbored
FIV-specific DNA and cocultivation with mitogen-activated, but
uninfected peripheral blood mononuclear cells (PBMC) resulted in
recovery of high-titered infectious virus. Double labeling of brain
cell monocultures explanted from persistently infected animals for
both Microglia
and FIV markers disclosed less than 1% of viral antigen expressing
Microglial
cells. This suggests that during the subclinical phase of the
infection only a small number of brain-resident macrophages are
productively infected. However, interaction of FIV-infected
Microglia
and inflammatory lymphocytes may promote viral replication, thus
supporting viral spread in brain tissue
Ito M, Baker JV, Mock DJ, Goodman AD, Blumberg BM, Shrier DA,
Powers JM (2000) Human herpesvirus 6-meningoencephalitis in an HIV
patient with progressive multifocal leukoencephalopathy. Acta
Neuropathol.(Berl) 100:337-341
Abstract: Human herpesvirus 6
(HHV6) has been reported as a rare cause of meningoencephalitis and
leukoencephalitis. We present an HIV-infected
patient with lesions of progressive multifocal leukoencephalopathy
(PML), but also meningoencephalitis apparently due to HHV6.
Immunohistochemistry for HHV6 antigens and in situ polymerase chain
reaction for HHV6 genome showed many positive lymphocytes and
Microglia
in the meningeal and cortical lesions. More importantly, dead and
dying neurons were conspicuous; some were undergoing neuronophagia
and some displayed evidence of HHV6 infection. A pathogenic role for
this almost universal, and usually commensal, virus in inflammatory
brain lesions and PML is briefly discussed
Jones MV, Bell JE, Nath A (2000) Immunolocalization of HIV
envelope gp120 in HIV
encephalitis with dementia. AIDS
14:2709-2713
Abstract: Numerous studies have shown that the HIV
envelope glycoprotein, gp120, is a potent neurotoxin. However, its
role in the pathogenesis of HIV
dementia had been questioned due to the lack of demonstration of its
presence in vivo. We now demonstrate conclusively the presence of
gp120 by immunohistochemistry in the brain of patients with HIV
encephalitis who also had dementia. A highly specific anti-gp120
polyclonal sera was used on formalin fixed tissue. Gp120 staining
cells were predominantly perivascular and included macrophages,
Microglia
and multinucleated giant cells. These studies provide an important
missing link for the role of gp120 in the neuropathogenesis of HIV
infection
Jung S, Aliberti J, Graemmel P, Sunshine MJ, Kreutzberg GW,
Sher A, Littman DR (2000) Analysis of fractalkine receptor CX(3)CR1
function by targeted deletion and green fluorescent protein reporter
gene insertion. Mol.Cell Biol. 20:4106-4114
Abstract: The
seven-transmembrane receptor CX(3)CR1 is a specific receptor for the
novel CX(3)C chemokine fractalkine (FKN) (neurotactin). In vitro
data suggest that membrane anchoring of FKN, and the existence of a
shed, soluble FKN isoform allow for both adhesive and
chemoattractive properties. Expression on activated endothelium and
neurons defines FKN as a potential target for therapeutic
intervention in inflammatory conditions, particularly central
nervous system diseases. To investigate the physiological function
of CX(3)CR1-FKN interactions, we generated a mouse strain in which
the CX(3)CR1 gene was replaced by a green fluorescent protein (GFP)
reporter gene. In addition to the creation of a mutant CX(3)CR1
locus, this approach enabled us to assign murine CX(3)CR1 expression
to monocytes, subsets of NK and dendritic cells, and the brain
Microglia.
Analysis of CX(3)CR1-deficient mice indicates that CX(3)CR1 is the
only murine FKN receptor. Yet, defying anticipated FKN functions,
absence of CX(3)CR1 interferes neither with monocyte extravasation
in a peritonitis model nor with DC migration and differentiation in
response to microbial antigens or contact sensitizers. Furthermore,
a prominent response of CX(3)CR1-deficient Microglia
to peripheral nerve injury indicates unimpaired neuronal-glial cross
talk in the absence of CX(3)CR1
Kitai R, Zhao ML, Zhang N, Hua LL, Lee SC (2000) Role of
MIP-1beta and RANTES in HIV-1
infection of Microglia:
inhibition of infection and induction by IFNbeta. J.Neuroimmunol.
110:230-239
Abstract: Microglia
are the major target of HIV-1
infection in the brain. Microglial
infection is CD4-dependent, but the role of chemokine receptors CCR5
and CCR3 and their natural ligands in modulating HIV-1
infection in Microglia
has been questioned. In primary human fetal Microglial
cultures, we demonstrate that HIV-1
infection of these cells is dependent on CCR5, since an antibody to
CCR5 completely blocked productive infection. Anti-CCR3, in
contrast, had a smaller inhibitory effect which was not
statistically significant. The chemokine ligands for CCR5, RANTES
and MIP-1beta, also potently inhibited HIV-1
infection in Microglia,
but the third ligand MIP-1alpha failed to show inhibition.
Interestingly, when Microglial
cultures were treated with antibodies specific to each of these
chemokines, HIV-1 infection
was enhanced by anti-RANTES and anti-MIP-1beta, but not by
anti-MIP-1alpha. These results demonstrate the presence of
endogenous chemokines that act as endogenous inhibitors of HIV-1
infection in Microglia.
Additionally, IFNbeta, a known anti-viral cytokine, also provided
potent inhibition of viral infection as well as induction of all
three chemokines in Microglia.
These results suggest the possibility that type I interferon can
down-modulate Microglial
HIV-1 infection in vivo by
multiple mechanisms
Kolson DL, Gonzalez-Scarano F (2000) HIV and HIV dementia. J.Clin.Invest 106:11-13
Major EO, Rausch D, Marra C, Clifford D (2000) HIV-associated dementia. Science 288:440-442
Mayne M, Holden CP, Nath A, Geiger JD (2000) Release of
calcium from inositol 1,4,5-trisphosphate receptor-regulated stores
by HIV-1 Tat regulates
TNF-alpha production in human macrophages. J.Immunol.
164:6538-6542
Abstract: HIV-1
protein Tat is neurotoxic and increases macrophage and Microglia
production of TNF-alpha, a cytopathic cytokine linked to the
neuropathogenesis of HIV
dementia. Others have shown that intracellular calcium regulates
TNF-alpha production in macrophages, and we have shown that Tat
releases calcium from inositol 1,4, 5-trisphosphate (IP3)
receptor-regulated stores in neurons and astrocytes. Accordingly, we
tested the hypothesis that Tat-induced TNF-alpha production was
dependent on the release of intracellular calcium from IP3-regulated
calcium stores in primary macrophages. We found that Tat transiently
and dose-dependently increased levels of intracellular calcium and
that this increase was blocked by xestospongin C, pertussis toxin,
and by phospholipase C and type 1 protein kinase C inhibitors but
not by protein kinase A or phospholipase A2 inhibitors. Xestospongin
C, BAPTA-AM, U73122, and bisindolylmalemide significantly inhibited
Tat-induced TNF-alpha production. These results demonstrate that in
macrophages, Tat-induced release of calcium from IP3-sensitive
intracellular stores and activation of nonconventional PKC isoforms
play an important role in Tat-induced TNF-alpha production
McManus CM, Weidenheim K, Woodman SE, Nunez J, Hesselgesser
J, Nath A, Berman JW (2000) Chemokine and chemokine-receptor
expression in human glial elements: induction by the HIV
protein, Tat, and chemokine autoregulation. Am.J.Pathol.
156:1441-1453
Abstract: Human immunodeficiency virus (HIV)
encephalitis is a prominent pathology seen in children infected with
HIV. Immunohistochemical
analyses of pediatric brain tissue showed distinct differences in
expression of C-C chemokines and their receptors between children
with HIV encephalitis and
those with non-CNS-related pathologies. Evidence suggests that
soluble factors such as HIV
Tat released from HIV-infected
cells may have pathogenic effects. Our results show Tat effects on
chemokines and their receptors in Microglia
and astrocytes as well as chemokine autoregulation in these cells.
These results provide evidence for the complex interplay of Tat,
chemokines, and chemokine receptors in the inflammatory processes of
HIV encephalitis and
illustrate an important new role for chemokines as autocrine
regulators
Meucci O, Fatatis A, Simen AA, Miller RJ (2000) Expression of
CX3CR1 chemokine receptors on neurons and their role in neuronal
survival. Proc.Natl.Acad.Sci.U.S.A 97:8075-8080
Abstract: Recent
in vitro and in vivo studies have shown that the chemokine
fractalkine is widely expressed in the brain and localized
principally to neurons. Central nervous system expression of
CX(3)CR1, the only known receptor for fractalkine, has been
demonstrated exclusively on Microglia
and astrocytes. Thus, it has been proposed that fractalkine
regulates cellular communication between neurons (that produce
fractalkine) and Microglia
(that express its receptor). Here we show, for the first time, that
hippocampal neurons also express CX(3)CR1. Receptor activation by
soluble fractalkine induces activation of the protein kinase Akt, a
major component of prosurvival signaling pathways, and nuclear
translocation of NF-kappaB, a downstream effector of Akt.
Fractalkine protects hippocampal neurons from the neurotoxicity
induced by the HIV-1
envelope protein gp120(IIIB), an effect blocked by anti-CX(3)CR1
antibodies. Experiments with two different inhibitors of the
phosphatidylinositol 3-kinase, a key enzyme in the activation of
Akt, and with a phospholipid activator of Akt demonstrate that Akt
activation is responsible for the neuroprotective effects of
fractalkine. These data show that neuronal CX(3)CR1 receptors
mediate the neurotrophic effects of fractalkine, suggesting that
fractalkine and its receptor are involved in a complex network of
both paracrine and autocrine interactions between neurons and glia
Milligan ED, Mehmert KK, Hinde JL, Harvey LO, Martin D,
Tracey KJ, Maier SF, Watkins LR (2000) Thermal hyperalgesia and
mechanical allodynia produced by intrathecal administration of the
human immunodeficiency virus-1 (HIV-1)
envelope glycoprotein, gp120. Brain Res. 861:105-116
Abstract:
Astrocytes and Microglia
in the spinal cord have recently been reported to contribute to the
development of peripheral inflammation-induced exaggerated pain
states. Both lowering of thermal pain threshold (thermal
hyperalgesia) and lowering of response threshold to light tactile
stimuli (mechanical allodynia) have been reported. The notion that
spinal cord glia are potential mediators of such effects is based on
the disruption of these exaggerated pain states by drugs thought to
preferentially affect glial function. Activation of astrocytes and
Microglia
can release many of the same substances that are known to mediate
thermal hyperalgesia and mechanical allodynia. The aim of the
present series of studies was to determine whether exaggerated pain
states could also be created in rats by direct, intraspinal immune
activation of astrocytes and Microglia.
The immune stimulus used was peri-spinal (intrathecal, i.t.)
application of the Human Immunodeficiency Virus type 1 (HIV-1)
envelope glycoprotein, gp120. This portion of HIV-1
is known to bind to and activate Microglia
and astrocytes. Robust thermal hyperalgesia (tail-flick, TF, and
Hargreaves tests) and mechanical allodynia (von Frey and
touch-evoked agitation tests) were observed in response to i.t.
gp120. Heat denaturing of the complex protein structure of gp120
blocked gp120-induced thermal hyperalgesia. Lastly, both thermal
hyperalgesia and mechanical allodynia to i.t. gp120 were blocked by
spinal pretreatment with drugs (fluorocitrate and CNI-1493) thought
to preferentially disrupt glial function
Minami M, Satoh M (2000) [Chemokines as mediators for
intercellular communication in the brain]. Nippon Yakurigaku Zasshi
115:193-200
Abstract: Chemokines constitute a large and still
growing family of structurally-related small (8-10 kDa) cytokines
that have chemotactic activity for leukocytes. Recently, some
receptors for chemokines were reported to be used as a co-receptor
by HIV at infection. In
addition to their well-established role in inflammatory response and
recently-reported role as a co-receptor for HIV,
recent data suggest that chemokines and their receptors
physiologically and pathologically play crucial roles as the
mediators for intercellular communication among the cells intrinsic
to and recruited into the brain; i.e., neurons, astrocytes,
Microglia,
endothelial cells and leukocytes. Some chemokines such as SDF-1 and
fractalkine are constitutively produced in the brain, implicating
that they have an important role in maintenance of CNS homeostasis
or determination of the patterning of neurons and/or glial cells in
developing brain and normal adult brain. Chemokines such as MCP-1,
MIP-1 alpha and CINC were shown to be induced by various
neuroinflammatory stimuli, suggesting that they are involved in
various neurodegenerative diseases such as multiple sclerosis,
Alzheimer's disease, stroke and AIDS
dementia syndrome. Chemokines and their receptors are potential
targets for therapeutic intervention in neurodegenerative diseases
Nebuloni M, Pellegrinelli A, Ferri A, Tosoni A, Bonetto S,
Zerbi P, Boldorini R, Vago L, Costanzi G (2000) Etiology of
Microglial
nodules in brains of patients with acquired immunodeficiency
syndrome. J.Neurovirol. 6:46-50
Abstract: Microglial
nodules associated with opportunistic and HIV-related
lesions are frequently found in the brains of AIDS
patients. However, in many cases, the causative agent is only
presumptively suspected. We reviewed 199 brains of AIDS
patients with micronodular lesions to clarify their etiology by
immunohistochemistry (to Toxoplasma gondii, cytomegalovirus, herpes
simplex virus I/II, varicella zoster virus and HIV-p24
core protein), PCR (for herpetic viruses and Mycobacterium
tuberculosis) and electron microscopy. Productive HIV
infection was observed in 110 cases (55.1%): 30 cases with
Toxoplasma gondii encephalitis, 30 with cytomegalovirus
encephalitis, eight with multiple cerebral diseases, while in the
remaining 42 cases HIV was
the only pathogenetic agent. Multinucleated giant cells (hallmark of
HIV infection) were found
in the MGNs of 85/110 cases with HIV-related
lesions; the remaining 25 cases had only p24 positive cells but no
multinucleated giant cells. In these latter cases the micronodular
lesions had been initially attributed to the main opportunistic
agent found in the brain, or defined as subacute encephalitis.
Individual Microglial
nodules positive for an opportunistic pathogen were generally
negative for HIV antigens.
In 13 cases no opportunistic agent or HIV
productive infection was found. In these cases, PCR and electron
microscopy examination for HIV
and other viral infections were negative. Our data suggest that
HIV-immunohistochemistry
should be used for the etiological diagnosis of micronodular lesions
in AIDS brains, even in the
presence of other pathogens. After extensive search, the etiology of
the Microglial
nodules remains unknown in only a small percentage of cases
Pugh CR, Johnson JD, Martin D, Rudy JW, Maier SF, Watkins LR
(2000) Human immunodeficiency virus-1 coat protein gp120 impairs
contextual fear conditioning: a potential role in AIDS
related learning and memory impairments. Brain Res.
861:8-15
Abstract: Many AIDS
patients suffer from cognitive impairments including deficits in
learning and memory. The Human Immunodeficiency Virus-1 (HIV-1)
envelope glycoprotein gp120 is one possible mediator of these
impairments. This is because gp120 activates brain Microglial
cells and astrocytes, and in vivo activation of glia leads to the
release of the proinflammatory cytokine interleukin-1 beta
(IL-1beta). gp120 induced IL-1beta release could be involved in
producing memory impairments associated with AIDS
because central IL-1beta activity adversely affects cognitive
function. The reported experiments evaluated the effects of i.c.v.
gp120 administration and subsequent IL-1beta activity on learning
and memory processes in the rat. Intracerebroventricular gp120
produced memory impairments on hippocampally dependent contextual
fear conditioning, but not hippocampally independent auditory-cue
fear conditioning following post-conditioning gp120 administration.
Central gp120 administration also caused increases in IL-1beta
protein levels in the hippocampus and frontal cortex but not in the
hypothalamus. gp120 induced memory impairments were blocked by 2
different IL-1 antagonists, alpha melanocyte stimulating hormone
(alphaMSH) and interleukin-1 receptor antagonist (IL-1ra). Finally,
heat denaturation of the tertiary structure of gp120 abolished its
effects on fear conditioning, suggesting that gp120 impairs
contextual fear conditioning by binding to its receptors on glia
Rostasy K, Monti L, Yiannoutsos C, Wu J, Bell J, Hedreen J,
Navia BA (2000) NFkappaB activation, TNF-alpha expression, and
apoptosis in the AIDS-Dementia-Complex.
J.Neurovirol. 6:537-543
Abstract: The role of NFkappaB activation
and its relationship to inflammatory mediators and apoptosis in the
HIV-infected brain have
remained uncertain. The cellular and regional distribution of
NFkappaB, TNF-alpha, and apoptosis was examined in the frontal
cortex (FC), deep white matter (DWM) and the basal ganglia (BG) of
17 patients with ADC. Nuclear staining for NFkappaB was localized
predominantly to perivascular Microglia/macrophages
in the BG and DWM and correlated with ADC severity. Correlations
were further found with HLA-DR, iNOS, TNF-alpha, and gp41 expression
in these regions. The number of TUNEL-positive cells, particularly
in the BG, correlated with ADC stage. Logistic regression analysis
further showed a significant relationship between the likelihood of
TUNEL staining in the BG and worsening cognitive impairment
Sheng WS, Hu S, Hegg CC, Thayer SA, Peterson PK (2000)
Activation of human Microglial
cells by HIV-1 gp41 and Tat
proteins. Clin.Immunol. 96:243-251
Abstract: The viral proteins,
Tat (HIV-1 nuclear protein)
and gp41 (HIV-1 coat
protein), detected in the brains of HIV-1-infected
patients have been shown to be neurotoxic. We investigated the
effects of HIV-1 Tat and
gp41 proteins on cytokine, chemokine, and superoxide anion (O(-)(2))
production by Microglia,
the resident macrophages of the brain. Tat and gp41 dose-dependently
stimulated cytokine and chemokine production by Microglia.
Peak production of these cytokines and chemokines differed in
Microglial
cells treated with gp41 and Tat. Expression of cytokine and
chemokine mRNA was also stimulated in gp41- and Tat-treated
Microglia.
Neither gp41 nor Tat alone stimulated O(-)(2) production by
Microglia.
Treatment of Microglial
cells with Tat but not with gp41 evoked an increase in intracellular
Ca(2+). The results of this study suggest that HIV-1
Tat and gp41 proteins impact several key functions of Microglial
cells which could contribute to the neuropathogenesis of HIV-1
Shieh JT, Martin J, Baltuch G, Malim MH, Gonzalez-Scarano F
(2000) Determinants of syncytium formation in Microglia
by human immunodeficiency virus type 1: role of the V1/V2 domains.
J.Virol. 74:693-701
Abstract: Microglia
are the main reservoir for human immunodeficiency virus type 1
(HIV-1) in the central
nervous system (CNS), and multinucleated giant cells, the result of
fusion of HIV-1-infected
Microglia
and brain macrophages, are the neuropathologic hallmark of HIV
dementia. One potential explanation for the formation of syncytia is
viral adaptation for these CD4(+) CNS cells. HIV-1(BORI-15),
a virus adapted to growth in Microglia
by sequential passage in vitro, mediates high levels of fusion and
replicates more efficiently in Microglia
and monocyte-derived-macrophages than its unpassaged parent (J. M.
Strizki, A. V. Albright, H. Sheng, M. O'Connor, L. Perrin, and F.
Gonzalez-Scarano, J. Virol. 70:7654-7662, 1996). Since the
interaction between the viral envelope glycoprotein and CD4 and the
chemokine receptor mediates fusion and plays a key role in tropism,
we have analyzed the HIV-1(BORI-15)
env as a fusogen and in recombinant and pseudotyped viruses. Its
syncytium-forming phenotype is not the result of a switch in
coreceptor use but rather of the HIV-1(BORI-15)
envelope-mediated fusion of CD4(+)CCR5(+) cells with greater
efficiency than that of its parental strain, either by itself or in
the context of a recombinant virus. Genetic analysis indicated that
the syncytium-forming phenotype was due to four discrete amino acid
differences in V1/V2, with a single-amino-acid change between the
parent and the adapted virus (E153G) responsible for the majority of
the effect. Additionally, HIV-1(BORI-15)
env-pseudotyped viruses were less sensitive to decreases in the
levels of CD4 on transfected 293T cells, leading to the hypothesis
that the differences in V1/V2 alter the interaction between this
envelope and CD4 or CCR5, or both. In sum, the characterization of
the envelope of HIV-1(BORI-15),
a highly fusogenic glycoprotein with genetic determinants in V1/V2,
may lead to a better understanding of the relationship between HIV
replication and syncytium formation in the CNS and of the importance
of this region of gp120 in the interaction with CD4 and CCR5
Speth C, Joebstl B, Barcova M, Dierich MP (2000) HIV-1
envelope protein gp41 modulates expression of interleukin-10 and
chemokine receptors on monocytes, astrocytes and neurones. AIDS
14:629-636
Abstract: OBJECTIVE: To analyse the effect of HIV-1
transmembrane protein gp41 on cytokine production and chemokine
receptor expression in blood and brain. DESIGN: Because previous
results had demonstrated that recombinant gp41 contributes to
HIV-induced dysfunction of
blood immune cells we investigated its effect on interleukin (IL)-10
synthesis and expression of the HIV
coreceptors CCR5 and CXCR4 in different human brain cells. METHODS:
Astrocytic, Microglial
and neuronal cell lines were incubated with the extracellular domain
of gp41 (aa565-647). Secretion of IL-10 into the medium was measured
by ELISA. Chemokine receptor expression was analysed by fluorescence
activated cell sorting and by RT-PCR. RESULTS: Incubation of the
astrocytic cell line U87 with gp41 induced more than a 10 fold
up-regulation of IL-10 secretion. This modulation was shown to be
time- and dose-dependent. Use of inhibitors for different signal
transduction pathways indicated a similar transduction cascade for
the alteration of IL-10 production in astrocytes as in monocytes
with participation of cAMP/adenylate cyclase and activation of p70S6
kinase. To a lesser extent IL-10 synthesis was also up-regulated by
gp41 in the neuronal cell line SK-N-SH. In all cell types
up-regulation of IL-10 paralleled by an enhanced expression of the
chemokine receptor and HIV-1
coreceptor CCR5. This up-regulation was driven by IL-10 as shown by
use of an IL-10 antibody. Expression of the chemokine receptor CXCR4
was only slightly altered. CONCLUSIONS: These findings suggest a
role for gp41 in the modulation of brain-specific host defence, cell
migration and cell infectivity by HIV
van der MP, Ulrich AM, Gonzalez-Scarano F, Lavi E (2000)
Immunohistochemical analysis of CCR2, CCR3, CCR5, and CXCR4 in the
human brain: potential mechanisms for HIV
dementia. Exp.Mol.Pathol. 69:192-201
Abstract: The CXC chemokine
receptor CXCR4 was the first molecule identified as a coreceptor
working in conjunction with CD4 to mediate cellular entry for the
human immunodeficiency virus (HIV-1).
Since that original discovery, 11 other seven-mtransmembrane domain
molecules, many of which are chemokine receptors, have been shown to
facilitate HIV entry into
cells. These include CCR5, CCR3, CCR2, CCR1, CCR8, CX3CR1, STRL33
(BONZO), GPR15 (BOB), GPR1, US28, and APJ. In studies done by this
and other labs, CCR3, CCR5, and CXCR4 have been identified in CNS
Microglia
and several laboratories, including ours, have shown that CXCR4 is
expressed in neurons. Neuronal expression of CCR2, CCR3, and CCR5
has been less consistent. We performed a semiquantitative
immunohistochemical analysis of the expression of CCR2, CCR3, CCR5,
and CXCR4 in 23 regions of the brain and in two sections of the
spinal cord. Hippocampal neurons were positive for CCR2, CCR3, and
CXCR4, but not for CCR5. In other regions of the brain, neurons, and
glial cells reacted with anti-CCR2, anti-CCR3, and anti-CXCR4
antibodies, whereas only glial cells (primarily Microglia)
were positive for CCR5. The areas of highest expression, however,
seem to be subcortical regions and the limbic system. The limbic
system plays a key role in memory, and the presence of CXCR4-which
can bind the viral envelope protein gp120-min a subset of neurons
from this system may play a role in the development of HIV-related
dementia
Vicenzi E, Alfano M, Ghezzi S, Gatti A, Veglia F, Lazzarin A,
Sozzani S, Mantovani A, Poli G (2000) Divergent regulation of HIV-1
replication in PBMC of infected individuals by CC chemokines:
suppression by RANTES, MIP-1alpha, and MCP-3, and enhancement by
MCP-1. J.Leukoc.Biol. 68:405-412
Abstract: We investigated the
role of different CC chemokines, including regulated upon activation
normal T cell expressed and secreted (RANTES), macrophage
inflammatory protein-lalpha (MIP-1alpha), monocyte chemotactic
protein-1 (MCP-1), and MCP-3 on virus replication in cultures
established from CD8+ T cell-depleted peripheral blood mononuclear
cells (PBMC) of HIV-infected
individuals that were either cocultivated with allogeneic T cell
blasts (ATCB) of uninfected individuals or directly stimulated by
mitogen plus interleukin-2. RANTES was the only chemokine that
showed a clear-cut suppressive effect on HIV
replication in both culture systems, although inhibitory effects
were frequently also observed with MIP-1alpha, MCP-3, and,
occasionally, with MCP-1. In contrast, MCP-1 frequently enhanced HIV
production in most patients' cultures or cocultures that were
characterized by secreting relatively low levels (<20 ng/mL) of
MCP-1. When CD8-depleted PBMC of HIV+
individuals were cocultivated with ATCB of uninfected healthy
donors, a positive correlation was observed between MCP-1
concentrations and the enhancement of HIV-1
replication occurring after depletion of CD8+ cells from donors'
cells. Depletion of CD14+ cells (monocytes) from ATCB resulted in
the down-regulation of virus replication during co-cultivation with
CD8-depleted PBMC of infected individuals. Of interest, MCP-1
up-regulated HIV production
in these CD14-depleted ATCB cocultures. Altogether these
observations suggest that MCP-1 may represent an important factor
enhancing HIV spreading,
particularly in anatomical sites, such as the brain, where infection
of macrophages and Microglial
cells plays a dominant role
Wiley CA, Achim CL, Hammond R, Love S, Masliah E,
Radhakrishnan L, Sanders V, Wang G (2000) Damage and repair of DNA
in HIV encephalitis.
J.Neuropathol.Exp.Neurol. 59:955-965
Abstract: Neuronal damage
and dementia are common sequelae of HIV
encephalitis. The mechanism by which HIV
infection of CNS macrophages results in neuronal damage is not
known. We examined the brains from 15 AIDS
autopsies (8 with HIV
encephalitis and 7 without) and 4 non-infected control autopsies for
the presence of DNA strand breaks, for associated changes in the
expression of the DNA repair enzymes KU80 and Poly (ADP-ribose)
polymerase (PARP), and for accumulation of amyloid precursor protein
(APP). Abundant DNA damage was observed with terminal
transferase-mediated dUTP nick end-labeling (TUNEL), however, there
was no morphologic evidence of significant neuroglial apoptosis. The
DNA repair enzyme KU80 was immunocytochemically detectable in
neuronal and glial cells in autopsy brains from patients with and
without HIV encephalitis;
however, in cases with HIV
encephalitis the staining was more prominent than in the infected or
non-infected controls without encephalitis. There was no difference
in KU80 immunostaining in oligodendroglia from autopsies with and
without encephalitis. Immunostaining for PARP was more intense in
gray and white matter of cases with HIV
encephalitis. No clear spatial relationship existed between
expression of DNA repair enzymes and the spatial proximity of
Microglial
nodules or HIV-infected
macrophages. The cytoplasm of cortical and subcortical neurons
immunostained for APP Stronger cortical neuronal APP staining was
observed in cases without HIV
encephalitis. Staining of deep gray matter neurons was similar,
irrespective of the presence or absence of encephalitis. While foci
of intense APP staining were noted in white matter not related to
HIV infection, they were
associated with foci of opportunistic infections (e.g. due to CMV or
PML). We conclude that damaged DNA and altered patterns of
expression of DNA repair proteins and APP are common findings in the
brains of AIDS patients at
autopsy, but do not have a spatial relationship to HIV-infected
macrophages
Wittekindt B, Betz H, Laube B (2000) Subunit-dependent
inhibition of recombinant rodent N-methyl-D-aspartate receptors by a
HIV-1 glycoprotein 120
derived peptide. Neurosci.Lett. 280:151-154
Abstract:
Considerable evidence suggests that low (picomolar) concentrations
of the HIV-1 envelope
glycoprotein gp120 induce neuronal cell death by stimulating the
release of Microglial
toxins, which in turn activate N-methyl-D-aspartate (NMDA)
receptors. Conversely, high (micromolar) concentrations of gp120
have been reported to directly inhibit NMDA receptor-mediated
currents and do not induce neurotoxicity. Here we show that
micromolar concentrations of a synthetic peptide corresponding to
the V3-loop of gp120 (V3-pep) inhibited agonist responses of
recombinant heteromeric rodent NMDA receptors expressed in Xenopus
laevis oocytes by decreasing their apparent glycine affinity.
Different combinations of NMDA receptor subunits displayed
differential sensitivities to inhibition by V3-pep, with a potency
rank order of NR1/2B > NR1/2D > NR1/2C > or = NR1/2A. Our
observations may provide an explanation for the reduced
neurotoxicity of high doses of gp120 in cell cultures and may be
useful for the pharmacological discrimination of NMDA receptor
subtypes
Xiong H, Zeng YC, Lewis T, Zheng J, Persidsky Y, Gendelman HE
(2000) HIV-1 infected
mononuclear phagocyte secretory products affect neuronal physiology
leading to cellular demise: relevance for HIV-1-associated
dementia. J.Neurovirol. 6 Suppl 1:S14-S23
Abstract: Viral and
cellular products from HIV-1-infected
and/or immune competent mononuclear phagocytes (MP) (brain
macrophages and Microglia)
affect neuronal function during HIV-1-associated
dementia (HAD). Neurotoxic MP factors include, but are not limited
to, pro-inflammatory cytokines, chemokines, platelet activating
factor, arachidonic acid and its metabolites, nitric oxide, progeny
virions and viral structural and regulatory proteins. The mechanisms
for immune-mediated neural injury in HAD, only now, are being
unraveled. In this regard, we reviewed the current knowledge of how
postmitotic neurons, which can neither divide nor be replaced, are
damaged by MP secretory activities. Linking neuronal function with
brain MP activation was made possible by placing viral and/or immune
products onto neurons and measuring cell signaling events or through
ex vivo electrophysiological tests on MP-treated brain slices. Such
linkages are shown, in this report, by select demonstrations of MP
factors which cause neuronal dysfunction in HAD
Yeh MW, Kaul M, Zheng J, Nottet HS, Thylin M, Gendelman HE,
Lipton SA (2000) Cytokine-stimulated, but not HIV-infected,
human monocyte-derived macrophages produce neurotoxic levels of l
-cysteine. J.Immunol. 164:4265-4270
Abstract: Approximately
one-quarter of individuals with AIDS
develop neuropathological symptoms that are attributable to
infection of the brain with HIV.
The cognitive manifestations have been termed HIV-associated
dementia. The mechanisms underlying HIV-associated
neuronal injury are incompletely understood, but various studies
have confirmed the release of neurotoxins by macrophages/Microglia
infected with HIV-1 or
stimulated by viral proteins, including the envelope glycoprotein
gp120. In the present study, we investigated the possibility that l
-cysteine, a neurotoxin acting at the N-methyl-d -aspartate subtype
of glutamate receptor, could contribute to HIV-associated
neuronal injury. Picomolar concentrations of gp120 were found to
stimulate cysteine release from human monocyte-derived macrophages
(hMDM) in amounts sufficient to injure cultured rat cerebrocortical
neurons. TNF-alpha and IL-1beta, known to be increased in
HIV-encephalitic brains, as
well as a cellular product of cytokine stimulation, ceramide, were
also shown to induce release of cysteine from hMDM in a
dose-dependent manner. A TNF-alpha-neutralizing Ab and an IL-1betaR
antagonist partially blocked gp120-induced cysteine release,
suggesting that these cytokines may mediate the actions of gp120.
Interestingly, hMDM infected with HIV-1
produced significantly less cysteine than uninfected cells following
stimulation with TNF-alpha. Our findings imply that cysteine may
play a role in the pathogenesis of neuronal injury in HIV-associated
dementia due to its release from immune-activated macrophages but
not virus-infected macrophages. Such uninfected cells comprise the
vast majority of mononuclear phagocytes (macrophages and Microglia)
found in HIV-encephalitic
brains
Zujovic V, Benavides J, Vige X, Carter C, Taupin V (2000)
Fractalkine modulates TNF-alpha secretion and neurotoxicity induced
by Microglial
activation. Glia 29:305-315
Abstract: Among the chemokine family,
fractalkine shows unusual properties: it exists as a membrane-bound
and soluble protein, and both fractalkine and its receptor CX(3)CR1
are expressed predominantly in the central nervous system. In rat
cell culture models, the chemokine fractalkine was expressed in
neurons and Microglia,
but not in astrocytes and its receptor exclusively localized to
Microglial
cells, where its expression was downregulated by treatment with the
bacterial endotoxin (LPS). In Microglial
cultures, LPS (10 ng/ml) induced a marked increase in the release of
the proinflammatory cytokine tumor necrosis factor-alpha
(TNF-alpha). The effects of LPS on TNF-alpha secretion were
partially blocked (30%) by fractalkine and the effects of
fractalkine were reversed by a polyclonal anti-fractalkine antibody.
When Microglial-associated
fractalkine was neutralized by anti-fractalkine antibody, the LPS
response was increased by 80%, suggesting tonic activation of
Microglial
fractalkine receptors by endogenous fractalkine. The effects of the
antibody were antagonized by the addition of fractalkine.
LPS-activated Microglia
were neurotoxic when added to neuronal hippocampal culture,
producing 20% neuronal death, as measured by NeuN-positive cell
counting. An anti-fractalkine antibody produced neurotoxic effects
of similar magnitude in this co-culture system and also markedly
potentiated the neurotoxic effects of LPS-activated Microglia
(40% neuronal death). These results suggest that endogenous
fractalkine might act tonically as an anti-inflammatory chemokine in
cerebral tissue through its ability to control and suppress certain
aspects of Microglial
activation. These data may have relevance to degenerative conditions
such as multiple sclerosis, in which cerebral inflammatory processes
may be activated
Adamson DC, McArthur JC, Dawson TM, Dawson VL (1999) Rate and
severity of HIV-associated
dementia (HAD): correlations with Gp41 and iNOS. Mol.Med.
5:98-109
Abstract: BACKGROUND: Fifteen to thirty percent of AIDS
patients develop some type of neurologic disorder during the course
of their illness and the vast majority of these neurologic disorders
will be HIV-associated
dementia (HAD). These patients can exhibit varying degrees of
severity and rates of progression of HAD. Neuropathologic variables
that are associated with the rate of progression of HAD are not
known. MATERIALS AND METHODS: Tissue was collected at autopsy from
the Johns Hopkins University HIV
Neurology Program. Seventy-one AIDS
patients of this prospectively characterized population were
followed until death to obtain information on dementia severity and
the rate of neurological progression. Immunoblot analysis of
immunological nitric oxide synthase (iNOS), HAM56, gp41, p24, gp120,
and beta-tubulin was performed and the levels of iNOS, HAM56, gp41,
and p24 were normalized to beta-tubulin and analyzed for
significance by means of the Kruskal-Wallis test for multiple
groups. RESULTS: We have identified unique groups within this
spectrum and designated them slow, moderate, and rapid progressors.
Slow and moderate progressors' neurological progression occurs over
a course of months to years, whereas the rapid progressors' disease
shows rapid increases in severity over weeks to months. In the
present study we demonstrate that the severity and rate of
progression of HAD correlates significantly with levels of the HIV-1
coat protein, gp41, iNOS, and HAM56, a marker of
Microglial/macrophage
activation. CONCLUSION: The severity and rate of progression of HAD
correlates with indices of immune activation as well as levels of
iNOS and gp41. There appears to be a threshold effect in which high
levels of gp41, iNOS, and immune activation are particularly
associated with severe (Memorial Sloan-Kettering score 3 to 4) and
rapidly progressive HAD
Adle-Biassette H, Chretien F, Wingertsmann L, Hery C, Ereau
T, Scaravilli F, Tardieu M, Gray F (1999) Neuronal apoptosis does
not correlate with dementia in HIV
infection but is related to Microglial
activation and axonal damage. Neuropathol.Appl.Neurobiol.
25:123-133
Abstract: To characterize the distribution of
apoptotic neurons and their relationships with the stage of disease,
a history of HIV-dementia,
and the degree of productive HIV
infection, Microglial
activation and axonal damage, we examined the brains of 40 patients.
Samples of frontal and temporal cortex, basal ganglia and brain stem
were taken post-mortem from 20 patients with AIDS
(including three with HIV-dementia,
and eight with cognitive disorders that did not fulfil the criteria
for HIV-dementia), 10
HIV-positive asymptomatic
cases and 10 seronegative controls. Neuronal apoptosis was
demonstrated by in situ end labelling in 18 AIDS
cases and two pre-AIDS
cases; a single apoptotic neuron was present in the temporal cortex
of a control. Semiquantitative evaluation showed that the severity
of neuronal apoptosis in the cerebral cortex correlated with the
presence of cerebral atrophy, but not with a history of HIV
dementia. There was no global quantitative correlation between
neuronal apoptosis and HIV
encephalitis or Microglial
activation. However, there was some topographical correlation
between these changes. In the basal ganglia, apoptotic neurons were
much more abundant in the vicinity of multinucleated giant cells
and/or p24 expressing cells. Microglial
activation was constantly present in these areas. Axonal damage was
identified using beta-amyloid-precursor protein (betaAPP)
immunostaining in 17 AIDS
and eight pre-AIDS brains.
Although no global quantitative correlation could be established
between axonal damage and neuronal apoptosis there was an obvious
topographic correlation supporting the view that axonal damage,
either secondary to local Microglial
activation or due to the intervention of systemic factors, may also
contribute to neuronal apoptosis
Albright AV, Frank I, Gonzalez-Scarano F (1999) Interleukin-2 treatment of Microglia has no effect on in vitro HIV infection. AIDS 13:527-528
Albright AV, Shieh JT, Itoh T, Lee B, Pleasure D, O'Connor
MJ, Doms RW, Gonzalez-Scarano F (1999) Microglia
express CCR5, CXCR4, and CCR3, but of these, CCR5 is the principal
coreceptor for human immunodeficiency virus type 1 dementia
isolates. J.Virol. 73:205-213
Abstract: Microglia
are the main human immunodeficiency virus (HIV)
reservoir in the central nervous system and most likely play a major
role in the development of HIV
dementia (HIVD). To
characterize human adult Microglial
chemokine receptors, we analyzed the expression and calcium
signaling of CCR5, CCR3, and CXCR4 and their roles in HIV
entry. Microglia
expressed higher levels of CCR5 than of either CCR3 or CXCR4. Of
these three chemokine receptors, only CCR5 and CXCR4 were able to
transduce a signal in Microglia
in response to their respective ligands, MIP-1beta and SDF-1alpha,
as recorded by single-cell calcium flux experiments. We also found
that CCR5 is the predominant coreceptor used for infection of human
adult Microglia
by the HIV type 1 dementia
isolates HIV-1DS-br,
HIV-1RC-br, and HIV-1YU-2,
since the anti-CCR5 antibody 2D7 was able to dramatically inhibit
Microglial
infection by both wild-type and single-round luciferase pseudotype
reporter viruses. Anti-CCR3 (7B11) and anti-CXCR4 (12G5) antibodies
had little or no effect on infection. Last, we found that virus
pseudotyped with the DS-br and RC-br envelopes can infect cells
transfected with CD4 in conjunction with the G-protein-coupled
receptors APJ, CCR8, and GPR15, which have been previously
implicated in HIV entry
Altmeyer R, Mordelet E, Girard M, Vidal C (1999) Expression
and detection of macrophage-tropic HIV-1
gp120 in the brain using conformation-dependent antibodies. Virology
259:314-323
Abstract: HIV-1
envelope proteins gp120 and gp41 are likely to play a role in the
pathogenesis of HIV-associated
neurocognitive disorders. While detection of gp120 in HIV-infected
cell cultures is easy, it has not yet been possible to identify
gp120 in human or animal brains in situ. The difficulty in detecting
gp120 could be due to low expression levels of the protein, to the
shedding of gp120 from infected macrophages/Microglia,
or to the use of inappropriate gp-specific antibodies. We addressed
these questions by analyzing the subcellular localization,
oligomeric structure, and shedding behavior of gp120 from a
macrophage-tropic, CCR5-dependent primary isolate, BX08, expressed
by a Semliki Forest virus replicon (SFVenvBX08) in vitro. We used
the same SFV system injected in vivo into the rat brain in an
attempt to detect gp120 in situ. Our results show that gp120/41 is
expressed as monomers, dimers, and trimers in cell culture.
Immunocytochemical analysis revealed that intracytoplasmic gp120 can
be recognized by an anti-V3 antibody, whereas gp120 at the plasma
membrane is detected exclusively by a conformation-dependent
antibody. In the rat brain, the SFV vector allows gene expression in
neurons from day 3 to day 9 after injection without any apparent
brain damage nor reactive astrogliosis. In SFVenvBX08-infected
neurons only conformation-dependent antibodies allowed gp120
labeling. These results suggest that previous difficulties in
detecting gp120 in brain tissues may be due to the use of antibodies
which were unable to recognize gp120 at the plasma membrane
An SF, Groves M, Giometto B, Beckett AA, Scaravilli F (1999)
Detection and localisation of HIV-1
DNA and RNA in fixed adult AIDS
brain by polymerase chain reaction/in situ hybridisation technique.
Acta Neuropathol.(Berl) 98:481-487
Abstract: In the brain of
patients with AIDS, HIV-1
is localised in a productive form in mononuclear cells. One issue
that still needs clarification is whether HIV
is localised in cells other than those of mononuclear lineage. Gene
amplification by polymerase chain reaction/in situ hybridisation
(PCR-IS) could shed light on it. In this study, formalin-fixed,
paraffin-embedded brain tissue from ten adult AIDS
sufferers was used. Five of them showed evidence of HIV
encephalitis (HIVE), five
did not show any abnormality. Nested PCR revealed HIV-1
DNA in all HIVE cases and
in three of the group without HIVE.
HIV-1 DNA and RNA were also
detected in situ in seven cases (all seven were also HIV-1
DNA positive in tube). A higher signal was located in the white than
in the grey matter. HIV-1
DNA was found in Microglia,
macrophages, perivascular cells, multinucleated gaint cells (MGC)
and in CD68-negative cells. Some of them were identified as
endothelial cells, astrocytes and oligodendrocytes. Reverse
transcriptase-PCR-IS was positive in macrophages, MGC, endothelial
and glial cells. These results confirm infection of endothelial
cells and other glial cells and give clues about the route of entry
of virus into the central nervous system and the pathogenesis of the
disease. This study did not give any convincing evidence supporting
an infection of neurons by HIV-1
An SF, Groves M, Gray F, Scaravilli F (1999) Early entry and
widespread cellular involvement of HIV-1
DNA in brains of HIV-1
positive asymptomatic individuals. J.Neuropathol.Exp.Neurol.
58:1156-1162
Abstract: There is overwhelming evidence that
invasion of the central nervous system (CNS) by HIV-1
takes place at an early stage of the infection. It has been
demonstrated that HIV-1 DNA
is present in brains of asymptomatic individuals. Evidence of immune
activation and increased expression of cytokines suggested that
neuropathological changes and neuronal and axonal damage could be
the effect of the presence of the virus. The purpose of the study is
to ascertain whether target cells for HIV-1
in brain of patients at early stage of the infection are the same as
those found in AIDS
sufferers or if the distribution seen in AIDS
patients results from the late spreading of the infection from cells
considered traditionally the reservoir of the virus, i.e. Microglial
cells. Eighteen brains, all HIV-1
DNA positive, as shown by nested polymerase chain reaction (PCR),
were selected among the group of HIV-1
positive asymptomatic cases. In 6 of them, HIV-1
DNA was detected by PCR in situ. Positive cells included astrocytes
and endothelial cells, in addition to Microglial
cells. We conclude that astrocytes and endothelial cells are already
infected at an early (asymptomatic) stage of the infection and
suggest that they might contribute to the damage of the CNS
Bagetta G, Corasaniti MT, Berliocchi L, Nistico R,
Giammarioli AM, Malorni W, Aloe L, Finazzi-Agro A (1999) Involvement
of interleukin-1beta in the mechanism of human immunodeficiency
virus type 1 (HIV-1)
recombinant protein gp120-induced apoptosis in the neocortex of rat.
Neuroscience 89:1051-1066
Abstract: The effect of subchronic
intracerebroventricular injection of the human immunodeficiency
virus type 1 (HIV-1)
recombinant protein gp120 (100 ng, given daily for up to seven
consecutive days) on interleukin-1beta expression was studied by
immunohistochemistry in the brain of adult rats. In comparison to
control, bovine serum albumin (300 ng, given
intracerebroventricularly for up to seven days) -treated animals
(n=6), interleukin-1beta immunoreactivity increased in the brain
cortex and hippocampus of rats (n=6) receiving a single injection of
the viral protein 24 h before analysis with more substantial
increases being observed in these regions of the brain (n=6) after
seven days treatment. Double-labelling immunofluorescence
experiments support a neuronal and, possibly, a Microglial
cell origin for gp120-enhanced interleukin-1beta expression.
Transmission electron microscopy analysis of brain tissue sections
revealed that combination treatments (given
intracerebroventricularly daily for seven days) with gp120 (100 ng)
and interleukin-1 receptor antagonist (80 ng) or with the
interleukin converting enzyme inhibitor II (100 pmol), but not with
leupeptin (100 pmol), prevented apoptotic death of rat (n=6/group)
brain cortical cells typically elicited by the viral protein. These
data demonstrate that gp120 enhances interleukin-1beta expression in
the brain and this may be involved in the mechanism underlying
apoptosis induced by gp120 in the brain cortex of rat. Further
support to this hypothesis comes from the evidence that
intracerebroventricular injection of murine recombinant
interleukin-1beta (200 U, given daily for seven consecutive days)
produces DNA fragmentation in the brain cortex of rat (n=6).
Interestingly, the latter treatment enhanced nerve growth factor
level in the hippocampus but not in the cerebral cortex and this
coincides with a similar effect recently reported in identical brain
areas of rats treated likewise with gp120. In conclusion, the
present data demonstrate that treatment with gp120 enhances
interleukin-1beta expression and this participates in the mechanism
of apoptotic cell death in the brain cortex of rat. By contrast, in
the hippocampus, gp120-enhanced interleukin-1beta expression
elevates nerve growth factor that may prevent or delay apoptosis in
this plastic region of the rat brain
Bencheikh M, Bentsman G, Sarkissian N, Canki M, Volsky DJ
(1999) Replication of different clones of human immunodeficiency
virus type 1 in primary fetal human astrocytes: enhancement of viral
gene expression by Nef. J.Neurovirol. 5:115-124
Abstract:
Dementia is a common complication of AIDS
which is associated with human immunodeficiency virus type 1 (HIV-1)
infection of brain macrophages and Microglia.
Recent studies have shown that astrocytes are also infected in the
brain but HIV-1 replication
in these cells is restricted. To determine virus specificity of this
restriction we tested the expression of 15 HIV-1
molecular clones in primary human fetal astrocytes by infection and
DNA transfection. Infection with cell-free viruses was poorly
productive and revealed no clone-specific differences. In contrast,
transfected cells produced transiently high levels of HIV-1
p24 core antigen, up to 50 nanograms per ml culture supernatant, and
nanogram levels of p24 were detected 3-4 weeks after transfection of
some viral clones. The average peak expression of HIV-1
in astrocytes varied as a function of viral clone used by a factor
of 15 but the differences and the subsequent virus spread did not
correlate with the tropism of the viral clones to T cells or
macrophages. Functional vif, vpu, and vpr genes were dispensable for
virus replication from transfected DNA, but intact nef provided a
detectable enhancement of early viral gene expression and promoted
maintenance of HIV-1
infection. We conclude that primary astrocytes present no
fundamental barriers to moderate expression of different strains of
HIV-1 and that the presence
of functional Nef is advantageous to virus infection in these cells
Berman NE, Marcario JK, Yong C, Raghavan R, Raymond LA, Joag
SV, Narayan O, Cheney PD (1999) Microglial
activation and neurological symptoms in the SIV model of NeuroAIDS:
association of MHC-II and MMP-9 expression with behavioral deficits
and evoked potential changes. Neurobiol.Dis. 6:486-498
Abstract:
HIV-1 causes cognitive and
motor deficits and HIV
encephalitis (HIVE) in a
significant proportion of AIDS
patients. Neurological impairment and HIVE
are thought to result from release of cytokines and other harmful
substances from infected, activated Microglia.
In this study, the quantitative relationship between Microglial
activation and neurological impairment was examined in the simian
immunodeficiency model of HIVE.
Macaque monkeys were infected with a passaged, neurovirulent strain
of simian immunodeficiency virus, SIV(mac)239(R71/17E). In
concurrent studies, functional impairment was assessed by motor and
auditory brainstem evoked potentials and by measurements of
cognitive and motor behavioral deficits. Brain tissue was examined
by immunohistochemistry using two markers of Microglia
activation, MHC-II and matrix metalloproteinase-9 (MMP-9). The
inoculated animals formed two groups: rapid progressors, which
survived 6-14 weeks postinoculation, and slow progressors, which
survived 87-109 weeks. In the rapid progressors, two patterns of
MHC-II expression were present: (1) a widely disseminated pattern of
MHC-II expressing Microglia
and Microglial
nodules in cortical gray matter and subcortical white matter, and
(2) a more focal pattern in which MHC-II expressing Microglia
were concentrated into white matter. Animals exhibiting both
patterns of Microglial
activation showed mild to severe changes in cognitive and motor
behavior and evoked potentials. All rapid progressors showed
expression of MMP-9 in Microglia
located in subcortical white matter. In the slow progressors MHC-II
and MMP-9 staining was similar to uninoculated control macaques, and
there was little or no evidence of HIVE.
These animals showed behavioral deficits at the end of the disease
course, but little changes in evoked potentials. Thus, increases in
MHC-II and MMP-9 expression are associated with development of
cognitive and motor deficits, alterations in evoked potentials, and
rapid disease progression
Boddeke EW, Meigel I, Frentzel S, Biber K, Renn LQ,
Gebicke-Harter P (1999) Functional expression of the fractalkine
(CX3C) receptor and its regulation by lipopolysaccharide in rat
Microglia.
Eur.J.Pharmacol. 374:309-313
Abstract: Functional expression of
CX3CR1, a recently discovered receptor for the chemokine
fractalkine, was investigated in cultured rat Microglia.
Reverse transcriptase polymerase chain reaction (PCR) experiments
show abundant expression of fractalkine receptor mRNA in Microglia.
mRNA expression of fractalkine was undetectable in astrocytes and
Microglia
but was very strong in cortical neurons. Incubation of Microglia
with lipopolysaccharide (100 ng/ml) transiently suppressed
expression of fractalkine receptor mRNA. Fractalkine induced a
concentration-dependent (10(-10)-10(-8) M) and, at high
concentrations, oscillatory mobilization of intracellular Ca2+ in
Microglia
The concentration-response curve of fractalkine was shifted to the
right after 12 h incubation with lipopolysaccharide. It is concluded
that treatment with endotoxin downregulates expression of
fractalkine receptor mRNA in rat Microglia
and suppresses the functional response to fractalkine
Bonwetsch R, Croul S, Richardson MW, Lorenzana C, Valle LD,
Sverstiuk AE, Amini S, Morgello S, Khalili K, Rappaport J (1999)
Role of HIV-1 Tat and CC
chemokine MIP-1alpha in the pathogenesis of HIV
associated central nervous system disorders. J.Neurovirol.
5:685-694
Abstract: Two syndromes affecting cognitive and motor
function in the setting of AIDS
have been described as HIV
encephalopathy (HIVE) and
progressive multifocal leukoencephalopathy (PML). HIVE
is characterized by the presence of Microglial
nodules with accompanying astrocytosis. PML is a fatal demyelinating
disease of the white matter induced by the human papovavirus JCV
which causes cytolytic destruction of glial cells. In addition to
the effect of HIV-1 induced
immune suppression, HIV may
act directly as a co-factor for stimulation of JCV replication in
AIDS patients, in part due
to Tat-induced activation of JCV gene transcription. Since Tat has
been implicated in CNS pathogenesis, we examined its localization in
CNS specimens from HIV
infected patients with HIVE
and PML as well as controls. Based on the observation of CC
chemokine induction in monocytes by Tat, we also examined the
cellular localization of the CC chemokine Macrophage Inflammatory
Protein-1alpha (MIP-1alpha) and its cognate receptor CCR-5 in these
samples. In HIVE, Tat was
primarily localized in astrocytes and Microglia,
within the nodular lesions. In PML, a marked increase in the number
of Tat positive astrocytes was observed. In both HIVE
and PML, prominent expression of MIP-1alpha and CCR-5 was found
within areas containing histopathological lesions. CCR-5 positivity
of Microglia
was localized primarily to nodular lesions in HIVE.
In PML, increased numbers of cells with monocyte/Microglial
morphology were observed relative to HIVE.
The increased MIP-1 alpha positivity, and potentially other
chemokines, may contribute to the pathogenesis of PML in the setting
of HIV infection. Tat may
play an important role in the pathogenesis of both HIV
associated CNS disease states, acting indirectly through cytokine
and chemokine dysregulation
Boven LA, Gomes L, Hery C, Gray F, Verhoef J, Portegies P,
Tardieu M, Nottet HS (1999) Increased peroxynitrite activity in AIDS
dementia complex: implications for the neuropathogenesis of HIV-1
infection. J.Immunol. 162:4319-4327
Abstract: Oxidative stress is
suggested to be involved in several neurodegenerative diseases. One
mechanism of oxidative damage is mediated by peroxynitrite, a
neurotoxic reaction product of superoxide anion and nitric oxide.
Expression of two cytokines and two key enzymes that are indicative
of the presence of reactive oxygen intermediates and peroxynitrite
was investigated in brain tissue of AIDS
patients with and without AIDS
dementia complex and HIV-seronegative
controls. RNA expression of IL-1beta, IL-10, inducible nitric oxide
synthase, and superoxide dismutase (SOD) was found to be
significantly higher in demented compared with nondemented patients.
Immunohistochemical analysis showed that SOD was expressed in
CD68-positive Microglial
cells while inducible nitric oxide synthase was detected in glial
fibrillary acidic protein (GFAP)-positive astrocytes and in equal
amounts in Microglial
cells. Approximately 70% of the HIV
p24-Ag-positive macrophages did express SOD, suggesting a direct
HIV-induced intracellular
event. HIV-1 infection of
macrophages resulted in both increased superoxide anion production
and elevated SOD mRNA levels, compared with uninfected macrophages.
Finally, we show that nitrotyrosine, the footprint of peroxynitrite,
was found more intense and frequent in brain sections of demented
patients compared with nondemented patients. These results indicate
that, as a result of simultaneous production of superoxide anion and
nitric oxide, peroxynitrite may contribute to the neuropathogenesis
of HIV-1 infection
Brenneman DE, Hauser J, Spong CY, Phillips TM, Pert CB, Ruff
M (1999) VIP and D-ala-peptide T-amide release chemokines which
prevent HIV-1 GP120-induced
neuronal death. Brain Res. 838:27-36
Abstract: Vasoactive
intestinal peptide (VIP) and DAPTA (D-ala(1)-peptide T-amide, a
gp120-derived octapeptide homologous to VIP) prevent neuronal cell
death produced by five variants of HIV-1
(human immunodeficiency virus) envelope protein (gp120). VIP or
DAPTA treatment of astrocyte cultures resulted in the release of
macrophage inflammatory protein-1alpha (MIP-1alpha) and RANTES, beta
chemokines known to block gp120 interactions with Microglial
chemokine receptors. In rat cerebral cortical cultures,
gp120-induced neuronal killing was partially or completely prevented
by chemokines that stimulate the CXCR4, CCR3 or CCR5 chemokine
receptors. Chemokines exhibited marked differences in potency and
efficacy in preventing toxicity associated with five gp120 variants
(LAV/BRU, CM243, RF, SF2, and MN). RANTES had the broadest and most
potent inhibition (IC(50)<3 pM for RF isolate). An octapeptide
derived from RANTES also exhibited neuroprotection from gp120 (RF
isolate) toxicity (IC(50)=0.3 microM). Treatment with chemokines
alone had no detectable effect on neuronal cell number. However,
antiserum to MIP-1alpha produced neuronal cell death that was
prevented by co-treatment with MIP-1alpha, suggesting that this
endogenous chemokine exerts a tonic regulation important to neuronal
survival. The neuroprotective action of VIP on gp120 was attenuated
by co-treatment with anti-MIP-1alpha. These studies suggest that the
neuroprotective action of VIP is linked in part to its release of
MIP-1alpha. Furthermore, neuroprotection produced by chemokines is
dependent on both the type of chemokine and the variant structure of
gp120 and may be relevant to drug strategies for the treatment of
AIDS dementia
Carson MJ, Sutcliffe JG, Campbell IL (1999) Microglia
stimulate naive T-cell differentiation without stimulating T-cell
proliferation. J.Neurosci.Res. 55:127-134
Abstract: A major
question relevant to the initiation and progression of inflammation
and autoimmune processes within the central nervous system (CNS) is
whether resident Microglia
or only infiltrating macrophage can productively interact with
T-cells that enter the CNS either actively through extravasation or
passively through defects in the blood brain barrier (BBB). We
isolated Microglia
and macrophage from the brains of healthy adult mice and transgenic
mice that displayed many features of multiple sclerosis and HIV
leukoencephalopathy due to the astrocytic expression of interleukin
(IL)-3 and compared their antigen-presenting cell (APC) functions.
We found that unactivated Microglia
isolated from healthy nontransgenic mice and activated Microglia
isolated from transgenic siblings are relatively weak stimulators of
naive T-cell proliferation compared to macrophage populations. The
APC function of activated, but not unactivated, Microglia
could be increased by treatment acutely with lipopolysaccharide
(LPS)/interferon gamma (IFN-gamma). However, this treatment also
induced the apparent production of prostaglandins, which reduced
T-cell proliferation when indomethacin was absent from the assay
cultures. Strikingly, even in the absence of stimulated T-cell
proliferation, both unactivated and activated Microglia
stimulated the differentiation of naive T-cells into Th1 effector
cells, although neither Microglial
population was a more effective inducer than macrophages or splenic
APCs. Thus, while Microglia
are clearly capable of productively interacting with naive T-cells,
macrophages have a more robust APC function
Clifford DB (1999) Central Neurologic Complications of HIV
Infection. Curr.Infect.Dis.Rep. 1:187-191
Abstract: Human
immunodeficiency virus enters the brain at the time of infection and
remains in the central nervous system (CNS) throughout the
infection. Three currently active topics of clinical importance will
be reviewed. First, the role of cerebrospinal fluid (CSF) viral
loads as a function of brain infection and performance will be
assessed. Evidence is building that CSF viral load is a useful
measure in assessing CNS infection in clinical trial settings with
possible application to monitoring the effect of therapy in
neurologically symptomatic subjects. Second, potential roles of
cytokines and their receptors for CNS disease will be updated. The
impact of cytokine receptors on modes of invasion of endothelial
cells, monocytes, Microglia,
and neurons will be discussed. Finally, recently reported controlled
therapeutic trials will be reviewed including the impact of
antiretroviral therapy and hypothesis-driven neuroprotective
strategy studies
Conant K, McArthur JC, Griffin DE, Sjulson L, Wahl LM, Irani
DN (1999) Cerebrospinal fluid levels of MMP-2, 7, and 9 are elevated
in association with human immunodeficiency virus dementia.
Ann.Neurol. 46:391-398
Abstract: Pathological evidence suggests
that alterations of the blood-brain barrier (BBB) may occur in
association with human immunodeficiency virus (HIV)
dementia (HIVD). Increased
BBB permeability could contribute to the development of dementia by
facilitating the entry of activated and infected monocytes, as well
as potentially toxic serum proteins, into the central nervous
system. One mechanism by which BBB permeability may be altered is
through increased activity of select matrix metalloproteinases
(MMPs). In the present study, we examined the possibility that MMPs
that target critical BBB proteins, including laminin, entactin, and
collagen type IV, are elevated in the cerebrospinal fluid (CSF) of
patients with HIVD. We also
examined the possibility that such MMPs could be produced by
brain-derived cells, and that MMP production by these cells might be
increased by tumor necrosis factor-alpha, an inflammatory cytokine
that is produced by HIV-infected
monocytes/Microglia
and is elevated in HIVD. By
using western blot and enzyme-linked immunosorbent assay, we
observed that CSF levels of pro-MMP-2 and pro-MMP-7 were increased
in association with HIVD.
In addition, through the use of gelatin substrate zymography, a
sensitive functional assay for MMP-2 and MMP-9, we observed that
MMP-2 or pro-MMP-9 activity was more frequently detectable in the
CSF of individuals with HIV
dementia (9/16) than in the CSF from either nondemented seropositive
(2/11) or seronegative (0/11) controls. Although the presence of
MMPs in the serum could contribute to elevated levels in the CSF, we
also show that brain-derived cells release MMP-2, 7, and 9, and that
such release is increased after their stimulation with tumor
necrosis factor-alpha. Together, these results suggest that elevated
CSF levels of select MMPs may reflect immune activation within the
central nervous system. They also suggest that further studies may
be warranted to determine whether these proteins may play a role in
the development of symptomatic neurological disease
Epstein LG, Gelbard HA (1999) HIV-1-induced
neuronal injury in the developing brain. J.Leukoc.Biol.
65:453-457
Abstract: HIV-1
infection of the nervous system causes neuronal injury and death,
resulting in cognitive, motor, and behavioral dysfunction in both
adults and children. In infants a characteristic feature of HIV-1
infection is impaired brain growth resulting in secondary
microcephaly with onset between 2 and 4 months of age. This
post-natal period of brain development is particularly vulnerable to
excitotoxic neuronal injury due to the active synaptogenesis and
pruning that takes place at this age associated with over-expression
of excitatory amino acid (EAA) receptors. HIV-1
infection of brain Microglia
and perivascular macrophages results in chronic inflammation
manifest pathologically as diffuse Microglial
activation and reactive astrogliosis. Several inflammatory products
of activated Microglia,
including tumor necrosis factor alpha (TNF-alpha) and
platelet-activating factor (PAF) have been shown to act as neuronal
toxins. This toxic effect can be antagonized by blocking NMDA (or
AMPA) glutamate receptors, suggesting that (weak) excitotoxicity
leads to oxidative stress, neuronal injury, and apoptosis. HIV-1
infection and chronic inflammation may also contribute disruption of
the blood-brain barrier and could result in further entry into the
CNS of toxic viral or cellular products or additional HIV-1-infected
cells. We hypothesize that prolonged Microglial
activation during HIV-1
infection underlies the neuronal injury and impaired brain growth in
affected infants. Further investigation of the interaction between
HIV-1-infected/activated
Microglia
and developing neurons seems warranted. The current understanding of
HIV neuropathogenesis
implies that therapeutic strategies should target the sustained
immune activation in Microglia,
attempt to repair the integrity of the blood-brain barrier, and
provide "neuroprotection" from excitotoxic neuronal injury
Gabuzda D, Wang J (1999) Chemokine receptors and virus entry
in the central nervous system. J.Neurovirol. 5:643-658
Abstract:
Several members of the chemokine receptor family are used as
coreceptors together with CD4 for HIV
and SIV entry in the central nervous system (CNS). CCR5 is the major
coreceptor for HIV-1
infection of macrophages and Microglia,
the major target cells for HIV-1
infection in the CNS. CXCR4 and CCR3 are also expressed on Microglia
and can mediate infection by certain HIV-1
isolates but at lower efficiency than CCR5. Additional chemokine
receptors that can function as HIV-1
and SIV coreceptors for a subset of viruses are expressed in the
brain (i.e. Apj, CX3CR1, STRL33/BONZO, and gpr1), but their role in
CNS infection has not been defined. The expression of CXCR4, and
possibly other chemokine receptors, on subpopulations of neurons and
glial cells may contribute to mechanisms of CNS injury that are
independent of viral infection. Understanding the role of chemokine
receptors and their chemokine ligands in HIV-1
and SIV infection of the CNS will elucidate mechanisms of viral
tropism and pathogenesis and advance the development of new
therapeutic strategies
Gonzalez-Scarano F, Baltuch G (1999) Microglia
as mediators of inflammatory and degenerative diseases.
Annu.Rev.Neurosci. 22:219-240
Abstract: Microglia
are the principal immune cells in the central nervous system (CNS)
and have a critical role in host defense against invading
microorganisms and neoplastic cells. However, as with immune cells
in other organs, Microglia
may play a dual role, amplifying the effects of inflammation and
mediating cellular degeneration as well as protecting the CNS. In
entities like human immunodeficiency virus (HIV)
infection of the nervous system, Microglia
are also critical to viral persistence. In this review we discuss
the role of Microglia
in three diseases in which their activity is at least partially
deleterious: HIV, multiple
sclerosis, and Alzheimer's disease
Hao HN, Lyman WD (1999) HIV
infection of fetal human astrocytes: the potential role of a
receptor-mediated endocytic pathway. Brain Res. 823:24-32
Abstract:
HIV infects Microglia
and astrocytes both in vivo and in vitro. Although there is a
significant amount of information about Microglial
infection, data regarding astrocytes are more limited. For example,
little is known about the initial membrane events occurring between
HIV and astrocytes. Also,
the mechanism by which HIV
enters these cells remains to be determined. To address these
questions, we exposed human astrocyte cultures to either HIV
or to the HIV glycoprotein
gp120. The cultures were analyzed for viral infection and gp120
binding to cultured cells by light and electron microscopy (EM) with
and without immunocytochemistry, respectively; ligand-receptor
biochemistry; and, Western, Northern and Southern blot analyses. The
results of these studies showed that HIV
binds to astrocytes via gp120 and a cell surface molecule weighing
approximately 65 kDa that is neither CD4 nor galactocerebroside.
Furthermore, binding of gp120 to astrocytes was concentration
dependent and displayed a curve consistent with ligand-receptor
binding. Additionally, radiolabeled gp120 binding was displaced by
unlabeled gp120 but not by deglycosylated gp120, suggesting that the
binding was specific. By EM, HIV
virions were seen in clathrin-coated pits and in cytoplasmic
vacuoles. This suggests linkage, in astrocytes, between a plasma
membrane-associated protein that can act as a receptor for HIV
and an endosomal pathway
Hibbitts S, Reeves JD, Simmons G, Gray PW, Epstein LG, Schols
D, De Clercq E, Wells TN, Proudfoot AE, Clapham PR (1999) Coreceptor
ligand inhibition of fetal brain cell infection by HIV
type 1. AIDS
Res.Hum.Retroviruses 15:989-1000
Abstract: The capacity of a
panel of HIV-1 isolates to
infect primary mixed fetal brain cell cultures was estimated and
their sensitivity to inhibition by a range of coreceptor ligands
assessed. Our results show that (1) HIV-1
strains that predominantly use CCR5 or only CXCR4 are able to infect
Microglia
in primary brain cell cultures, and (2) ligands to these two
coreceptors can inhibit brain cell infection. CCR5 ligands
(including AOP-RANTES, a potent inhibitor of CCR5-dependent
infection), however, blocked infection only weakly, raising the
possibility that alternative unidentified coreceptors are also used.
Interestingly, vMIP-II, a chemokine encoded by the Kaposi
sarcoma-associated herpes virus (KSHV), reduced brain cell infection
by all HIV-1 strains
tested, including both R5 and X4 viruses. Our results therefore
indicate that novel drugs targeted to the major HIV-1
coreceptors will influence HIV
replication in the brain, if they cross the blood-brain barrier
Howard SA, Nakayama AY, Brooke SM, Sapolsky RM (1999)
Glucocorticoid modulation of gp120-induced effects on
calcium-dependent degenerative events in primary hippocampal and
cortical cultures. Exp.Neurol. 158:164-170
Abstract: The HIV
coat protein gp120 has been implicated in damaging the nervous
system and may play a role in AIDS-related
dementia complex. The glycoprotein triggers the release of a
glutamatergic agent from infected Microglia
and macrophages, causing NMDA receptor- and calcium-dependent
excitotoxic damage to neurons. We have previously shown that
glucocorticoids, the adrenal steroids secreted during stress, worsen
gp120 neurotoxicity and calcium mobilization in various brain
regions. This study explores events down-stream of gp120-induced
calcium mobilization, specifically, generation of reactive oxygen
species (ROS) and subsequent lipid peroxidation, destruction of the
cytoskeleton through spectrin proteolysis, and the glucocorticoid
modulation of these events in primary hippocampal cultures. We
observe that 200 pM gp120 causes a significant accumulation of ROS,
including superoxide, and of lipid peroxidation. Counter to our
predictions, pretreatment with the glucocorticoid corticosterone
(CORT) did not worsen the effects of gp120 on ROS accumulation, but
did increase lipid peroxidation. We also observed that neither gp120
alone nor gp120 plus CORT caused detectable proteolysis of the
cytoskeletal protein spectrin, whose breakdown has been shown to be
a damaging consequence of calcium excess in other models of necrotic
neuronal injury
James HJ, Sharer LR, Zhang Q, Wang HG, Epstein LG, Reed JC,
Gelbard HA (1999) Expression of caspase-3 in brains from paediatric
patients with HIV-1
encephalitis. Neuropathol.Appl.Neurobiol. 25:380-386
Abstract:
Apoptosis of neurones, macrophages, and Microglia
occurs in the brains of paediatric patients with human
immunodeficiency virus (HIV)
type 1 encephalitis, which is often associated with pre-mortem
neurological disease (progressive encephalopathy). We have
previously reported that TUNEL-positive neurones in brain tissue
from paediatric patients with HIV
type 1 encephalitis and progressive encephalopathy are strikingly
devoid of the pro-apoptotic gene product Bax, in marked contrast to
brain-resident macrophages and Microglia.
Using immunocytochemical methods, the present study demonstrate that
neurones in patients with HIV
type 1 encephalitis and progressive encephalopathy, as well as
macrophages and Microglia,
but not astrocytes, overexpress caspase-3, a pro-apoptotic enzyme
that is proteolytically activated downstream of Bax-Bcl-2
dysregulation. Co-localization of neuronal cytoplasmic caspase-3 and
nuclear TUNEL staining, a marker for fragmented DNA, was also
infrequently observed in brain tissue from patients with HIV
type 1 encephalitis and progressive encephalopathy. These findings
suggest that vulnerable neurones in brain tissue from patients with
HIV virus type 1
encephalitis and progressive encephalopathy undergo apoptosis by a
mechanism that involves upregulation of caspase-3 in a pathway that
is independent of Bax-Bcl-2 dysregulation. Furthermore, caspase-3
upregulation in apoptotic neurones likely occurs prior to DNA
fragmentation
Kaul M, Lipton SA (1999) Chemokines and activated macrophages
in HIV gp120-induced
neuronal apoptosis. Proc.Natl.Acad.Sci.U.S.A 96:8212-8216
Abstract:
HIV-1 glycoprotein gp120
induces injury and apoptosis in rodent and human neurons in vitro
and in vivo and is therefore thought to contribute to HIV-associated
dementia. In addition to CD4, different gp120 isolates bind to the
alpha- or beta-chemokine receptors CXCR4 and CCR5, respectively.
These and other chemokine receptors are on brain
macrophages/Microglia,
astrocytes, and neurons. Thus, apoptosis could occur via direct
interaction of gp120 with neurons, indirectly via stimulation of
glia to release neurotoxic factors, or via both pathways. Here we
show in rat cerebrocortical cultures that recapitulate the type and
proportion of cells normally found in brain, i.e., neurons,
astrocytes, and macrophages/Microglia,
that the beta-chemokines RANTES (regulated on activation, normal T
cell expressed and secreted) and macrophage inflammatory protein
(MIP-1beta) protect neurons from gp120SF2-induced apoptosis. The
gp120SF2 isolate prefers binding to CXCR4 receptors, similar to the
physiological alpha-chemokine ligands, stromal cell-derived factor
(SDF)-1alpha/beta. SDF-1alpha/beta failed to prevent gp120SF2
neurotoxicity, and in fact also induced neuronal apoptosis. We could
completely abrogate gp120SF2-induced neuronal apoptosis with the
tripeptide TKP, which inhibits activation of macrophages/Microglia.
In contrast, TKP or depletion of macrophages/Microglia
did not prevent SDF-1 neurotoxicity. Inhibition of p38
mitogen-activated protein kinase ameliorated both gp12
Koutsilieri E, Sopper S, Heinemann T, Scheller C, Lan J,
Stahl-Hennig C, ter M, V, Riederer P, Gerlach M (1999) Involvement
of Microglia
in cerebrospinal fluid glutamate increase in SIV-infected rhesus
monkeys (Macaca mulatta). AIDS
Res.Hum.Retroviruses 15:471-477
Abstract: Cerebrospinal fluid
(CSF) samples were collected from 24 uninfected and 24 SIV251
MPBMC-infected rhesus monkeys during early infection and from 6
animals in a longitudinal design up to 7 months postinfection to
investigate excitatory and inhibitory amino acid neurotransmitter
levels. During the early infection period CSF amino acid
concentrations of infected animals were not significantly different
from those of uninfected animals. However, long-term studies
demonstrated that gamma-aminobutyric acid (GABA) concentrations were
decreased while glutamate concentrations were increased late in
infection compared with the preinfection values of the same animals.
Moreover, we showed that the source of increased glutamate in
animals with AIDS is, at
least partially, Microglial
cells. Our data support the hypothesis that excitotoxicity is
involved in immunodeficiency virus-induced neurological disease and
propose Microglia
as a contributor to excitotoxic damage
McArthur JC, Sacktor N, Selnes O (1999) Human
immunodeficiency virus-associated dementia. Semin.Neurol.
19:129-150
Abstract: HIV-associated
dementia will eventually develop in 15-20% of individuals with
advanced HIV disease. It
has become one of the leading causes of dementia in the young, with
10,000 new cases annually in the USA. The clinical syndrome includes
progressive development of psychomotor slowing and memory
impairment, eventually with brain atrophy and neurol loss. The
pathology is characterized by infection of macrophages and
Microglia,
marked activation of macrophages, and release of a variety of
postinflammatory cytokines into the parenchyma. Antiretroviral
therapy has impacted positively on the incidence rates, and at least
partial reversal of neurologic deficits can be achieved in
established dementias
Mengozzi M, De Filippi C, Transidico P, Biswas P, Cota M,
Ghezzi S, Vicenzi E, Mantovani A, Sozzani S, Poli G (1999) Human
immunodeficiency virus replication induces monocyte chemotactic
protein-1 in human macrophages and U937 promonocytic cells. Blood
93:1851-1857
Abstract: We have recently described a significant
correlation between human immunodeficiency virus-1 (HIV-1)
RNA replication and monocyte chemotactic protein-1 (MCP-1) levels in
the cerebrospinal fluid (CSF) of individuals with the acquired
immunodeficiency syndrome (AIDS)
with HIV encephalitis (E).
Because local macrophages (Microglia)
are the cells predominantly infected in the brain, we investigated
whether in vitro HIV
infection affects MCP-1 production in mononuclear phagocytes (MP).
MCP-1 secretion and expression were consinstently upregulated over
constitutive levels in human monocyte-derived macrophages (MDM)
infected with the M-tropic R5 BaL strain of HIV-1.
HIV replication was
required for this effect, as demonstrated by the absence of
chemokine upregulation after infection in the presence of
3'-azido-3'-deoxythimidine (AZT) or cell-exposure to
heat-inactivated (triangle up degrees ) virus. MCP-1 induction was
not restricted to HIV-1
BaL, but was also observed during productive infection of MDM with
two primary isolates differing for entry coreceptor usage and of
U937 cells with the X4 HIV-1
MN strain. Based on the observation that exogenous HIV-1
Tat induced MCP-1 expression in astrocytes, we also investigated its
role in MDM and U937 cells. Exogenous Tat induced MCP-1 production
from MDM in a concentration-dependent manner, however, it was not
effective on uninfected U937 cells or on the chronically infected
U937-derived cell line U1. Transfection of Tat-expressing plasmids
moderately activated HIV
expression in U1 cells, but failed to induce MCP-1 expression in
this cell line or in uninfected U937 cells. HIV
replication-dependent expression of MCP-1 in MP may be of particular
relevance for the pathogenesis of HIV
infection in nonlymphoid organs such as the brain
Miller RJ, Meucci O (1999) AIDS
and the brain: is there a chemokine connection? Trends Neurosci.
22:471-479
Abstract: Many HIV-1-positive
individuals suffer from a variety of neurological problems known
collectively as the HIV-1-related
cognitive-motor complex. However, the molecular mechanisms that
underlie HIV-1-induced
neuropathology are unclear. They might include a combination of
indirect effects, which result from the release of neurotoxins from
activated astrocytes and Microglia,
and the direct effects of HIV-1-related
proteins, such as gp120, on neurons. As the interaction of gp120
with immune cells has been shown to require the participation of
chemokine receptors, this article explores the possibility that such
receptors participate in the events underlying HIV-1-induced
neuropathology. It is now clear that many types of cell in the brain
possess chemokine receptors, including Microglia,
glia and neurons, and the interaction of gp120 with neuronal
chemokine receptors initiates apoptotic death of neurons in vitro.
Such effects might be modified by the actions of chemokines that act
at these same receptors. However, the importance of this direct
interaction with neurons in vivo and its relevance in the
pathogenesis of AIDS-related
dementia still needs to be established. Furthermore, the existence
of chemokine receptors on neurons suggests that chemokines might
regulate neuronal functions physiologically
Nath A (1999) Pathobiology of human immunodeficiency virus
dementia. Semin.Neurol. 19:113-127
Abstract: The pathobiology of
dementia that accompanies infection with the human immunodeficiency
virus involves complex interactions of the virus with the host. The
virus enters the brain either as free viral particles or hidden in
infected monocytes (the "Trojan Horse" mechanism). Within
the brain it infects Microglial
cells, causing a productive and cytopathic infection, and infects
astrocytes, causing a latent or restricted infection. The brain thus
acts as an important reservoir for the virus. These infected cells
release several viral proteins, some of which are toxic to neurons
and are called "virotoxins." These virotoxins activate
glial cells to release a number of soluble factors that are either
toxic to neurons or cause chemotaxis of monocytes into the brain.
Because the glial cells outnumber the neurons by 10:1, this is an
important mechanism by which the virotoxins amplify their toxic
potential and initiate a self-perpetuating cascade of events,
resulting in a "domino effect" on the brain. Only a
transient exposure to virotoxins is necessary to initiate these
positive feedback loops. Thus, a "hit and run" phenomenon
may be operative within the brain. Therapeutic approaches are based
on decreasing the viral burden in the brain and blocking the actions
of the key neurotoxic substances at various levels within the
various cascades
Persidsky Y (1999) Model systems for studies of leukocyte
migration across the blood - brain barrier. J.Neurovirol.
5:579-590
Abstract: The blood - brain barrier (BBB) plays a
crucial role in central nervous system (CNS) homeostasis. Serving as
the brain's protective shield it regulates soluble factor and
cellular exchanges from blood to brain. Critical to its function,
the BBB is composed of brain microvascular endothelial cells
(BMVEC), a collagen matrix, and astrocytes. Astrocytic endfeet
surround the BMVEC abluminal surface and influence the 'tightness'
and trafficking role of the barrier. In neurodegenerative disorders
(for example stroke, multiple sclerosis and HIV
encephalitis) the BBB becomes compromised. This is, in part, immune
mediated. An accumulating body of evidence demonstrates that the
cellular components of the BBB are themselves immunocompetent.
Perivascular cells (astrocytes, macrophages and Microglial
cells) and BMVEC produce inflammatory factors that affect BBB
permeability and expression of adhesion molecules. These affect cell
trafficking into the CNS. Leukocyte BBB migration can be influenced
by cytokines and chemokines produced by glia. Astrocytes and
macrophages secrete a multitude of factors that affect brain immune
responses. Interactions between BMVEC, leukocytes and/or glia,
immunological activation and noxious (infectious, toxic and
immune-mediated) brain insults all appear to play important roles in
this BBB cell trafficking. New information gained into the
mechanisms of leukocyte-brain penetration may provide novel insights
in the pathogenesis and treatment strategies of neurodegenerative
disorders
Peterson PK, Gekker G, Hu S, Lokensgard J, Portoghese PS,
Chao CC (1999) Endomorphin-1 potentiates HIV-1
expression in human brain cell cultures: implication of an atypical
mu-opioid receptor. Neuropharmacology 38:273-278
Abstract:
Endogneous delta and kappa opioid peptides possess a variety of
immunomodulatory properties, and kappa-opioid receptor ligands
recently were shown to suppress the expression of human
immunodeficiency virus type 1 (HIV-1)
in Microglial
cells, the resident macrophages of the brain. To determine whether
the newly discovered endogenous mu-opioid receptor ligands
endomorphin-1 and -2 would affect HIV-1
replication, these peptides were added to acutely infected brain
cell cultures. Endomorphin-1 potentiated viral expression, in a
bell-shaped dose-response manner with maximal enhancement
approximately equal to 35% at 10(-10) M, in both mixed
glial/neuronal cell and purified Microglial
cell cultures. Endomorphin-1's amplifying effect was blocked by
pretreatment of brain cells with either the mu-opioid receptor
selective antagonist beta-funaltrexamine or the G protein inhibitor
pertussis toxin. However, the classical mu receptor agonists
morphine and DAMGO (Tyr-d-Ala-Gly-N-Me-Phe-Gly-ol) had no effect on
viral expression or on endomorphin-1's amplifying effect. Taken
together, these findings suggest that in this in vitro model of
HIV-1 brain infection,
endomorphin-1 potentiates viral expression via activation of an
atypical mu-selective opioid receptor. They also provide evidence,
for the first time, that an endogenous mu-opioid peptide has
neuroimmunomodulatory activity
Petito CK, Kerza-Kwiatecki AP, Gendelman HE, McCarthy M, Nath A, Podack ER, Shapshak P, Wiley CA (1999) Review: neuronal injury in HIV infection. J.Neurovirol. 5:327-341
Saadati HG, Khan IA, Lin XH, Kadakia AB, Heller KB, Sadun AA
(1999) Immunolocalization of IL-1beta and IL-6 in optic nerves of
patients with AIDS.
Curr.Eye Res. 19:264-268
Abstract: PURPOSE. Immunohistochemical
procedures were employed to test the hypothesis that cytokines such
as interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) are
involved in AIDS-related
optic neuropathy and to determine the primary cell types involved.
METHODS. Fixed sections of six human HIV-1
infected optic nerves were immunostained for the presence of
IL-1beta and IL-6, using horseradish peroxidase and diaminobenzidine
as markers. RESULTS. IL-1beta and IL-6 were found in astrocytes,
macrophages, Microglia,
and endothelial cells. The great majority of astrocytes demonstrated
strong immunoreactivity. CONCLUSION. Our findings support the
premise that IL-1beta and IL-6 are significant pro-inflammatory
mediators in AIDS-related
optic neuropathy. This finding supports the theory that HIV
infection stimulates the release of IL-1beta and IL-6 in astrocytes,
macrophages, and endothelial cells in the optic nerve which
ultimately leads to demyelination, astrogliosis, and neuronal
destruction
Sabri F, Tresoldi E, Di Stefano M, Polo S, Monaco MC, Verani
A, Fiore JR, Lusso P, Major E, Chiodi F, Scarlatti G (1999)
Nonproductive human immunodeficiency virus type 1 infection of human
fetal astrocytes: independence from CD4 and major chemokine
receptors. Virology 264:370-384
Abstract: Human immunodeficiency
virus type 1 (HIV-1)
infection of the brain is associated with neurological
manifestations both in adults and in children. The primary target
for HIV-1 infection in the
brain is the Microglia,
but astrocytes can also be infected. We tested 26 primary HIV-1
isolates for their capacity to infect human fetal astrocytes in
culture. Eight of these isolates, independent of their biological
phenotype and chemokine receptor usage, were able to infect
astrocytes. Although no sustained viral replication could be
demonstrated, the virus was recovered by coculture with receptive
cells such as macrophages or on stimulation with interleukin-1beta.
To gain knowledge into the molecular events that regulate attachment
and penetration of HIV-1 in
astrocytes, we investigated the expression of several chemokine
receptors. Fluorocytometry and calcium-mobilization assay did not
provide evidence of expression of any of the major HIV-1
coreceptors, including CXCR4, CCR5, CCR3, and CCR2b, as well as the
CD4 molecule on the cell surface of human fetal astrocytes. However,
mRNA transcripts for CXCR4, CCR5, Bonzo/STRL33/TYMSTR, and APJ were
detected by RT-PCR. Furthermore, infection of astrocytes by HIV-1
isolates with different chemokine receptor usage was not inhibited
by the chemokines SDF-1beta, RANTES, MIP-1beta, or MCP-1 or by
antibodies directed against the third variable region or the CD4
binding site of gp120. These data show that astrocytes can be
infected by primary HIV-1
isolates via a mechanism independent of CD4 or major chemokine
receptors. Furthermore, astrocytes are potential carriers of latent
HIV-1 and on activation may
be implicated in spreading the infection to other neighbouring
cells, such as Microglia
or macrophages
Starling I, Wright A, Arbuthnott G, Harkiss G (1999) Acute in
vivo neurotoxicity of peptides from Maedi Visna virus
transactivating protein Tat. Brain Res. 830:285-291
Abstract:
Lentiviruses such as Maedi Visna virus (MVV) in sheep, and human
immunodeficiency virus (HIV)
in man often cause a variety of neurological syndromes in later
stages of infection. Neuropathological investigations reveal damage
to myelin and astrocytosis in both white and grey matter. MVV
infection induces axonal damage with some areas of necrosis while
neuronal loss, and synaptic damage have been reported in HIV-1
infection. It is not clear, at present, how this neurodegeneration
is mediated but, as these viruses do not directly infect neurons, an
indirect neurotoxic action of the viruses is indicated. Previous
experiments have shown that the intra-striatal injection in rats of
a synthetic peptide derived from the basic region of the MVV
transactivating protein Tat causes considerable neurotoxicity 1 week
post-operatively. By in vivo stereotaxic injections of the same
synthetic peptide, and subsequent immunocytochemical detection of
neurons, astrocytes and Microglia,
we show that this neurotoxicity displays a distinctive and unusual
lesion profile and is evident as rapidly as 0.5 h post-operatively.
Furthermore, neuroprotection studies suggest that the early effects
of the MVV tat peptide may involve glutamate neurotoxicity via the
N-methyl-D-aspartate (NMDA) receptors since the application of
dizolcipine (MK801) reduces the volume of the lesion seen at 1 h
after the injection of neurotoxic peptide, while L-NAME is
ineffective. The mechanism of this early neurotoxicity is thus
different from the longer term actions already described
Swindells S, Zheng J, Gendelman HE (1999) HIV-associated
dementia: new insights into disease pathogenesis and therapeutic
interventions. AIDS
Patient.Care STDS. 13:153-163
Abstract: Remarkable progress was
made in recent years in the therapeutics of HIV-1-associated
dementia (HAD) and in unraveling the complex pathophysiology that
follows viral invasion of the central nervous system (CNS). Viral
replication in and outside of the CNS was significantly reduced in
HIV-1 infected subjects by
new potent antiretroviral therapies. This has resulted in partial
repair of cellular immune function with improvement in, and the
prevention of, neurologic deficits associated with progressive HIV-1
disease. In regard to HAD pathophysiology, it is now known that CNS
damage induced by HIV-1
infection occurs indirectly. Neuronal loss is mediated through
immune activation and viral infection of mononuclear phagocytes
(MPs) (brain macrophages and Microglia).
Cellular and viral factors secreted by brain MPs produce, over time,
neuronal damage and drop out. Viral growth in the brain appears
necessary, but not sufficient, to produce cognitive and motor
impairments in affected individuals. Indeed, the best predictor for
neurologic impairment following HIV-1
infection is the absolute number of immune-competent macrophages;
not the level of viral production in affected brain tissue. As yet,
an understanding of macrophage-related neurodegeneration has not
translated into significant improvements in the treatment of this
devastating complication of HIV
disease. Nonetheless, adjunctive antiinflammatory and
neuroprotective therapies are being developed. New ideas regarding
HAD neuropathogenesis, and implications for the diagnosis and
treatment of HAD are summarized in this article
Tomlinson GS, Simmonds P, Busuttil A, Chiswick A, Bell JE
(1999) Upregulation of Microglia
in drug users with and without pre-symptomatic HIV
infection. Neuropathol.Appl.Neurobiol. 25:369-379
Abstract: It is
generally thought that infection of the central nervous system (CNS)
by HIV-1 can occur early,
even around the time of seroconversion, and evidence from animal
studies supports this. However, the mode and timing of viral entry
remain poorly understood since there have been comparatively few
studies of the early neuropathology of HIV
infection. In this study, samples of frontal and temporal lobes, and
basal ganglia, were selected from 12 HIV-positive
drug users who had been infected for 4-130 months before death, 10
HIV-negative drug users and
10 non-drug using controls, all age and sex matched. Routine and
immunocytochemical staining showed that leptomeningeal and
perivascular lymphocytic infiltrate was upregulated in HIV-infected
cases compared with the two control groups, and choroid plexitis was
confined to the HIV-positive
subjects, suggesting an association with viral infection. In
contrast, CD68-positive Microglia
were enhanced in both HIV-
positive and HIV-negative
drug users, considerably above the baseline seen in normal controls.
However, there was no statistical difference between the three
groups in relation to astrocytes. Screening and competitive
polymerase chain reaction (PCR) undertaken on multiple samples
including brain tissue, choroid plexus and leptomeninges from four
of the HIV-positive
subjects and one control case showed that the pro-viral burden was
never more than 13 copies/microg DNA and was negative in multiple
samples from one HIV-positive
case and one control case. All the basal ganglia samples were
PCR-negative. This study has not revealed any t spots' of viral load
in brain tissue, choroid plexus or meninges, either early or late in
the course of pre-symptomatic HIV
infection. Drug use alone is associated with significant
upregulation of Microglia
and this may predispose to HIV
infection of the nervous system in drug users
Vincent VA, De Groot CJ, Lucassen PJ, Portegies P, Troost D,
Tilders FJ, Van Dam AM (1999) Nitric oxide synthase expression and
apoptotic cell death in brains of AIDS
and AIDS dementia patients.
AIDS 13:317-326
Abstract:
OBJECTIVES: To determine the occurrence and cellular localization of
inducible nitric oxide synthase (iNOS), NOS activity and its
association with cell death in brains of AIDS
and AIDS dementia complex
(ADC) patients. DESIGN AND METHODS: Post-mortem cerebral cortex
tissue of eight AIDS
patients, eight ADC patients and eight control subjects was
processed for iNOS immunocytochemistry, NADPH-diaphorase activity
staining as an index of NOS activity, and in situ end-labelling to
detect cell death. RESULTS: iNOS-positive cells were present in the
white matter of 14 out of 16 AIDS
and ADC patients, whereas two out of eight control subjects showed
iNOS-positive cells. iNOS immunoreactivity was exclusively localized
in activated macrophages and Microglial
cells that both showed NADPH-diaphorase activity. In addition,
NADPH-diaphorase activity, not related to iNOS immunoreactivity, was
observed in astrocytes in both white and grey matter of AIDS
and ADC patients. All AIDS
and ADC patients, and only one control subject showed characteristic
features of apoptotic cell death. CONCLUSIONS: Different forms of
NOS are present in Microglial
cells and astrocytes of AIDS
and ADC patients but are largely absent in control subjects.
Although more NOS-expressing cells occur in ADC than in AIDS
patients, apoptotic cell death was found in both patient groups to
the same extent. We postulate that NO production in brains of AIDS
patients results in cumulative cortical cell loss, which becomes
neurologically evident at later stages of disease and is expressed
as ADC
Wiley CA, Achim CL, Christopherson C, Kidane Y, Kwok S,
Masliah E, Mellors J, Radhakrishnan L, Wang G, Soontornniyomkij V
(1999) HIV mediates a
productive infection of the brain. AIDS
13:2055-2059
Abstract: BACKGROUND: Approximately one quarter of
patients with AIDS develop
severe cognitive deficits called HIV-associated
dementia complex. There is some controversy regarding the importance
of viral load and distribution in mediating this neurologic disease.
OBJECTIVE: Brain HIV
proviral and RNA loads were compared to define the molecular nature
of HIV infection of the
brain. METHOD: Neuropathologic examination was performed on brains
from 10 autopsies of patients with AIDS
that had short post-mortem intervals and no evidence of
opportunistic infection. Viral DNA and RNA were extracted and
quantified from multiple brain regions. These findings were compared
with triple-label immunofluorescence for viral and cell markers.
RESULTS: Brains with histopathologic evidence of HIV
encephalitis contained abundant HIV
RNA and DNA. Regions without productive HIV
infection showed minimal proviral load. By immunocytochemistry, only
brain macrophages/Microglia
double labeled for viral proteins. CONCLUSIONS: HIV
mediates a productive infection of brain macrophages/Microglia.
There was no evidence supporting the hypothesis of substantial
neuronal or macroglial infection, or evidence of substantial
proviral burden prior to the development of productive infection
Xiong H, Zheng J, Thylin M, Gendelman HE (1999) Unraveling
the mechanisms of neurotoxicity in HIV
type 1-associated dementia: inhibition of neuronal synaptic
transmission by macrophage secretory products. AIDS
Res.Hum.Retroviruses 15:57-63
Abstract: The cognitive and motor
impairments of HIV-1-associated
dementia (HAD) often result from neuronal damage of drop-out. In the
infected human host, virus-infected immune-competent mononuclear
phagocytes (MPs) (brain macrophages and Microglia)
are the target cells for HIV-1
and the producers of bioactive molecules that mediate neural damage.
Indeed, in laboratory experiments, activated HIV-1-infected
macrophages placed into human or rodent brain tissues induce
neuronal apoptosis. Nonetheless, the mechanisms for neuronal
dysfunction in HAD have yet to be discerned. To these ends, we
studied the effects of HIV-1-infected
monocyte-derived macrophage (MDM) secretions,
electrophysiologically, on neuronal synaptic transmission. Bath
application of HIV-1-infected
MDM culture fluids onto rat hippocampal brain slices resulted in
inhibition of evoked field excitatory postsynaptic potentials
(EPSPs). In contrast, fluids from uninfected MDMs showed mild
effects on the EPSPs. HIV-1-associated
inhibition of EPSPs was enhanced by LPS activation, both for
HIV-1-infected and
uninfected MDMs. Importantly, paired-pulse facilitation ratio tests
showed that factors secreted by HIV-1-infected
MDMs acted transiently on presynaptic terminals, providing insights
into the site of action and mechanism of the MDM-induced neuronal
dysfunction. These results, taken together, demonstrate that factors
produced as a consequence of MDM infection and activation affect
neuronal synaptic transmission
Zink WE, Zheng J, Persidsky Y, Poluektova L, Gendelman HE
(1999) The neuropathogenesis of HIV-1
infection. FEMS Immunol.Med.Microbiol. 26:233-241
Abstract: HIV
encephalitis is the common pathologic correlate of HIV-dementia
(HAD). HIV-infected brain
mononuclear phagocytes (MP) (macrophages and Microglia)
are reservoirs for persistent viral infection. When activated, MP
contribute to neuronal damage. Such activated and virus-infected
macrophages secrete cellular and viral factors, triggering neural
destructive immune responses. Our Center's laboratories have begun
to decipher the molecular and biochemical pathways for MP-mediated
neuronal damage in HAD. This review will discuss the salient
clinical and pathological features of HAD and highlight the recent
advances made, by our scientists and elsewhere, in unraveling
disease mechanisms, including the role of chemokines and their
receptors in the neuropathogenesis of HIV-1
encephalitis
Andersson LM, Fredman P, Lekman A, Rosengren L, Gisslen M
(1998) Increased cerebrospinal fluid ganglioside GD3 concentrations
as a marker of Microglial
activation in HIV type 1
infection. AIDS
Res.Hum.Retroviruses 14:1065-1069
Abstract: Human
immunodeficiency virus type 1 (HIV-1)
invades the central nervous system (CNS) early in the infectious
course. The predominant, productively infected cell type within the
CNS is the Microglial
cell. We have analyzed the cerebrospinal fluid (CSF) levels of the
ganglioside GD3, a Microglia/macrophage
and astrocyte marker, in 22 HIV-1-infected
individuals at different stages of the disease, and in 44
age-matched HIV-negative,
healthy controls. To distinguish between Microglial/macrophage
and astroglial involvement, the GD3 levels were compared with CSF
levels of the glial fibrillary acidic protein (GFAp), which is
expressed exclusively in astrocytes. A significantly higher mean CSF
concentration of GD3 was found in HIV-1-infected
patients compared to controls (56.7 and 40.1 nmol/L, respectively, p
< 0.001). Seven of 22 HIV-1-infected
patients had increased CSF levels of GD3 (above mean + 2 SD in
controls), all but one of these had normal levels of GFAp,
indicating a Microglial
activation or proliferation as the major source of the increased GD3
levels
Avgeropoulos N, Kelley B, Middaugh L, Arrigo S, Persidsky Y,
Gendelman HE, Tyor WR (1998) SCID mice with HIV
encephalitis develop behavioral abnormalities.
J.Acquir.Immune.Defic.Syndr.Hum.Retrovirol. 18:13-20
Abstract:
Severe combined immunodeficient (SCID) mice inoculated
intracerebrally (i.c.) with HIV-infected
human monocytes develop brain pathology similar to that in humans
with HIV encephalitis. This
includes HIV-positive
macrophages and multinucleated giant cells, astrogliosis, Microglial
nodules, and neuronal dropout. These xenografts survive about 1
month. To develop a model of chronic HIV
encephalitis and to assay the resulting behavioral abnormalities, we
reinoculated SCID mice i.c. every 4 weeks for 3 months with either
HIV-infected human
monocytes (n = 5) or uninfected human macrophages (n = 4) or
administered no inoculation (n = 6); these three groups were
monitored for behavioral abnormalities. Tests of cognitive function
in a Morris water maze 3.5 months after the first inoculation
suggested that HIV-infected
mice performed poorly compared with controls. Following testing in
the water maze on days 4 and 5 of acquisition, motor activity of
infected mice was reduced in comparison with that of controls.
Retention of goal location when tested 1 week later was impaired in
HIV-infected mice compared
with controls. Histopathologic analysis of brains revealed
significant astrogliosis and strongly suggested higher numbers of
major histocompatibility complex (MHC) class II-positive
multinucleated macrophages in HIV-infected
compared with control mice. Thus, our preliminary studies indicate
that SCID mice with HIV
encephalitis develop behavioral abnormalities reminiscent of human
disease. These behavioral abnormalities are associated with
significantly increased astrogliosis, the presence of HIV,
and probably multinucleated giant cells. These studies further
support the use of this SCID animal model system for studies of the
pathogenesis of HIV
encephalitis and for drug interventions
Bell JE (1998) The neuropathology of adult HIV
infection. Rev.Neurol.(Paris) 154:816-829
Abstract: Since the
onset of the acquired immune deficiency syndrome (AIDS)
epidemic fifteen years ago, much has been learned about the effects
of the human immunodeficiency virus (HIV)
in the nervous system. This review summarizes the pathology findings
in the central nervous system (CNS). There is now abundant evidence
that HIV can infect the CNS
directly, leading to a characteristic HIV
encephalitis (HIVE) which
occurs in 10-50 p. 100 of AIDS
autopsy series. Multinucleated giant cells are the pathognomonic
feature of HIVE and are
found predominantly in the central white matter and deep grey
matter. Evidence of productive HIV
infection in the CNS is confined to cells of the
Microglial/macrophage
lineage, from which the giant cells are almost certainly derived.
These cells are known to express both CD4 and beta-chemokine
receptors, which act in conjunction to permit HIV
entry. Restricted infection of astrocytes has also been identified
by a variety of methods. HIVE
is frequently associated with white matter damage ranging from
inflammatory (Microglia,
macrophages and sparse lymphocytes) to degenerative (myelin loss and
axonal damage) pathology. Although giant cells are seen less
frequently in neocortical grey matter, significant neuronal loss has
been established in a number of studies. Recent investigations using
markers of apoptosis, (including TUNEL, Bcl-2 and BAX), have
established the presence of DNA damage in some neurons and in other
cell types. Axonal damage has also been confirmed by evidence of
amyloid precursor protein expression. The CNS is also vulnerable to
opportunistic infections and high grade B-cell lymphomas as a result
of the immune suppression of advanced HIV
infection. Cytomegalovirus (CMV) infection is reported in 10-30 p.
100 of AIDS cases at
autopsy, toxoplasma in 10-25 p. 100, progressive multifocal
leucoencephalopathy in about 5 p. 100 and lymphomas, usually
primary, in up to 10 p. 100. A wide variety of other infections has
also been reported. These may coexist with HIVE
and may be difficult to diagnose in life. CMV gives rise to
Microglial
nodular encephalitis, ventriculitis, necrotising encephalitis and
myelo-radiculitis. Presymptomatic HIV
positive patients do not show HIVE
or opportunistic infections or lymphomas in the CNS. They frequently
display a low-grade T-cell infiltrate in the leptomeninges and
parenchyma, particularly around vessels. This lymphocytic infiltrate
has been attributed to presumed early invasion of the CNS by HIV
although the exact timing of entry is uncertain. It is possible that
reported abnormalities in presymptomatic cases such as gliosis,
Microglial
activation and rising proviral load may anticipate the onset of HIVE
but most studies show that significant CNS damage and HIV-related
pathology is confined to patients with AIDS.
HIV-related pathology in
the spinal cord includes not only HIV
myelitis, opportunistic infections and lymphomas, but also vacuolar
myelopathy (VM) which affects predominantly the dorsolateral white
matter tracts. The cause of VM is not understood and has not been
unequivocally linked with HIV
infection. It is noted that none of these neuropathological features
(including HIVE) correlates
exactly with the clinical expression of AIDS-related
dementia (ARD). The exact contribution of macrophage activation and
cytokine release, astrocytic infection, neuronal loss and axonal
damage to the neuropsychiatric syndromes of advanced HIV
infection remain to be determined. While the current understanding
of the pathogenesis of HIVE
and ARD is beyond the scope of this review it is axiomatic that
accurate documentation of neuropathology findings will help to
resolve the outstanding dilemmas relating to HIV
infection of the CNS. There is considerable optimism that progress
in therapeutic regimes for HIV-infected
patients will succeed in eliminating the virus from the blood and
from lymphoid tissue. (ABSTRACT TRUNCATED)
Bell JE, Brettle RP, Chiswick A, Simmonds P (1998) HIV
encephalitis, proviral load and dementia in drug users and
homosexuals with AIDS.
Effect of neocortical involvement. Brain 121 ( Pt
11):2043-2052
Abstract: In this consecutive autopsy study, the
pathological evidence of HIV
encephalitis, which included the presence of giant cells and/or HIV
p24 immunopositivity, was found more frequently in drug users (25 of
45; 56%) than in homosexual men (6 of 35; 17%) with AIDS
(P < 0.01). Productive infection, as shown by HIV
p24 positivity, was found in frontal lobe white matter in 29 of the
31 HIV encephalitis cases,
but was also present in grey matter in 50% of the HIV
encephalitis cases. Immunopositivity was confined to Microglia,
monocytes and most but not all giant cells. HIV-1
proviral load was determined by quantitative PCR in 65 of the 80
cases (separately in grey and white matter in 49 of these), and
correlated well with the presence of HIV
encephalitis (P < 0.001). Twenty-five patients with AIDS
(13 male homosexuals, 12 drug users) showed no HIV
encephalitis, opportunistic infection or cerebral lymphoma, while 18
(2 male homosexuals, 16 drug users) showed pure HIV
encephalitis. Cognitive function had been assessed prospectively in
this cohort and graded as normal or mildly, moderately or severely
impaired. Because opportunistic infections and lymphomas of the
brain may also lead to dementia, patients found to have these
conditions at autopsy were excluded from the final analysis of the
cases with dementia, so that the precise correlation between
cognitive impairment and pure HIV
encephalitis could be determined in this cohort without possible
confounding variables. Fourteen of 18 patients with pure HIV
encephalitis had shown cognitive impairment. Severe dementia
correlated better with pure HIV
encephalitis in cases in which grey matter involvement was present
(7 out of 9) than in those in which only white matter was involved
(2 out of 9) (P < 0.05), although milder degrees of cognitive
impairment had been present in a further 5 HIV
encephalitis cases. No correlation was found between zidovudine
therapy and the degree of cognitive impairment. Systemic and
cerebral opportunistic infections and lymphoma showed a negative
association with HIV
encephalitis, being more common in homosexuals than in drug users,
despite comparable CD4 counts in the two groups. These findings
suggest that neocortical productive HIV
infection is a significant factor in AIDS-related
dementia, although this may reflect merely a higher overall viral
burden in the brain
Bertrand E, Lewandowska E, Nerurkar V, Bratosiewicz J,
Yanagihara R, Zaborski J, Liberski PP (1998) Progressive multifocal
leukoencephalopathy (PML) and cerebral toxoplasmosis in an adult
patient, with no symptoms of underlying immunosuppressing illness.
Folia Neuropathol. 36:229-234
Abstract: We present a case of the
coincidence of progressive multifocal leukoencephalopathy (PML) and
central nervous system (CNS) toxoplasmosis in an adult patient,
without a detectable cause of cell-mediated immunity impairment. The
proper diagnosis was made postmortem on the basis of histological
changes typical of both pathological processes. PML was
characterized by the presence of subcortical focal demyelination,
containing enlarged, densely basophilic oligodendrocyte nuclei,
often with intranuclear inclusion, and bizarre astrocytes, mimicking
neoplastic cells. PML was confirmed by detecting numerous papova
virus particles in oligo- and astroglial nuclei by thin-section
electron microscopy. Cerebral toxoplasmosis was characterized by the
presence of multiple well-circumscribed necrotizing abscesses.
Numerous Toxoplasma gondii (T. gondii) cysts and free, non-encysted
protozoan parasites were found among the inflammatory infiltrates.
The diagnosis of cerebral toxoplasmosis was further confirmed by
immunocytochemistry. In order to detect putative immunosuppressive
background underlying both pathological processes, HIV
infection was taken into consideration, however, no
histopathological changes indicative of AIDS
either in the CNS or in the peripheral organs were eventually found.
Moreover no HIV provirus
genome was identified in the formalin-fixed, paraffin embedded brain
tissue by the polymerase chain reaction (PCR). Current view on the
selected aspects of the pathogenesis of both disorders were
discussed
Bjugstad KB, Flitter WD, Garland WA, Su GC, Arendash GW
(1998) Preventive actions of a synthetic antioxidant in a novel
animal model of AIDS
dementia. Brain Res. 795:349-357
Abstract: Accumulating evidence
indicates that the mechanism for causing AIDS
dementia complex (ADC) involves the release of damaging
inflammatory-related agents by HIV-infected
Microglia
in the brain resulting in CNS oxidative damage. One such agent,
tumor necrosis factor alpha (TNF-alpha) is consistently elevated in
the brains of ADC patients compared to non-demented HIV
patients. To model this aspect of ADC in rats, chronic ventricular
infusions of TNF-alpha were given and found to induce several
aspects of ADC, including weight loss, learning/memory impairment,
enlarged lateral ventricles, and increased apoptosis. Concurrent
oral treatment with the antioxidant CPI-1189 prevented all of these
TNF-alpha induced effects. The results support TNF-alpha as a key
toxic agent in ADC and provide the first in vivo evidence that
chronic treatment with a synthetic antioxidant may protect
HIV-infected patients
against ADC. Our findings may also have implications in other
neurological diseases where brain TNF-alpha levels are elevated and
inflammation/oxidative stress is suspected to be a contributing
cause, such as Alzheimer's disease and Parkinson's disease
Buttini M, Westland CE, Masliah E, Yafeh AM, Wyss-Coray T,
Mucke L (1998) Novel role of human CD4 molecule identified in
neurodegeneration. Nat.Med. 4:441-446
Abstract: The human CD4
molecule (hCD4) is expressed on T lymphocytes and macrophages and
acts as a key component of the cellular receptor for HIV.
At baseline, hCD4 transgenic mice expressed hCD4 on Microglia,
the resident mononuclear phagocytes of the brain, and showed no
neuronal damage. Activation of brain Microglia
by peripheral immune challenges elicited neurodegeneration in hCD4
mice but not in nontransgenic controls. In post-mortem brain tissues
from AIDS patients with
opportunistic infections, but without typical HIV
encephalitis, hCD4 expression correlated with neurodegeneration. We
conclude that hCD4 may function as an important mediator of indirect
neuronal damage in infectious and immune-mediated diseases of the
central nervous system
Cinque P, Vago L, Mengozzi M, Torri V, Ceresa D, Vicenzi E,
Transidico P, Vagani A, Sozzani S, Mantovani A, Lazzarin A, Poli G
(1998) Elevated cerebrospinal fluid levels of monocyte chemotactic
protein-1 correlate with HIV-1
encephalitis and local viral replication. AIDS
12:1327-1332
Abstract: OBJECTIVE: To investigate whether the
CC-chemokine monocyte chemotactic protein (MCP)-1 could play a role
in the pathogenesis of HIV
infection of the central nervous system. This hypothesis was
suggested by previous observations, including our finding of
elevated cerebrospinal fluid (CSF) levels of this chemokine in
patients with cytomegalovirus (CMV) encephalitis. DESIGN AND
METHODS: CSF levels of MCP-1 were determined in 37 HIV-infected
patients with neurological symptoms, and were compared with both the
presence and severity of HIV-1
encephalitis at post-mortem examination and CSF HIV
RNA levels. MCP-1 production by monocyte-derived macrophages was
tested after in vitro infection of these cells by HIV.
RESULTS: CSF MCP-1 levels were significantly higher in patients with
(median, 4.99 ng/ml) than in those without (median, 1.72 ng/ml) HIV
encephalitis. Elevated CSF MCP-1 concentrations were also found in
patients with CMV encephalitis and with concomitant HIV
and CMV encephalitis (median, 3.14 and 4.23 ng/ml, respectively).
HIV encephalitis was
strongly associated with high CSF MCP-1 levels (P = 0.002), which
were also correlated to high HIV-1
RNA levels in the CSF (P = 0.007), but not to plasma viraemia. In
vitro, productive HIV-1
infection of monocyte-derived macrophages upregulated the secretion
of MCP-1. CONCLUSIONS: Taken together, these in vivo and in vitro
findings support a model whereby HIV
encephalitis is sustained by virus replication in Microglial
cells, a process amplified by recruitment of mononuclear cells via
HIV-induced MCP-1
Corasaniti MT, Bagetta G, Rotiroti D, Nistico G (1998) The
HIV envelope protein gp120
in the nervous system: interactions with nitric oxide,
interleukin-1beta and nerve growth factor signalling, with
pathological implications in vivo and in vitro. Biochem.Pharmacol.
56:153-156
Abstract: The neuronal loss often described at
post-mortem in the brain neocortex of patients suffering from AIDS
has been proposed to be responsible for the development of the AIDS
dementia complex. Neuroinvasive strains of the HIV
virus infect macrophages, Microglial
cells, and multinucleated giant cells, but not neurones. Processing
of the virus by cells of the myelomonocytic lineage yields viral
products known to initiate a complex network of events that may lead
to the death of neurones and to the development of AIDS-associated
neurological syndrome. The HIV-1
coat protein gp120, in particular, has been proposed as a likely
etiologic agent of the described neuronal loss because it causes the
death of neurones in culture. More recently, it has been shown that
brain cortical cell death caused in rats by intracerebroventricular
injection of gp120 occurs via apoptosis. This observation broadens
our knowledge of the pathophysiology of the reported neuronal cell
loss and opens a new avenue of experimental research for the
development of novel therapeutic strategies for the treatment of
patients suffering from AIDS-associated
neurological syndrome
Couraud PO (1998) Infiltration of inflammatory cells through
brain endothelium. Pathol.Biol.(Paris) 46:176-180
Abstract: The
blood-brain barrier (BBB) restricts exchanges of soluble factors and
cells between the blood and the brain, thus playing a crucial role
in maintenance of cerebral homeostasis. It is composed of the
endothelial cells that line the cerebral capillaries. Cerebral
capillaries have a number of distinctive morphological
characteristics, including the presence of tight intercellular
junctions. Also, the cerebral capillaries are surrounded by
astrocytic projections that exert a positive regulatory effect on
BBB tightness. One effect of the BBB is that the number of
leukocytes that patrol the central nervous system is far lower than
in peripheral organs. Nevertheless, massive leukocyte infiltration
occurs in some disease states: for instance, numerous activated
leukocytes are found in the cerebral parenchyma in patients with
multiple sclerosis, and HIV
encephalitis is probably due to passage of HIV-infected
monocytes through the BBB. Compelling evidence has been obtained
that the perivascular astrocytes and Microglial
cells, as well as the cerebral endothelial cells, locally produce
inflammatory cytokines that increase BBB permeability. Advances have
also been made in the identification of leukocyte adhesion molecules
expressed at the surface of cerebral endothelial cells. Expression
of these molecules is induced by inflammatory cytokines.
Interactions between these adhesion molecules and their leukocyte
ligands may induce modifications within endothelial cells, including
cytoskeleton reorganization and opening of intercellular junctions,
which may allow leukocytes to cross the BBB. It is to be hoped that
the new insights gained into the mechanisms of leukocyte penetration
through the BBB may help to develop novel treatment strategies for
neuroinflammatory disorders
Epstein LG (1998) HIV
neuropathogenesis and therapeutic strategies. Acta Paediatr.Jpn.
40:107-111
Abstract: Human immunodeficiency virus (HIV)-1
neuropathogenesis can be divided into three important components:
(i) virus entry into the nervous system; (ii) the role of viral
proteins and/or cellular products in neural tissue damage; (iii) the
mechanisms of neuronal injury/death. Both blood derived macrophages
or trafficking HIV-1
infected T-lymphocytes have been implicated in viral entry to the
central nervous system (CNS). The major cell type harboring
productive HIV-1 infection
in the nervous system is the perivascular macrophage/Microglia.
The HIV-1 infection of
brain astrocytes, restricted to the expression of regulatory gene
products, may cause astrocyte dysfunction and contribute to neuronal
injury or to disruption of the blood-brain barrier (BBB). Studies of
cerebrospinal fluid and postmortem tissues reveal chronic
inflammation/immune activation in the nervous system during the
later stages of HIV-1
infection associated with disruption of BBB integrity. Blood-brain
barrier damage may underlie the white matter pallor described in
HIV-1 infection and could
result in further entry into the CNS of toxic viral or cellular
products, or additional HIV-1
infected cells. The HIV
infected and activated macrophages/Microglia
produce excessive amounts of pro-inflammatory cytokines, including
tumor necrosis factor alpha, and platelet activating factor. These
products are directly toxic to human neurons in vitro. The HIV-1
envelope glycoprotein, gp 120 may stimulate the release of toxic
factors from brain macrophages. Blocking N-methyl-D-aspartate (NMDA;
or AMPA) glutamate receptors can antagonize candidate toxins of both
viral and cellular origin. It has been postulated that (weak)
excitotoxicity leads to oxidative stress in neurons and ultimately
to apoptosis. Neuronal apoptosis occurs in the brains of both
children and adults with HIV-1
infection. This understanding of HIV
neuropathogenesis implies that therapeutic strategies should
include: (i) anti-retroviral medications to decrease systemic and
CNS virus load, and possibly to prevent perinatal transmission of
HIV; (ii) anti-inflammatory
compounds to decrease the chronic immune activation in Microglia
and allow the restoration of BBB integrity; and (iii)
neuroprotective compounds to reduce neuronal injury and apoptotic
death
Galasso JM, Harrison JK, Silverstein FS (1998) Excitotoxic
brain injury stimulates expression of the chemokine receptor CCR5 in
neonatal rats. Am.J.Pathol. 153:1631-1640
Abstract: Chemokines
interact with specific G-protein-coupled receptors to activate and
direct recruitment of immune cells. Some chemokines are up-regulated
in pathological conditions of the central nervous system, and
recently several chemokine receptors, including CCR5, were
identified in the brain. However, little is known about the
regulation of expression of chemokine receptors in the brain. Direct
intracerebral injection of N-methyl-D-aspartate (NMDA), an
excitatory amino acid agonist, elicits reproducible focal
excitotoxic brain injury; in neonatal rats, intrahippocampal NMDA
injection stimulates expression of pro-inflammatory cytokines and
elicits a robust Microglia/monocyte
response. We hypothesized that NMDA-induced neurotoxicity would also
stimulate expression of CCR5 in the neonatal rat brain. We evaluated
the impact of intrahippocampal injections of NMDA on CCR5 expression
in postnatal day 7 rats. Reverse transcription polymerase chain
reaction revealed an increase in hippocampal CCR5 mRNA expression 24
hours after lesioning, and in situ hybridization analysis
demonstrated that CCR5 mRNA was expressed in the lesioned
hippocampus and adjacent regions. Western blot analysis demonstrated
increased CCR5 protein in hippocampal tissue extracts 32 hours after
lesioning. Complementary immunocytochemistry studies identified both
infiltrating Microglia/monocytes
and injured neurons as the principal CCR5-immunoreactive cells.
These results provide the first evidence that acute excitotoxic
injury regulates CCR5 expression in the developing rat brain
Ghorpade A, Xia MQ, Hyman BT, Persidsky Y, Nukuna A, Bock P,
Che M, Limoges J, Gendelman HE, Mackay CR (1998) Role of the
beta-chemokine receptors CCR3 and CCR5 in human immunodeficiency
virus type 1 infection of monocytes and Microglia.
J.Virol. 72:3351-3361
Abstract: Human immunodeficiency virus type
1 (HIV-1) infection in
mononuclear phagocyte lineage cells (monocytes, macrophages, and
Microglia)
is a critical component in the pathogenesis of viral infection.
Viral replication in macrophages serves as a reservoir, a site of
dissemination, and an instigator for neurological sequelae during
HIV-1 disease. Recent
studies demonstrated that chemokine receptors are necessary
coreceptors for HIV-1 entry
which determine viral tropism for different cell types. To
investigate the relative contribution of the beta-chemokine
receptors CCR3 and CCR5 to viral infection of mononuclear phagocytes
we utilized a panel of macrophage-tropic HIV-1
strains (from blood and brain tissue) to infect highly purified
populations of monocytes and Microglia.
Antibodies to CD4 (OKT4A) abrogated HIV-1
infection. The beta chemokines and antibodies to CCR3 failed to
affect viral infection of both macrophage cell types. Antibodies to
CCR5 (3A9) prevented monocyte infection but only slowed HIV
replication in Microglia.
Thus, CCR5, not CCR3, is an essential receptor for HIV-1
infection of monocytes. Microglia
express both CCR5 and CCR3, but antibodies to them fail to inhibit
viral entry, suggesting the presence of other chemokine receptors
for infection of these cells. These studies demonstrate the
importance of mononuclear phagocyte heterogeneity in establishing
HIV-1 infection and
persistence
Gold LH, Fox HS, Henriksen SJ, Buchmeier MJ, Weed MR, Taffe
MA, Huitron-Resendiz S, Horn TF, Bloom FE (1998) Longitudinal
analysis of behavioral, neurophysiological, viral and immunological
effects of SIV infection in rhesus monkeys. J.Med.Primatol.
27:104-112
Abstract: A model is proposed in which a
neurovirulent, Microglial-passaged,
simian immunodeficiency virus (SIV) is used to produce central
nervous system (CNS) pathology and behavioral deficits in rhesus
monkeys reminiscent of those seen in humans infected with human
immunodeficiency virus (HIV).
The time course of disease progression was characterized by using
functional measures of cognition and motor skill, as well as
neurophysiologic monitoring. Concomitant assessment of immunological
and virological parameters illustrated correspondence between
impaired behavioral performance and viral pathogenesis. Convergent
results were obtained from neuropathological findings indicative of
significant CNS disease. In ongoing studies, this SIV model is being
used to explore the behavioral sequelae of immunodeficiency virus
infection, the viral and host factors leading to neurologic
dysfunction, and to begin testing potential therapeutic agents
Gray F, Belec L, Chretien F, Dubreuil-Lemaire ML, Ricolfi F,
Wingertsmann L, Poron F, Gherardi R (1998) Acute, relapsing brain
oedema with diffuse blood-brain barrier alteration and axonal damage
in the acquired immunodeficiency syndrome.
Neuropathol.Appl.Neurobiol. 24:209-216
Abstract: A 38-year-old
homosexual male with AIDS
suffered four neurological episodes including headaches, confusion,
visual impairment, memory disturbances, and dysarthria which
resolved spontaneously in a few days. He was admitted to hospital
during a fifth episode. Neurological examination revealed a
cerebellar syndrome. General examination was normal. CD4 count was
90. CSF contained two WBCs/mm(3) and 12.30 mg/dL protein. MRI
revealed diffuse ill defined increased signal on T2-weighted images
in the white matter. His condition worsened rapidly with vomiting
and he died 1 month after admission. Neuropathological examination
revealed diffuse brain oedema with ventricular compression, central
diencephalic herniation and bilateral tonsilar herniation in the
absence of a focal lesion. Microscopical examination revealed
predominant involvement of the white matter with diffuse myelin
pallor and massive perivascular dilatation containing an exudate
expressing serum proteins and occasional macrophages. The same
exudate was also diffuse in the leptomeninges. Parenchymal damage
predominated around the perivascular spaces and included loosening
of tissue, axonal damage with spheroids and reactive astrocytosis.
There was no evidence of productive HIV
encephalitis, no multinucleated giant cells; p24 immunostaining and
RT-PCR for HIV genome were
negative. There was neither significant inflammation nor Microglial
activation. In this illustrative case, the relapsing course of the
neurological signs, the diffuse topography of the blood-brain
barrier breakdown and the absence of local cause make it likely that
the diffuse leak and axonal damage could be related to circulating
factors
Gray F (1998) [Dementia and human inmmunodeficiency virus
infection]. Rev.Neurol.(Paris) 154 Suppl 2:S91-S98
Abstract:
HIV-associated neurological
manifestations: dementia, myelopathy, and neuropathy, have become
one of the commonest causes of neurological disorders in young
people. Cognitive impairment develops in about 30 p. 100 of patients
with AIDS and frank
dementia in 15 to 20 p. 100 with an annual incidence after AIDS
of approximatively 7 p. 100. Typically, the onset of dementia is
relatively abrupt over a few weeks or months. The clinical
manifestations of the encephalopathy now termed "HIV-dementia",
suggest predominant subcortical or frontal involvement. Typical
presentation includes apathy and inertia, memory loss and cognitive
slowing, minor depressive symptoms and withdrawal from usual
activities. Neurological examination may show hypertonia of lower
limbs, tremor, clonus, frontal release signs and hyperactive
reflexes. Terminally, the patient is bedbound, incontinent, abulic
or mute with decorticate posturing leading to death over 3 to 6
months. However, a stabilisation and even a regression of the
cognitive disorders have been observed following antiretroviral
treatment. Radiological features of HIV
dementia include both central and cortical atrophy and white matter
rarefaction. However they are neither invariable nor specific.
Together with CSF examination, they are more important to exclude
opportunistic infections. Indeed, although a completely normal CSF
profile may reasonably exclude the diagnosis; at present, no single
test or combination of tests can reliably diagnose HIV
dementia. Although the clinical characteristics of HIV-dementia
are now clearly established, its pathogenesis is unclear and its
pathological counterpart remains a matter of debate. A number of
"HIV-induced"
lesions may be found in the brain of AIDS
patients and their causative role in HIV-dementia
has been considered. They include HIV
encephalitis due to productive CNS infection by the virus, diffuse
white matter pallor "HIV-leukoencephalopathy"
reflecting an abnormality of the blood brain barrier, involvement of
the grey matter, "diffuse poliodystrophy", with neuronal
loss that results, at least partly, from a process of programmed
cell death and axonal damage. These changes are variably associated
in patients with HIV
dementia, however none of them can be closely related to the
cognitive disorders. This suggests that the neuronal dysfunction
underlying HIV-dementia
results from different mechanisms that are variably associated and
may interact mutually. These include production of viral proteins,
Microglial
activation with consequent production of neurotoxic factors such as
proinflammatory cytokines, free radicals, derivates of arachidonic
acid, or quinoleic acid, and blood borne neurotoxic factors in
particular cytokines
Janabi N, Di Stefano M, Wallon C, Hery C, Chiodi F, Tardieu M
(1998) Induction of human immunodeficiency virus type 1 replication
in human glial cells after proinflammatory cytokines stimulation:
effect of IFNgamma, IL1beta, and TNFalpha on differentiation and
chemokine production in glial cells. Glia 23:304-315
Abstract:
Although evidence for human immunodeficiency virus 1 (HIV-1)
presence in the central nervous system (CNS) of infected patients is
well established, the intensity of viral replication within the
brain is not usually known. In vitro, human embryonic Microglial
cells internalized HIV-1
through a CD4-dependent pathway but were not permissive to viral
replication. We observed that HIV
replication was induced when CNS cell cultures were stimulated for
14 days by a combination of proinflammatory cytokines including
IFNgamma, IL1beta, and TNFalpha. After long-term cytokine
stimulation, morphologically differentiated glial cells appeared, in
which HIV-1 tat antigen was
detected after infection. Thus, variations in the stage of
maturation/activation of CNS cells under inflammatory conditions
probably play a major role in facilitating massive production of
HIV-1. We then studied the
effect of prolonged cytokine stimulation on the secretion of
inflammatory mediators by glial cells. An early increased secretion
of prostaglandin F2alpha and chemokines
(RANTES>>MIP-1alpha>>MIP-1beta) was observed, due to
both Microglia
and astrocytes. In contrast to persistent PGF2alpha production, an
extinction of RANTES and MIP-1beta but not of MIP-1alpha secretion
occurred during the 14 days of stimulation and was inversely
correlated with the ability of glial cells to replicate HIV-1.
The study of the secretory factors produced in response to a
persistent inflammation could provide a better understanding of the
modulation of HIV
replication in glial cells
Kolson DL, Lavi E, Gonzalez-Scarano F (1998) The effects of
human immunodeficiency virus in the central nervous system.
Adv.Virus Res. 50:1-47
Abstract: More than a decade after the
first description of HIV
DNA in the nervous system the pathophysiology of HIVD
remains largely enigmatic, with data supporting a number of
potential mechanisms for the development of neuronal dysfunction.
Nevertheless, a few key findings have considerable support in the
literature devoted to this subject: 1. HIV
dementia is caused by HIV
itself; no other pathogen has been consistently found in the brains
of patients with HIVD. 2.
In comparison with other viral encephalopathies, there appears to be
a significant discordance between the amount of virus being produced
in the brains of patients with HIVD
and the degree of neurological deterioration. 3. The key cell types
responsible for viral production within the CNS are the resident
macrophages or Microglial
cells. 4. Other elements within the CNS, particularly astrocytes,
are probably infected with HIV
as well, but all of these infections are highly restricted in terms
of production of virus or viral structural proteins. 5. At least one
component of the pathogenesis of HIVD
may be the generation of neurotoxins by infected Microglia,
although the type of neurotoxin, and the specific compound most
likely to be involved, are quite controversial. Advances with
combination antiviral therapy have successfully reduced plasma viral
load in a high proportion of individuals, leading to the speculation
(previously almost heretical) that it may be possible to eradicate
HIV completely from the
systemic immune system. If that were the case, potential "sanctuary"
sites such as the immunologically protected CNS might remain as
important reservoirs for reseeding of lymphoid tissues. Microglia
may be particularly suited for this purpose because they are long
lived, can produce HIV for
several weeks (at least in culture), and they are apparently
relatively immune to virus-induced cytopathology such as syncytium
formation. One can speculate about several scenarios resulting from
the continued presence of replication-competent HIV
within brain. In the worst case, a smoldering infection of the
nervous system could lead to neurological deterioration without
reinfection of systemic immune cells. The epidemiological data
indicating that HIVD is a
disease primarily associated with immunodeficiency suggest that the
systemic immune system plays a role in maintaining virus residing
within the CNS under control. Thus it is quite possible that this
scenario would not occur for many years after the systemic infection
is controlled. Alternatively, virus could be transported from the
CNS by circulating lymphocytes and monocytes and reinfect systemic
organs. This would necessitate restarting therapy for those
individuals who were previously thought to be cured, but presumably
virus within the CNS would not have developed resistance to
antivirals. In either case, the techniques currently available do
not permit an accurate assessment of CNS HIV
load in living people, and this question will remain unanswered
until antivirals are discontinued in a few individuals with
persistently negative tests for systemic virus. In addition to this
most critical question, the relationship between viral levels and
HIVD is largely unexplored,
as is the possibility that some strains are particularly virulent or
neuroinvasive. Furthermore, the potential contribution of host
genotype in the development of dementia is unknown. In view of the
strong influence of major chemokine receptor (CCR5) truncations on
HIV replication, it is
entirely possible that more discrete genetic polymorphisms have a
subtle effect on either brain invasion or virulence
Lanjewar DN, Jain PP, Shetty CR (1998) Profile of central
nervous system pathology in patients with AIDS:
an autopsy study from India. AIDS
12:309-313
Abstract: OBJECTIVE: To study the spectrum of
neuropathological brain lesions in HIV/AIDS
cases. DESIGN: Retrospective autopsy study between 1988 and mid-1996
at a tertiary level public hospital. METHODS: Eighty-five adult
brains, with at least 21 sections from each, were examined using
routine and special stains. RESULTS: Risk factors in 64 men (75%)
and 21 women (25%) included heterosexual contact with multiple
sexual partners (83 cases, 98%), homosexual behaviour (one case, 1%)
and blood transfusion (one case, 1%). Central nervous system (CNS)
lesions were observed in 67 cases (79%). Opportunistic infections
were present in 33 cases (39%), which included toxoplasmosis (11
cases, 13%), tuberculosis (10 cases, 12%), cryptococcosis (seven
cases, 8%), and cytomegalovirus infection (six cases, 7%).
Multifocal myelin loss was observed in 18 cases (21%), Microglial
nodules in 15 cases (18%), and angiocentric pallor in five cases
(6%). Infarcts/haemorrhages were present in 13 cases (15%), choroid
plexitis in 21 cases (25%), lymphocytic meningitis without
opportunistic infection in 21 cases (25%), and calcification in four
cases (5%). A dual infectious pathology was observed in one case
(1%). Multinucleated giant cells and primary CNS lymphoma were not
found in any of our cases. CONCLUSIONS: Patient profile and risk
factors for AIDS in India
differ from those reported in industrialized countries. Although not
reported from India in the pre-AIDS
era, toxoplasmosis was the most frequently observed CNS
opportunistic infection in our study. CNS tuberculosis is frequently
observed in Indian AIDS
cases compared with reports from industrialized countries where its
occurrence is uncommon. Death due to systemic opportunistic
infections may punctuate the course of HIV
encephalitis and prevent its full-blown morphological expression
Lavi E, Kolson DL, Ulrich AM, Fu L, Gonzalez-Scarano F (1998)
Chemokine receptors in the human brain and their relationship to HIV
infection. J.Neurovirol. 4:301-311
Abstract: Chemokine receptors
have been recently identified as the important co-factors which in
conjunction with CD4, mediate entry of HIV
into its target cells. The brain is one of the most prominent
targets of HIV infection,
where it leads to HIV
encephalitis (HIVE) and
HIV-associated dementia.
Knowledge of the distribution, physiology, and pathology of
chemokines and chemokine receptors in the human brain is fundamental
for understanding the pathogenesis of the interaction between HIV
and the central nervous system (CNS). There is also increasing
evidence that chemokine receptors expression in the CNS increases
during pathological, especially inflammatory, conditions. The major
co-factors for HIV
infection, CCR5, CCR3, and CXCR4 have been detected in the human
brain in a variety of cell types including Microglia,
astrocytes, neurons, and vascular endothelial cells. Furthermore,
antibodies to chemokine receptors can also block HIV
infectivity in cultured CNS cells. This indicates that chemokine
receptors are likely to have a functional role in the pathogenesis
of HIVE
Levi G, Minghetti L, Aloisi F (1998) Regulation of prostanoid
synthesis in Microglial
cells and effects of prostaglandin E2 on Microglial
functions. Biochimie 80:899-904
Abstract: Brain prostanoid levels
are normally low but can increase after ischemia and during
inflammatory and infectious diseases. High prostanoid levels can
affect brain function in several ways. In particular, prostaglandin
E2 (PGE2) might exert both immunodepressive and proinflammatory
actions. The present short review focuses on the regulation of
prostanoid synthesis in Microglial
cultures and on the possible role of PGE2 in the down-regulation of
Microglial
activation induced by lipopolysaccharide (LPS). Our studies were
carried out using purified mouse or rat Microglial
cultures. LPS induced a dose-dependent expression of the inducible
isoform of cyclooxygenase (COX-2), both in neonatal and adult
Microglial
cultures. In the latter, the inducibility of COX-2 increased with
time in culture, paralleling the acquisition of a more 'activated'
Microglial
phenotype, and appeared to account for the time-dependent increase
in the PGE2/TXB2 production ratio. The LPS-induced COX-2 expression
and prostanoid production were down-regulated by potentially
neurotoxic agents, such as nitric oxide (NO), the proinflammatory
cytokine IFN-gamma (which acted both directly and indirectly,
through its NO-inducing activity) and the HIV
regulatory protein tat. On the other hand, COX-2 expression was
up-regulated by the macrophage-deactivating cytokine TGF-beta 1, by
exogenous PGE2 itself, which acted through EP2 receptors linked to
cyclic AMP generation, and by non steroidal anti-inflammatory drugs.
Interestingly, PGE2 utilized the same EP2 receptor-mediated signal
transduction mechanism to down-regulate the expression of the
inducible NO synthase and the production of NO. Largely, but not
exclusively, through its effect on cyclic AMP, PGE2 can also: i)
depress the expression of major histocompatibility complex class II
antigens and of the costimulatory molecule B7-2; ii) down-regulate
TNF and up-regulate IL-10 Microglial
production; iii) inhibit Microglial
IL-12 secretion. These observations, together with literature data
on in vivo models of central nervous system (CNS) diseases, suggest
a neuroprotective role of PGE2 in pathological conditions
Liestael K, Goplen AK, Dunlop O, Bruun JN, Maehlen J (1998) Kaposi's sarcoma and protection from HIV dementia. Science 280:361-362
Lipton SA (1998) Neuronal injury associated with HIV-1:
approaches to treatment. Annu.Rev.Pharmacol.Toxicol.
38:159-177
Abstract: Mounting evidence suggests that cognitive
dysfunction developing as a result of HIV-1
infection is mediated at least in part by generation of excitotoxins
and free radicals in the brain. This syndrome is currently
designated HIV-1-associated
cognitive/motor complex, was originally termed the AIDS
Dementia Complex, and for simplicity, is called AIDS
dementia in this review. Recently, brains of patients with AIDS
have been shown to manifest neuronal injury and apoptotic-like cell
death. How can HIV-1 result
in neuronal damage if neurons themselves are only rarely, if ever,
infected by the virus? Experiments from several different
laboratories have lent support to the existence of HIV-
and immune-related toxins in a variety of in vitro and in vivo
paradigms. In one recently defined pathway to neuronal injury,
HIV-infected macrophages
and Microglia,
or immune-activated macrophages and astrocytes (activated by the
shed HIV-1 envelope
protein, gp120, or other viral proteins and cytokines), appear to
secrete excitants and neurotoxins. These substances may include
arachidonic acid, platelet-activating factor, free radicals (NO. and
O2.-), glutamate, quinolinate, cysteine, amines, and as yet
unidentified factors emanating from stimulated macrophages and
reactive astrocytes. A final common pathway for neuronal
susceptibility is operative, similar to that observed in stroke and
several neurodegenerative diseases. This mechanism involves
excessive activation of N-methyl-D-aspartate (NMDA)
receptor-operated channels, with resultant excessive influx of Ca2+
and the generation of free radicals, leading to neuronal damage.
With the very recent development of clinically tolerated NMDA
antagonists, there is hope for future pharmacological intervention
Lokensgard JR, Chao CC, Gekker G, Hu S, Peterson PK (1998)
Benzodiazepines, glia, and HIV-1
neuropathogenesis. Mol.Neurobiol. 18:23-33
Abstract: Although the
precise mechanisms whereby HIV-1
infection induces neurodegeneration have yet to be determined, a
great deal of evidence has incriminated glial cells and the
production of proinflammatory mediators in this pathologic process.
For this reason, ideal therapeutic agents for the treatment of AIDS
dementia would attenuate HIV-1
neuropathogenesis through both direct inhibition of viral expression
and suppression of brain cell-produced immune mediators.
Benzodiazepines (BDZs), such as Valium, are extensively prescribed
drugs for anxiety disorders, which readily cross the blood-brain
barrier and have demonstrated immunomodulatory properties. BDZs bind
to primary human Microglial
cells, the principal site of HIV-1
replication in the brain, and inhibit lipopolysaccharide (LPS)
induced tumour necrosis factor (TNF-alpha) production by these cells
in a concentration-dependent manner. Treatment of HIV-1-infected
primary human Microglial,
as well as mixed glial/neuronal, cell cultures with BDZs inhibits
the expression of HIV-1 p24
antigen. BDZ-induced inhibition of HIV-1
expression in chronically infected promonocytic (U1) cells has been
found to be associated with decreased activation of the nuclear
transcription factor kappa B (NF-kappa B). Because HIV-1
expression is critically dependent on the cellular transcription
machinery, inhibition of the activation of transcription factors,
which participate in both HIV-1
expression and the production of neurotoxic immune mediators, by BDZ
analogs may provide new therapeutic options for AIDS
dementia
McCarthy M, He J, Wood C (1998) HIV-1
strain-associated variability in infection of primary neuroglia.
J.Neurovirol. 4:80-89
Abstract: Qualitative differences among
strains of Human Immunodeficiency Virus type 1 (HIV-1)
may influence viral infectivity for cells of the central nervous
system (CNS) and determine or at least significantly influence the
neuropathogenesis of brain infection. In this study, we compared
infectivity for these cells in vitro among several different
laboratory-adapted HIV-1
strains differing in cellular tropism. These strains included three
lymphotropic strains (SF2, NL4-3, and SG3.1), two macrophage-tropic
strains (SF128A, SF162), and one brain-derived strain (YU2). In
Microglia,
macrophage-tropic strain SF128A established productive infection
while the lymphotropic strain SF2 did not. In infected astrocytes,
all HIV-1 strains
transiently produced variable and much lower levels of p24 antigen.
Viral DNA env or tat gene sequences were amplified from infected
astrocytes; the amplified signals varied among HIV-1
strains, but the strongest viral DNA signals were obtained from
cells infected by the lymphotropic strains SF2 and SG3.1.
Transfection of astrocytes with infectious HIV-1
proviral DNA clones confirmed the observation that HIV-1
strains differ in their ability to replicate in astrocytes.
Transfection revealed post-entry blocks to replication by
macrophage-tropic proviruses pSF128A and pSF162. However,
cytomegalovirus (CMV) superinfection of transfected astrocytes
enhanced p24 production by lymphotropic HIV-1
proviruses twofold and stimulated p24 production by the otherwise
inactive macrophage-tropic proviruses. This study demonstrates the
spectrum of HIV-1
strain-associated variation in infectivity for neuroglia, and
suggests, in addition, that herpesviral factors or viral-induced
cellular factors may stimulate HIV-1
infection in astrocytes and expand the neural cell tropism of
certain HIV-1 strains
McManus CM, Brosnan CF, Berman JW (1998) Cytokine induction
of MIP-1 alpha and MIP-1 beta in human fetal Microglia.
J.Immunol. 160:1449-1455
Abstract: Leukocyte infiltration into
the central nervous system (CNS) is a key event in the inflammatory
processes of neuroimmunologic diseases. Microglia,
resident macrophages of the CNS, may contribute to this process by
elaborating chemoattractants that are capable of recruiting
leukocytes across the blood-brain barrier. Such factors have been
detected in the CNS of animal models of multiple sclerosis and in
the brains of human and nonhuman primates with AIDS
encephalitis. As the expression of these chemoattractants may play
an important role in the initiation and progression of
neuroimmunologic diseases, we analyzed expression of the chemokines
MIP-1 alpha, MIP-1 beta, MCP-1, and RANTES in human fetal Microglial
cultures. Unstimulated Microglia
expressed minimal levels of MIP-1 alpha, MIP-1 beta, and MCP-1,
while RANTES was undetectable. In response to LPS, TNF-alpha, or
IL-1 beta, both MIP-1 alpha and MIP-1 beta were induced at the mRNA
and protein levels in a dose- and time-dependent manner. IFN-gamma
did not significantly induce chemokine expression. MCP-1 was
detectable in LPS- and cytokine-treated Microglia.
TGF-beta, a cytokine with down-modulatory effects on other cell
types, had little effect on chemokine expression in Microglia
when used concomitantly before or during treatment with LPS. These
results illustrate the ability of certain inflammatory stimuli to
induce expression of MIP-1 alpha, MIP-1 beta, and MCP-1 by human
fetal Microglia.
The expression of these chemoattractants may function to recruit
inflammatory cells into the CNS during the course of
neuroimmunologic diseases and may modulate the ability of HIV
to infect the CNS
Montgomery MM, Wood A, Stott EJ, Sharp C, Luthert PJ (1998)
Changes in neuron size in cynomolgus macaques infected with various
immunodeficiency viruses and poliovirus. Neuropathol.Appl.Neurobiol.
24:468-475
Abstract: Human immunodeficiency virus (HIV)
infection leads to clinically significant neuronal pathology, but
the underlying mechanism remains unclear. Infection of rhesus
macaques with the simian immunodeficiency virus SIVmac251 has been
shown to cause atrophy of hippocampal pyramidal cells. The aim of
the current investigation was to determine whether SIVmac251 and
other viruses with differing abilities to cause immune suppression
or encephalitis could cause neuronal atrophy in cynomolgus macaques.
Animals infected with SIVmac251 (n = 22), HIV-2
(n = 6). SIVmac239 (n = 7) and poliovirus (n = 10) were
investigated, together with 16 controls. Hippocampal pyramidal cell
diameter, averaged across the four CA subfields, was reduced by
16.6% in the SIVmac251 group (P < 0.0001) and by 13.3% in the
HIV-2 group (P < 0.001),
even though the latter virus does not generally cause
immunosuppression. Conversely, SIVmac239, which does cause
immunosuppression, caused an average neuronal hypertrophy of 6.8% (P
= 0.033). Of possible relevance to the different behaviour of the
two SIVs is that SIVmac239 is lymphocyte tropic and does not infect
CNS Microglia
in vivo whereas SIVmac251 does. Animals inoculated with poliovirus
into the lumbar spinal cord for polio vaccine neurovirulence testing
acted as positive controls for CNS inflammation and they also showed
an increase in neuronal diameter (4.1%, P = 0.025). The atrophy seen
with SIVmac251 and HIV-2
involved all CA subfields but the hypertrophy following SIVmac239 or
poliovirus infection was restricted to CA1 and CA2. These
observations show a dissociation between the ability of
immunodeficiency viruses to cause immune suppression and neuronal
pathology and demonstrate that CNS inflammation per se may cause
neuronal hypertrophy
Nishiyori A, Minami M, Ohtani Y, Takami S, Yamamoto J,
Kawaguchi N, Kume T, Akaike A, Satoh M (1998) Localization of
fractalkine and CX3CR1 mRNAs in rat brain: does fractalkine play a
role in signaling from neuron to Microglia?
FEBS Lett. 429:167-172
Abstract: Localization of the mRNAs for
fractalkine, a CX3C chemokine, and for its receptor CX3CR1 was
investigated in the rat brain. In situ hybridization study revealed
that fractalkine mRNA was dominantly expressed in neuronal cells
particularly in the olfactory bulb, cerebral cortex, hippocampus,
caudate putamen and nucleus accumbens. In vitro study using enriched
neuronal or glial culture supported the dominant expression of
fractalkine mRNA in neurons. On the other hand, CX3CR1 mRNA was
dominantly expressed in glial cells throughout the whole brain. The
in vitro study suggested the cells expressing CX3CR1 mRNA are
Microglia,
not astrocytes or neurons. Fractalkine appears to function as a
signal molecule from neuron to Microglia
Power C, McArthur JC, Nath A, Wehrly K, Mayne M, Nishio J,
Langelier T, Johnson RT, Chesebro B (1998) Neuronal death induced by
brain-derived human immunodeficiency virus type 1 envelope genes
differs between demented and nondemented AIDS
patients. J.Virol. 72:9045-9053
Abstract: Human immunodeficiency
virus type 1 (HIV-1)
infection of the brain results in viral replication primarily in
macrophages and Microglia.
Despite frequent detection of viral genome and proteins in the
brains of AIDS patients
with and without HIV
dementia, only 20% of AIDS
patients become demented. To investigate the role of viral envelope
gene variation in the occurrence of dementia, we examined regions of
variability in the viral envelope gene isolated from brains of AIDS
patients. Brain-derived HIV-1
V1-V2 envelope sequences from seven demented and six nondemented
AIDS patients displayed
significant sequence differences between clinical groups, and by
phylogenetic analysis, sequences from the demented group showed
clustering. Infectious recombinant viruses containing brain-derived
V3 sequences from both clinical groups were macrophagetropic, and
viruses containing brain-derived V1, V2, and V3 sequences from both
clinical groups spread efficiently in macrophages. In an indirect in
vitro neurotoxicity assay using supernatant fluid from
HIV-1-infected macrophages,
recombinant viruses from demented patients induced greater neuronal
death than viruses from nondemented patients. Thus, the HIV-1
envelope diversity observed in these patient groups appeared to
influence the release of neurotoxic molecules from macrophages and
might account in part for the variability in occurrence of dementia
in AIDS patients
Rafalowska J (1998) HIV-1-infection
in the CNS. A pathogenesis of some neurological syndromes in the
light of recent investigations. Folia Neuropathol.
36:211-216
Abstract: The main factors in the pathogenesis of
AIDS-dementia complex (ADC)
are analyzed. The author suggests that these factors can be divided
into two groups. The "nonspecific" factors present in
every immunologic processes manifested by inflammation compose the
first group. They are cytotoxic lymphocytes T, the immunoactivation
of infected macrophages, cytokines, NO, NOS and iNOS, the increase
of the BBB permeability, the accumulation of beta-amyloid precursor
protein, excitotoxic amino acids, various and numerous cells
adhesion molecules. The second group may contain factors connected
with HIV-1 infection of
CNS. In the pathogenesis of AIDS
an important role is played by toxic glycoproteins gp 120 and gp 41
which are in the coat of HIV-1
virus, nucleotide sequences variability, possibility of various
virus replication in various parts of CNS, the participation of
lymphokines IL-4 and IL-10, and presence of co-receptors to HIV-1
virus on lymphocytes, macrophages, neurons and Microglial
cells
Sanders VJ, Pittman CA, White MG, Wang G, Wiley CA, Achim CL
(1998) Chemokines and receptors in HIV
encephalitis. AIDS
12:1021-1026
Abstract: BACKGROUND: Chemokines are involved in the
migration of leukocytes and have been implicated in several
inflammatory diseases of the central nervous system. Some of their
receptors have been proposed to mediate HIV
infection. OBJECTIVE: To determine changes in chemokine and receptor
expression in HIV
encephalitis, and to determine whether upregulation leads to
recruitment of infected monocytes across the blood-brain barrier and
participates in HIV
neuropathology. METHODS: Immunocytochemistry and double-label
immunofluorescent laser confocal microscopy was performed with
antibodies to chemokines and their receptors on brain tissues from
patients who died with or without HIV
encephalitis. In vivo distribution was compared with in vitro
cultures of human neuroglial cells. RESULTS: The beta-chemokines
monocyte chemotactic protein-1, macrophage inflammatory
protein-1alpha, and RANTES were detected on brain macrophages. Their
presence was associated with the histopathological signs of HIV
encephalitis. The alpha-chemokines IP-10 (10 kDa inflammatory
protein) and interleukin-8 were expressed by astrocytes in all
tissues, including controls. Presence of the CXC-chemokine receptor
(CXCR)-4 was seen on brain macrophages/Microglia,
neurons, and astrocytes. CC-Chemokine receptor (CCR)-5 was detected
only on macrophages/Microglia.
CCR-3 and CCR-1 were expressed by macrophages and endothelial cells.
In vitro studies examining the presence of CCR-3, CCR-5, and CXCR-4
on human brain cell cultures demonstrated abundant neuronal and
Microglial
expression. CONCLUSIONS: Expression of a variety of chemokines and
receptors was shown to be increased in HIV
encephalitis brain tissues particularly in areas of neuroglial
reaction. The expression pattern supported their involvement in the
recruitment of inflammatory infiltrates and formation of Microglial
nodules. Presence of chemokine receptors on neurons may be involved
in the pathogenesis of neurologic damage in AIDS
patients
Scorziello A, Florio T, Bajetto A, Schettini G (1998)
Intracellular signalling mediating HIV-1
gp120 neurotoxicity. Cell Signal. 10:75-84
Abstract: During the
last few years several studies have been undertaken to characterise
the role of gp120, the HIV-1
envelope glycoprotein, in the pathogenesis of neurological defects
associated with AIDS.
However, neurons did not appear to be the main target of the virus,
since the widespread neuronal damage is not associated with a
productive viral infection in neurons. The current opinion supports
the hypothesis that an indirect mechanism exists to explain the
neuronal cell death which occurs in patients infected by HIV-1.
In particular, several reports suggest that gp120 may be the main
candidate as mediator of the neurological deficits during HIV-1
infection and demonstrate that this molecule affects neuronal
survival through a direct interaction with non-neuronal cell types
such as monocytes, macrophages/Microglia
and astrocytes
Shieh JT, Albright AV, Sharron M, Gartner S, Strizki J, Doms
RW, Gonzalez-Scarano F (1998) Chemokine receptor utilization by
human immunodeficiency virus type 1 isolates that replicate in
Microglia.
J.Virol. 72:4243-4249
Abstract: The role of human
immunodeficiency virus (HIV)
strain variability remains a key unanswered question in HIV
dementia, a condition affecting around 20% of infected individuals.
Several groups have shown that viruses within the central nervous
system (CNS) of infected patients constitute an independently
evolving subset of HIV
strains. A potential explanation for the replication and
sequestration of viruses within the CNS is the preferential use of
certain chemokine receptors present in Microglia.
To determine the role of specific chemokine coreceptors in infection
of adult Microglial
cells, we obtained a small panel of HIV
type 1 brain isolates, as well as other HIV
strains that replicate well in cultured Microglial
cells. These viruses and molecular clones of their envelopes were
used in infections, in cell-to-cell fusion assays, and in the
construction of pseudotypes. The results demonstrate the predominant
use of CCR5, at least among the major coreceptors, with minor use of
CCR3 and CXCR4 by some of the isolates or their envelope clones
Soontornniyomkij V, Wang G, Pittman CA, Wiley CA, Achim CL
(1998) Expression of brain-derived neurotrophic factor protein in
activated Microglia
of human immunodeficiency virus type 1 encephalitis.
Neuropathol.Appl.Neurobiol. 24:453-460
Abstract: The role of
neurotrophic factors and their therapeutic potential have been
investigated in various neurodegenerative disorders. In
neurodegeneration associated with human immunodeficiency virus (HIV)
infection, neuronal function and survival may be affected by
abnormal neurotrophic regulation involving HIV-infected
Microglia
and reactive astrocytes. To characterize the cellular localization
of brain-derived neurotrophic factor (BDNF) and its high-affinity
tyrosine kinase receptor, trkB, proteins in HIV-1
encephalitis, we examined post-mortem brains from patients with
acquired immunodeficiency syndrome and brains from non-HIV-infected
controls. Using double immunofluorescent confocal microscopy, we
found that BDNF immunoreactivity was distributed in neocortical
neuronal perikarya and neuritic processes, while in the striatum
only neurites were BDNF-immunoreactive. Additionally, the striatum
with HIV infection was
characterized by BDNF immunoreactivity in infiltrating activated
Microglia/macrophages
and multinucleated giant cells. Catalytic trkB receptor
immunoreactivity was observed in neuronal perikarya in the neocortex
and striatum, as well as in reactive astrocytes within HIV-infected
regions. Our findings suggest that expression of BDNF by activated
Microglia
in HIV-1 encephalitis may
affect neuronal survival and astroglial response through
corresponding trkB receptors
Suzumura A, Sawada M, Makino M, Takayanagi T (1998)
Propentofylline inhibits production of TNFalpha and infection of
LP-BM5 murine leukemia virus in glial cells. J.Neurovirol.
4:553-559
Abstract: We examined the effects of a xanthine
derivative, propentofylline, on TNFalpha production by glial cells
and on infection ofglial cells with a murine leukemia virus, LP-BM5,
which induces murine AIDS
in susceptible mice. Propentofylline suppressed TNFalpha production
in glial cells and also effectively suppressed infection ofglial
cells with LP-BM5 in vitro. Addition ofTNFalpha, but not IL-1 or
IL-6, abolished the suppressive effects ofpropentofylline.
Anti-TNFalpha antibody also suppressed infection of LP-BM5 in these
cells. These findings suggest that propentofylline suppressed LP-BM5
infection in glial cells by suppressing TNFalpha production by these
cells. Because propentofylline reportedly passes through the
blood-brain barrier, it may be useful in the treatment of central
nervous system involvement by HIV
infection or neurological diseases in which TNFalpha plays a
causative role, such as multiple sclerosis
Tan SV, Guiloff RJ (1998) Hypothesis on the pathogenesis of
vacuolar myelopathy, dementia, and peripheral neuropathy in AIDS.
J.Neurol.Neurosurg.Psychiatry 65:23-28
Abstract: Certain aspects
of the clinical syndrome of dementia, cerebral atrophy,
predominantly sensory neuropathy, and vacuolar myelopathy in AIDS
resemble those seen in vitamin B12 deficiency. Pathologically, there
are similarities not only in the changes in the spinal cord, but
also in the brain and peripheral nerves. The pathogenesis of
vacuolar myelopathy may be secondary to a combination of immune
mediated myelin and oligodendrocyte injury, and simultaneous
impairment of repair mechanisms due to a deficiency of
S-adenosylmethionine (SAM). Products derived from macrophages may
interfere directly with the methyl transfer cycle through the
generation of reactive oxygen intermediates and reactions involving
nitric oxide and peroxynitrite which may limit the supply of
methionine for conversion to SAM, both by direct interaction as well
as through inhibition of methionine synthase. Macrophage activation
with secretion of cytokines and other biologically reactive
substances within the nervous system is sustained in the late stages
of HIV infection by the
general effects of immune depletion, including loss of T cells (with
concomitant reduction of macrophage regulatory molecules) and
recurrent opportunistic infections, and may be further augmented by
the local presence of the virus itself (or its surface glycoprotein
gp120). This would account for the common, but not exclusive,
occurrence of vacuolar myelopathy in AIDS.
The ability of the virus and its products to stimulate macrophage
and Microglial
activation may also explain the association between severity of
vacuolar myelopathy and the presence of HIV
encephalitis. A similar mechanism may underlie the pathogenesis of
dementia, cerebral atrophy, and peripheral neuropathy. Local factors
or differential susceptibility between the central and peripheral
nervous system may determine whether myelinotoxic or neurotoxic
processes predominate; the prominence of myelin involvement in the
spinal cord, and axonal involvement peripherally may reflect both
ends of this range, with the brain manifesting a more equal balance
of both processes
Yeung MC, Geertsma F, Liu J, Lau AS (1998) Inhibition of
HIV-1 gp120-induced
apoptosis in neuroblastoma SK-N-SH cells by an antisense
oligodeoxynucleotide against p53. AIDS
12:349-354
Abstract: OBJECTIVES: This study examines the
cytotoxicity potential and the mechanism of toxicity of the HIV-1
gp120 on human neuroblastoma cells. DESIGN: Previous data from our
group have suggested that the HIV-1
envelope protein gp120 promotes the secretion of tumor necrosis
factor-alpha and other factors by astrocytes and Microglial
cells present in primary human brain cell cultures, thereby
contributing to the injury of neurons in these cultures. This study
investigates the cytotoxicity potential and the mechanism of
toxicity of gp120 on human neuroblastoma cells. METHODS: SK-N-SH
cells were treated with HIV-1
gp120, and was followed by in situ DNA fragmentation staining and
small molecular weight DNA extraction studies to ascertain the
induction of apoptosis by gp120 in these cells. To evaluate a
potential role of the growth suppressor gene p53, gp120-treated
SK-N-SH cells were subjected to reverse transcription polymerase
chain reaction (RT-PCR) and Western blot analyses for the induction
of p53. An antisense oligodeoxynucleotide against p53 was used to
investigate the role of p53 in the gp120-induced apoptosis in these
cells. RESULTS: Data from T7 DNA polymerase staining and small
molecular weight DNA extraction studies demonstrated that
gp120-induced DNA breakage in SK-N-SH cells with fragmentation
patterns characteristic of apoptosis. RT-PCR and Western blot
analyses revealed that the gp120-mediated induction of apoptosis was
dependent on a gp120-induced and gp120-sustained upregulation of
p53. The induction of p53 by gp120 was specific, since an antibody
against gp120 prevented both the induction of p53 and subsequent
apoptosis in SK-N-SH cells. The critical role of p53 was further
illustrated by the effectiveness of a p53 antisense
oligodeoxynucleotide to inhibit the gp120-induced apoptosis. As a
control, the apoptosis-inducing potential of gp120 on SK-N-SH cells
was not seen in the HIV-1
Gag proteins even when used at up to 5 nM. CONCLUSIONS: These
results established that HIV-1
gp120 is potentially cytotoxic to human neuronal cells through the
induction of p53, which may eventually lead to induction of
apoptosis
Belichenko PV, Miklossy J, Celio MR (1997) HIV-I
induced destruction of neocortical extracellular matrix components
in AIDS victims.
Neurobiol.Dis. 4:301-310
Abstract: Neurological dysfunction is
not uncommon in patients suffering from acquired immunodeficiency
syndrome (AIDS) and, when
manifested, intimates involvement of the central nervous system.
Here, the human immunodeficiency virus (HIV)
infects preferentially Microglial
cells, which thereby release substances known to interfere with
neuronal function. One class of agents set free in this manner are
proteases; these degrade certain components within, and thereby
undermine the integrity of, the extracellular matrix (ECM)
compartment, which plays a vital role in cell-to-cell communication.
We wished to ascertain whether the ECM compartment is indeed
disrupted in the brains of AIDS
victims. We examined the neocortical areas of 27 AIDS
autopsy cases, including 9 with diagnosed HIV-encephalopathy
(HIVE); 8 HIV-seronegative
cases with various types of brain lesion, including viral
infections, were also included in this study. HIV-antigens
and DNA were identified by use of immunohistochemistry and in situ
hybridization, and ECM components by lectin staining and
immunohistochemistry. Of the 27 AIDS
cases examined, each of the 9 with HIVE
was completely devoid of labeled ECM components; 8 of the 18 without
HIVE had incurred
substantial losses, and only 2 manifested a normal complement of
constituents within this compartment. With respect to stratal and
topographic variations, layers II and III were less affected than
layers V to VII, as was the frontal cortex relative to other areas.
These findings confirmed our expectations of the brain's ECM
undergoing degradation following HIV
infection, and these changes may well underlie the neurological
disturbances manifested in AIDS
patients
Cunningham AL, Naif H, Saksena N, Lynch G, Chang J, Li S,
Jozwiak R, Alali M, Wang B, Fear W, Sloane A, Pemberton L, Brew B
(1997) HIV infection of
macrophages and pathogenesis of AIDS
dementia complex: interaction of the host cell and viral genotype.
J.Leukoc.Biol. 62:117-125
Abstract: AIDS
dementia complex (ADC) develops in only a third of HIV-infected
patients who progress to AIDS.
Macrophages and Microglial
cells are the major cellular sites of productive HIV
replication in brain. Using 11 blood isolates of HIV
from asymptomatic patients there was marked variation in tropism and
the level of productive infection in recently adherent monocytes and
monocyte-derived macrophages cultured in vitro. However, less
variation was seen with 19 blood isolates from advanced HIV
infection and 11 postmortem tissue isolates from brain,
cerebrospinal fluid, spleen, and lung. Newly adherent monocytes
expressed CCR5 in all seven patients tested, consistent with their
susceptibility to infection but not explaining the above
variability. There is, also marked regional variability in
neuropathology in the brain of patients with ADC. We have
demonstrated that there was marked variation in the V3 sequences of
HIV clones from different
regions of the cortex of a patient with ADC, suggesting independent
evolution of HIV
replication in brain. Furthermore, production of the neurotoxin
quinolinic acid from HIV-infected
macrophages varied, depending on the host and source of HIV
isolate. Hence variations in viral genotype, production by infected
macrophages, and subsequent toxin production may contribute to the
variability in neuropathology between individuals and between
different regions of the brain in the same individual
Dal Canto MC (1997) Mechanisms of HIV
infection of the central nervous system and pathogenesis of
AIDS-dementia complex.
Neuroimaging Clin.N.Am. 7:231-241
Abstract: In many patients with
AIDS, severe neurologic
deficits develop that have been designated the cf2HIV-associated
cognitive-motor complex. cf1 Pathologically, these symptoms
correlate with a low-grade inflammatory condition, referred to as
cf2HIV encephalitis,cf1 in
which the most characteristic change is the presence of
multinucleated giant cells. Cortical changes include neuronal loss
and alterations of dendrites and synapses. There is pallor of white
matter generally associated with the mononuclear inflammatory
infiltrates. The only cells that seem to be directly infected by HIV
are the Microglia/monocyte
and the giant cells derived from fusion of monocytes. It is
hypothesized, therefore, that cortical and white matter alterations
in patients with this syndrome depend on the production of injurious
soluble factors liberated by these cells and by astrocytes under the
influence of many of these same factors. This article reviews recent
advances in the understanding of these secondary effects and
discusses pathogenetic mechanisms of tissue injury
Dick AD, Pell M, Brew BJ, Foulcher E, Sedgwick JD (1997)
Direct ex vivo flow cytometric analysis of human Microglial
cell CD4 expression: examination of central nervous system biopsy
specimens from HIV-seropositive
patients and patients with other neurological disease. AIDS
11:1699-1708
Abstract: OBJECTIVE: To define a clear ex vivo flow
cytometric phenotype for adult human Microglia
that would distinguish it from all other macrophage lineage cells in
the central nervous system (CNS) or blood, and to utilize this
phenotype to examine the activation state and CD4 expression of
Microglia
freshly derived from CNS tissue of HIV-positive
patients and those with other neurological diseases. DESIGN: Fresh
human CNS tissue from both HIV-uninfected
and HIV-infected
individuals was obtained by biopsy or resection, and cells isolated
immediately, labelled for flow cytometry and analysed. METHODS: A
Percoll density gradient isolation technique and phenotypic
characteristics used for rodent Microglia
were applied and modified. RESULTS: Resident Microglia
could clearly be defined by the flow cytometric phenotype CD45low
CD4- CD11b+ CD11chigh major histocompatibility complex (MHC) class
II+
Fiala M, Looney DJ, Stins M, Way DD, Zhang L, Gan X,
Chiappelli F, Schweitzer ES, Shapshak P, Weinand M, Graves MC, Witte
M, Kim KS (1997) TNF-alpha opens a paracellular route for HIV-1
invasion across the blood-brain barrier. Mol.Med.
3:553-564
Abstract: BACKGROUND: HIV-1
invades the central nervous system early after infection when
macrophage infiltration of the brain is low but myelin pallor is
suggestive of blood-brain-barrier damage. High-level plasma viremia
is a likely source of brain infection. To understand the invasion
route, we investigated virus penetration across in vitro models with
contrasting paracellular permeability subjected to TNF-alpha.
MATERIALS AND METHODS: Blood-brain-barrier models constructed with
human brain microvascular endothelial cells, fetal astrocytes, and
collagen I or fibronectin matrix responded in a dose-related fashion
to cytokines and ligands modulating paracellular permeability and
cell migration. Virus penetration was measured by infectious and
quantitative HIV-1 RNA
assays. Barrier permeability was determined using inulin or dextran.
RESULTS: Cell-free HIV-1
was retained by the blood-brain barrier with close to 100%
efficiency. TNF-alpha increased virus penetration by a paracellular
route in a dose-dependent manner proportionately to basal
permeability. Brain endothelial cells were the main barrier to
HIV-1. HIV-1
with monocytes attracted monocyte migration into the brain chamber.
CONCLUSIONS: Early after the infection, the blood-brain barrier
protects the brain from HIV-1.
Immune mediators, such as TNF-alpha, open a paracellular route for
the virus into the brain. The virus and viral proteins stimulate
brain Microglia
and macrophages to attract monocytes into the brain. Infiltrating
macrophages cause progression of HIV-1
encephalitis
Gelman BB, Wolf DA, Rodriguez-Wolf M, West AB, Haque AK,
Cloyd M (1997) Mononuclear phagocyte hydrolytic enzyme activity
associated with cerebral HIV-1
infection. Am.J.Pathol. 151:1437-1446
Abstract: In patients with
HIV encephalitis, activated
macrophages and Microglial
cells in the brain are infected by the human immunodeficiency virus
(HIV-1). Immune activation
can release neurotoxic chemicals including cytokines, free radicals,
autocoids, and hydrolytic enzymes. In this study, the presence of
hydrolytic enzymes in acquired immune deficiency syndrome
(AIDS)-related
neurodegeneration was addressed. Activities of four lysosomal
hydrolases were assayed in the frontal lobe of 69 males who died
with AIDS and 31
age-matched control men. Activities of all four enzymes were
increased significantly (1.6 to 3.6 times) in white matter of
patients with AIDS. Less
pronounced increases were present in cerebral cortex. Of 69 of the
subjects with AIDS, 50
(72%), had at least one abnormally active enzyme. Patients with HIV
encephalitis and other neuropathological changes were affected as
were many subjects without any clear neuropathological anomaly.
Lysosomal cathepsin D immunostaining revealed increased lysosomes
within perivascular macrophages, multinucleated cells, activated
Microglial
cells, and hypertrophic astrocytes. Increased enzyme activity was
correlated significantly with assay results for HIV-1
DNA using the polymerase chain reaction. The release of acid
hydrolases associated with cerebral HIV-1
infection could lead to unopposed hydrolysis of matrix and surface
proteins. These post-translational disturbances could contribute to
white matter and synaptic injury in AIDS
Gonzalez-Scarano F, Strizki JM, Albright A, Shieh J (1997) Use of primary CNS cultures to investigate HIV neurotropism. J.Neurovirol. 3 Suppl 1:S11-S13
Goodkin K, Wilkie FL, Concha M, Asthana D, Shapshak P, Douyon
R, Fujimura RK, LoPiccolo C (1997) Subtle neuropsychological
impairment and minor cognitive-motor disorder in HIV-1
infection. Neuroradiological, neurophysiological,
neuroimmunological, and virological correlates. Neuroimaging
Clin.N.Am. 7:561-579
Abstract: HIV-1
infection of brain may be associated with multiple treatment
targets, only the most severe of which is represented by HAD.
Focusing on earlier treatment targets such as MCMD and
cognitive-motor impairment in the absence of any clinical disorder
(as well as neuroprotection) may prove to be of greater clinical
utility in the treatment and prevention of such impairment than a
focus on later-stage cognitive-motor disease, when neuronal cell
death is already extensive. This may be especially important now
that improvements using the protease inhibitors in triple-drug
combination regimens have reduced plasma viral load to unmeasurable
levels, while these drugs do not penetrate the CSF well. Currently,
peripheral blood markers do not appear to be highly sensitive for
central nervous system impairment, and specific CSF laboratory
markers have some limited value at present-while requiring a lumbar
puncture to obtain. Hence, a role for noninvasive techniques using
neuroimaging exists in the clinical management of HIV-1-infected
patients. To date, structural imaging techniques have proven limited
in value for HIV-1-specific
impairment. Several functional techniques (PET, SPECT, and MR
spectroscopy) have now provided promising results for the purposes
of identifying clinically significant dysfunction, relating such
dysfunction to clinical neuropsychiatric symptom status, and for
treatment response monitoring. Further studies are needed to examine
the extent to which such imaging modalities not only parallel
clinically relevant aspects of HIV-1
disease progression, but also match specific types of
neuropsychologic performance deficits with potential significance
for neuroanatomical localization. It is particularly important to
include neurophysiological, neuroimmunological, and virological
measures in studies that examine clinical neuropsychiatric status
with neuroimaging techniques. In addition, the inclusion of
neuropathology data, where possible, is important because
demonstration of HIV-1
encephalitis cannot be equated with clinical disorder and because
specific HIV-1-associated
pathological changes have not yet been proven to be assessed well
with neuroimaging techniques (e.g., the extent of Microglial
cell and macrophage activation). Also, treatment response studies
are needed in conjunction with primary antiretroviral therapy
regimens specifically aimed at central nervous system penetration
(e.g., GW1592, GW141, and nevirapine). The results of such work will
provide the data required to determine whether these promising
functional neuroimaging techniques will aid in meeting the expected,
imminent increase in clinical burden of this frequent complication
of HIV-1 infection
Gray F (1997) [Lesions of the central nervous system in the
early stages of human immunodeficiency virus infection].
Rev.Neurol.(Paris) 153:629-640
Abstract: Early HIV-1
invasion of the central nervous system has been demonstrated by many
cerebrospinal fluid studies; however, most HIV-1
carriers remains neurologically unimpaired during the so called
"asymptomatic" period lasting from seroconversion to
symptomatic AIDS.
Therefore, there are very few neuropathological studies in the early
pre-AIDS stages and the
natural history of central nervous system changes in HIV-1
infection remains poorly understood. Examination of brains of
asymptomatic HIV-1 positive
individuals who died accidentally and of rare cases with acute fatal
encephalopathy revealing HIV
infection, and comparison with experimental simian immunodeficiency
virus and feline immunodeficiency virus infections suggest that
invasion of the CNS by HIV-1
occurs at the time of primary infection and induces an immunological
process in the central nervous system. This includes an inflammatory
T-cell reaction with vasculitis and leptomeningitis, and immune
activation of brain parenchyma with increased number of Microglial
cells, upregulation of major histocompatibility complex class II
antigens and local production of cytokines. Myelin pallor and
gliosis of the white matter are usually found are likely to be the
consequence of opening of the blood brain barrier due to vasculitis;
direct damage to oligodendrocytes by cytokines may also interfere.
These white matter changes may explain, at least partly, the early
cerebral atrophy observed, by magnetic resonance imaging, in
asymptomatic HIV-1
carriers. In contrast, cortical damage seems to be a late event in
the course of HIV-1
infection. There is no significant neuronal loss at the early stages
of the disease, no accompanying increase in glial fibrillary acid
protein staining in the cortex, and only exceptional neuronal
apoptosis. Although HIV-1
proviral DNA may be demonstrated in a number of brains, viral
replication remains very low during the asymptomatic stage of HIV-1
infection. This makes it likely that, although opening of the blood
brain barrier may facilitate viral entry into the brain, specific
immune responses including both neutralising antibodies and
cytotoxic T-lymphocytes, continuously inhibits viral replication at
that stage
Hao HN, Chiu FC, Losev L, Weidenheim KM, Rashbaum WK, Lyman
WD (1997) HIV infection of
human fetal neural cells is mediated by gp120 binding to a cell
membrane-associated molecule that is not CD4 nor galactocerebroside.
Brain Res. 764:149-157
Abstract: HIV
infection of central nervous system (CNS) tissue is a common finding
in both adult and pediatric AIDS.
Because most children are believed to be infected perinatally, we
have developed a model of HIV
CNS infection that utilizes explant organotypic cultures of human
fetal CNS tissue. Using this model we previously reported that both
lymphocytotropic and monocytotropic HIV
isolates infect Microglia
and astrocytes. However, the mechanism by which HIV
infects these cells remains to be elucidated. We have observed that
neural cell infection in these cultures may be the result of
receptor-mediated endocytosis. In order to confirm this observation
and to determine the ligand responsible for this process,
organotypic cultures were exposed to untreated HIV,
HIV pretreated with soluble
CD4 (sCD4) or, as a control, heat-inactivated HIV.
To address the question of a putative receptor for HIV
infection, CNS cultures were either untreated or pretreated with
gp120 or with the deglycosylated form of this protein. Other
cultures were treated with antibodies to CD4 (anti-T4A) or to
galactocerebroside (GC). Results demonstrate that pretreatment of
either HIV with sCD4 or CNS
cultures with gp120 significantly inhibits HIV
infection. The inhibition of infection was demonstrated by a
reduction in the number of cells positive for HIV
proteins and by decreases in HIV
proviral DNA and p24 production. Pretreatment of CNS cultures with
deglycosylated gp120, anti-T4A or anti-GC antibodies did not inhibit
HIV infection. These data
suggest that HIV gp120 is
needed for binding to a surface molecule on CNS cells that is not
CD4 nor GC and that this molecule may function as a receptor and
lead to infection of neural cells
He J, Chen Y, Farzan M, Choe H, Ohagen A, Gartner S,
Busciglio J, Yang X, Hofmann W, Newman W, Mackay CR, Sodroski J,
Gabuzda D (1997) CCR3 and CCR5 are co-receptors for HIV-1
infection of Microglia.
Nature 385:645-649
Abstract: Several members of the chemokine
receptor family are used together with CD4 for HIV-1
entry into target cells. T cell line-tropic (T-tropic) HIV-1
viruses use the chemokine receptor CXCR4 as a co-receptor, whereas
macrophage-tropic (M-tropic) primary viruses use CCR5 (refs 2-6).
Individuals with defective CCR5 alleles exhibit resistance to HIV-1
infection, suggesting that CCR5 has an important role in vivo in
HIV-1 replication. A subset
of primary viruses can use CCR3 as well as CCR5 as a co-receptor,
but the in vivo contribution of CCR3 to HIV-1
infection and pathogenesis is unknown. HIV-1
infects the central nervous system (CNS) and causes the dementia
associated with AIDS. Here
we report that the major target cells for HIV-1
infection in the CNS, the Microglia,
express both CCR3 and CCR5. The CCR3 ligand, eotaxin, and an
anti-CCR3 antibody inhibited HIV-1
infection of Microglia,
as did MIP-1beta, which is a CCR5 ligand. Our results suggest that
both CCR3 and CCR5 promote efficient infection of the CNS by HIV-1
Lannuzel A, Barnier JV, Hery C, Huynh VT, Guibert B, Gray F,
Vincent JD, Tardieu M (1997) Human immunodeficiency virus type 1 and
its coat protein gp120 induce apoptosis and activate JNK and ERK
mitogen-activated protein kinases in human neurons. Ann.Neurol.
42:847-856
Abstract: Detection of apoptotic neurons and
Microglial
cells in the brains of human immunodeficiency virus type 1
(HIV-1)-infected patients
has suggested that programmed cell death may be implicated in the
physiopathology of HIV-1
encephalopathy. To analyze in vitro the intracellular signals
induced by HIV-1 in human
neurons and the associated neuronal death, we tested cultured human
central nervous system (CNS) cells for apoptosis induced by HIV-1
and gp120 and for signaling pathways activated by gp120. HIV-1
and gp120 induced apoptosis of neurons and Microglial
cells but not of astrocytes or transformed Microglial
cells. Gp120 activated c-Jun N-terminal kinase (JNK) and p42
extracellular-regulated kinase (ERK) in primary CNS cells, with an
early peak of activation at 2 to 5 minutes that was not present when
pure Microglial
or astrocyte cultures were tested, followed by a late and sustained
activation (10 and 60 minutes) in primary and enriched glial cell
cultures as well as in transformed Microglial
cells. This demonstrates that gp120 could be an effector of
HIV-1-induced apoptosis in
the CNS and act directly on neuronal and glial cells
Lavi E, Strizki JM, Ulrich AM, Zhang W, Fu L, Wang Q,
O'Connor M, Hoxie JA, Gonzalez-Scarano F (1997) CXCR-4 (Fusin), a
co-receptor for the type 1 human immunodeficiency virus (HIV-1),
is expressed in the human brain in a variety of cell types,
including Microglia
and neurons. Am.J.Pathol. 151:1035-1042
Abstract: Entry of the
type 1 human immunodeficiency virus into most cells requires the
presence of the CD4 protein in combination with one of several
recently described co-receptors. CXCR-4 (fusin) was the first
identified, and it serves as co-receptor for T-cell-line tropic
(T-tropic) HIV-1 isolates.
To determine the expression of CXCR-4 in the brain, a major target
of HIV pathology, we used
immunohistochemistry and reverse transcriptase polymerase chain
reaction with CXCR-4-specific antibodies and probes. We found that
CXCR-4 was expressed in several cell types in brain, but notably in
neurons and Microglia,
a finding that was replicated in tissue culture. The study of the
expression of CXCR-4 in the brain, which may be one of many
chemokine receptors in the central nervous system, may provide
further insight into the interactions between brain cells,
pathogens, and the immune system, and help understand the
pathogenesis of HIV
dementia
Limoges J, Persidsky Y, Bock P, Gendelman HE (1997)
Dexamethasone therapy worsens the neuropathology of human
immunodeficiency virus type 1 encephalitis in SCID mice.
J.Infect.Dis. 175:1368-1381
Abstract: Human immunodeficiency
virus (HIV) dementia is a
late complication of viral infection. Cognitive dysfunction revolves
around the secretion of neurotoxins from immunologically competent
virus-infected brain macrophages and Microglia.
Such macrophage neurotoxins are inflammatory factors that produce
selective neuronal dysfunction and ultimately cell death. To
evaluate the potential efficacy of antiinflammatory therapy for HIV
dementia, dexamethasone was administered to severe combined
immunodeficient mice with HIV-1
encephalitis. Mice were given therapeutic doses of dexamethasone
before intracerebral inoculation with HIV-1-infected
human monocytes. Histochemical evaluation showed a worsening of
neuropathology after treatment, with astrogliosis and increased
apoptosis of neurons. Laboratory investigation of the mechanisms for
the dexamethasone effects revealed increased viability of
HIV-infected macrophages
and incomplete suppression of neurotoxic inflammatory secretions.
The results suggest the need for caution in administering
glucocorticoids for treatment of HIV
encephalitis in humans
Lin XH, Kashima Y, Khan M, Heller KB, Gu XZ, Sadun AA (1997)
An immunohistochemical study of TNF-alpha in optic nerves from AIDS
patients. Curr.Eye Res. 16:1064-1068
Abstract: PURPOSE: Both in
vitro and in vivo studies have implicated a role for tumor necrosis
factor (TNF-alpha) in the pathology of demyelinating diseases. The
purpose of this study was to address the hypothesis that TNF-alpha
is a mediator of AIDS-related
optic nerve injury and to determine the cell types involved in the
proliferation of TNF-alpha in the AIDS
optic nerve. METHODS: Ten optic nerves from seven patients with
AIDS, and three from
persons who were HIV
negative were stained, using the indirect immunoperoxidase method.
Six of the ten AIDS optic
nerves were positive for cytomegalovirus (CMV), but the remainder
did not have abnormal fundus findings. RESULTS: In all the optic
nerves from AIDS patients
with or without CMV retinitis, the vast majority of astrocytes
stained strongly for TNF-alpha. Microglial
cells (MPS-derived macrophages) varied from not staining to staining
strongly positive for TNF-alpha. However, oligodendrocytes were not
labeled positively for TNF-alpha. Some endothelial cells also
stained for TNF-alpha. Examination of normal optic nerves and
controls did not reveal any cell type that stained positively for
TNF-alpha. CONCLUSIONS: The present study supports the contention
that TNF-alpha is a major mediator of AIDS-associated
optic neuropathy. HIV
infection induces the production of TNF-alpha in macrophages and
astrocytes, which probably causes demyelination and other neuronal
damage
Lokensgard JR, Gekker G, Ehrlich LC, Hu S, Chao CC, Peterson
PK (1997) Proinflammatory cytokines inhibit HIV-1(SF162)
expression in acutely infected human brain cell cultures. J.Immunol.
158:2449-2455
Abstract: An understanding of how viral replication
in glial cells responds to proinflammatory cytokines is important in
delineating HIV-1
neuropathogenesis. Because no information is available in the
literature regarding the regulatory effects of exogenous cytokines
on acute HIV-1 replication
in human brain cells, we studied the impact of cytokine treatment on
viral p24 Ag expression. Based upon reports using mononuclear
phagocytes derived from somatic sources, we hypothesized that
TNF-alpha, IL-1 beta, and IL-6 would up-regulate the expression of
HIV-1(SF162) (a
monocytotropic strain) in purified Microglial
cells and in mixed brain cell cultures. This hypothesis was not
supported. In fact, a contrary, unexpected result was obtained;
whereas in purified Microglial
cultures TNF-alpha displayed a mild stimulatory effect on HIV-1
expression (15% increase in p24 Ag production compared with control
cultures), surprisingly, IL-1 beta and IL-6 were highly suppressive
(91 and 83% inhibition of HIV
expression, respectively). In contrast to the findings in Microglial
cell cultures, TNF-alpha profoundly suppressed (84%) HIV-1
expression in mixed brain cell cultures, as did IL-1 beta (82%), and
IL-6 was moderately suppressive (55% inhibition). In an attempt to
identify factors responsible for the differential effects of
TNF-alpha in the two brain cell infection models, it was found that
compared with Microglial
cell cultures, TNF-alpha treatment of mixed brain cell cultures
released significantly greater amounts of RANTES (regulated upon
activation, normal T cell expressed and secreted) and macrophage
inflammatory protein-1 alpha, beta-chemokines that have been
suggested to have anti-HIV-1
effects. Thus, these data suggest that proinflammatory cytokines
possess anti-HIV-1 activity
in the central nervous system
Masliah E, Heaton RK, Marcotte TD, Ellis RJ, Wiley CA,
Mallory M, Achim CL, McCutchan JA, Nelson JA, Atkinson JH, Grant I
(1997) Dendritic injury is a pathological substrate for human
immunodeficiency virus-related cognitive disorders. HNRC Group. The
HIV Neurobehavioral
Research Center. Ann.Neurol. 42:963-972
Abstract: To determine
the neuropathological substrate of human immunodeficiency virus
(HIV)-associated
neurocognitive disorders, we examined persons with acquired
immunodeficiency syndrome before their death and related their
antemortem neuropsychological performance to postmortem indicators
of HIV encephalitis, viral
burden, and presynaptic and postsynaptic neuronal injury. Of 20
prospectively examined cases, 9 were neurocognitively normal, 5
showed neuropsychological impairment, 5 had minor cognitive/motor
disorder, and 1 was demented. Degree of neurocognitive impairment
was strongly related to the amount of dendritic simplification based
on microtubule-associated protein 2 immunohistochemical staining,
somewhat less so to a semiquantitative viral burden score based on
numbers of HIV
gp41-immunoreactive cells, and much less so to the presence of
multinucleated giant cells or Microglial
nodules. It appears that even milder neurocognitive impairment
reflects microneuroanatomical injury to synaptic structures
Mayer V, Schmidtmayerova H (1997) [Encephalopathy in
AIDS--increased formation
of beta-chemokines in monocytes after HIV-1
virus infection: mechanisms of CNS involvement]. Bratisl.Lek.Listy
98:330-334
Abstract: The characteristic trait of the family of
lentiviruses (Retroviridae) which includes the human immune
deficiency virus (HIV), is
the tendency to cause a subacute neurologic disease in their animal
host. The neuraxis can be inflicted at all its levels. In the
advanced stage of HIV
disease, more than 60 percent of patients suffer from a clinically
evident neurological dysfunction. Neuropathologic changes are
demonstrated in 75 - 90 percent of them at autopsy. HIV
enters the CNS during the early phase of infection. HIV
replicates predominantly in the nervous tissue macrophages which
serve also as intrathecal reservoirs of infection. HIV
isolated from the CNS is usually macrophagotropic. Neural cells are
not susceptible to a productive HIV
infection, contrasting with the permissivity of activated astroglial
cells. The neuropathological picture of the brain involvement is
typical by the giant multinuclear cells, i.e. fused
monocytes/macrophages, then neuronal loss and changes in the white
matter. The clinical manifestations of CNS involvement (AIDS
encephalopathy) in HIV
disease are variable protean, frequently associated with dementia.
The pathogenesis of the neurological disease remains elusive. The
cells supporting the HIV
replication in the CNS (Microglia,
monocytes, astroglia) do not play a major role in dementia
development. The neurotoxicity of viral glycoproteins, virus-induced
cytokines and neurotoxin produced by CNS macrophages infected with
particularly efficiently replicating HIV
strains are being intensively studied. Dementia is associated with
an increased virus load in the brain in the advanced stage of HIV
disease. Neurotoxicity associated with HIV-infected
Microglial
cells and macrophages activity remain to be considered, for the time
being, as the most likely pathogenetic mechanism of neural
dysfunction and injury. Our investigations have demonstrated that
HIV infection of
macrophages stimulate considerably the synthesis of MIP-1-alpha,
MIP-1-beta RANTES chemokines (subgroup CC). These substances by
their chemoattractant and activating properties may participate in
the pathogenesis of HIV/AIDS
encephalopathy, contributing to leukocytosis and inflammation,
increasing thus the population of HIV-susceptible
cells, facilitating their infection and enhancing finally the
intrathecal spread of virus. (Tab. 2, Ref. 22.)
Meeker RB, Thiede BA, Hall C, English R, Tompkins M (1997)
Cortical cell loss in asymptomatic cats experimentally infected with
feline immunodeficiency virus. AIDS
Res.Hum.Retroviruses 13:1131-1140
Abstract: Specific
pathogen-free cats experimentally infected with feline
immunodeficiency virus (FIV) were used to evaluate the development
of central nervous system changes during the asymptomatic stages of
viral infection. The brains of asyptomatic cats were examined at
postinoculation times ranging from 8 weeks to 3 years for changes in
neuron density, glutamate receptor density, and synaptophysin
immunoreactivity. At 2-3 years postinoculation a small decrease in
neuronal density was found in layers 2-3 and layer 5 of the frontal
cortex (-14.4%), parietal cortex (-18.1%), and striatum (-29.5%).
The only other indications of pathology within these regions were a
mild diffuse astrogliosis, occasional Microglial
nodules, and the accumulation of satellite cells around selected
neurons. An average loss of large neurons of 56-68% was seen in the
cortex of four random source cats euthanized with AIDS.
These values contrasted with the absence of any significant cell
loss in FIV-infected cats 18 weeks after inoculation or FIV-negative
controls. The loss of neurons in the asymptomatic cats showed a
significant positive correlation with a decrease in the blood
CD4:CD8 ratios. Morphometric evaluation of synaptic terminal
densities immunocytochemically stained with synaptophysin revealed a
significant increase in the asymptomatic cats at 2-3 years
postinoculation that correlated negatively with the CD4:CD8 ratios.
Random source AIDS cats
showed a 34% decrease in synaptophysin-immunoreactive profiles.
Glutamate binding in the cortex did not change significantly in the
asymptomatic cats (4-7% decline). Thus, experimentally infected
specific pathogen-free cats show a loss of cortical neurons similar
to what has been observed in postmortem studies of humans infected
with HIV. The detection of
neuronal loss during the asymptomatic stage of disease and the
correlation with the peripheral CD4:CD8 cell ratios indicate that
neurodegeneration may progress in parallel with peripheral disease
Mrak RE, Griffin WS (1997) The role of chronic
self-propagating glial responses in neurodegeneration: implications
for long-lived survivors of human immunodeficiency virus.
J.Neurovirol. 3:241-246
Abstract: Within the last decade there
has arisen increasing appreciation of the role of glia-derived
immune and neurotrophic cytokines, especially Microglia-derived
interleukin-1 and astrocyte-derived S100beta, in the pathophysiology
of Alzheimer's disease and of neurodegeneration in general.
Available evidence now suggests that these neurotrophic and immune
cytokines, produced in response to neuronal cell dysfunction or
death, may elicit cellular and molecular responses resulting in
further activation of glia and glial cytokine secretion, producing a
cytokine cycle. In conditions characterized by chronic glial
activation this cycle becomes self propagating, promoting further
neurodegeneration and subsequent further induction of glial cell
activation with production of cytokines. In Alzheimer's disease, for
instance, such self-propagation is essential to the progressive
accumulation of neuropathological changes that underlie progressive
dementia. Conditions that predispose one to Alzheimer-type 'senile'
neuropathological changes, and to later development of Alzheimer's
disease, also exhibit glial activation and overexpression of glial
cytokines, providing further evidence of a pathogenic role for glial
activation and cytokine cycle elements in the initiation and
propagation of Alzheimer lesions. HIV
produces a chronic viral infection of the central nervous system
that has been associated with chronic glial activation and
overexpression of some of the same cytokines that have been
implicated in Alzheimer pathogenesis. These observations, together
with established functions of cytokine cycle elements, suggest that
chronic HIV infection in
sufficiently long-lived HIV-infected
individuals might confer additional risk for later development of
Alzheimer's disease
Mussa M, Preux PM, Debrock C, Chazot-Balcon M, Melaku Z,
Druet-Cabanac M, Kayembe K, Dumas M (1997) [HIV-1
cognitive and motor syndrome]. Sante 7:187-193
Abstract: The
central nervous system (CNS) is often affected by HIV-1
infection. Over 40% of AIDS
cases present with neurological symptoms and CNS lesion are detected
by anatomical and pathological studies in 80 to 90% of AIDS
cases. There may be infections and tumors secondary to the
immunodeficiency and pathologies may occur directly due to the
neurotropism of the virus. Neurological problems associated with
HIV-infection include
encephalopathies, myelopathies, neuropathies and myopathies.
HIV-1-induced
encephalopathy may develop at any stages of HIV-1
infection and affects all risk groups equally. Its frequency
worldwide is between 4 and 65% among individuals seropositive for
HIV-1. The frequencies
reported differ between studies due to differences in sampling
methods, geographical factors, diagnostic criteria and investigative
methods used. The pathogenesis of HIV-1-associated
encephalopathy is not understood, but there are several hypotheses.
The involvement of HIV-1
infected macrophages and Microglial
cells has been demonstrated. Indirect mechanisms such as release of
lymphokines (tumor necrosis factor-TNF alpha- and interleukin-1) and
neurotoxicity of the HIV
envelope protein, gp 120, have also been suggested. This disorder is
known as HIV-1-associated
cognitive and motor syndrome. It presents clinically as a form of
sub-cortical dementia with cognitive problems, motor deficits and
behavioral disorders depending on the type and stage of HIV
infection. The diagnosis can only be made after all other infections
and tumors common in HIV-1
patients have been ruled out by appropriate investigations such as
cerebrospinal fluid analysis, cerebral scan and magnetic resonance
imaging. Electrophysiological studies, such as evoked responses and
electroencephalograms, are particularly useful in its diagnosis.
Anatomical examination shows diffuse paleness of the white matter,
multi-nucleated giant cells and Microglial
nodes. Neuropsychological studies could be of value in diagnosis and
in assessing the response to anti-retroviral treatment. There is
currently no specific therapy for HIV-1-associated
cognitive and motor syndrome. The use of new nucleoside analogue
drugs in combination with existing drugs may provide new approaches
to managing these patients
New DR, Ma M, Epstein LG, Nath A, Gelbard HA (1997) Human
immunodeficiency virus type 1 Tat protein induces death by apoptosis
in primary human neuron cultures. J.Neurovirol. 3:168-173
Abstract:
Neuronal loss in HIV
encephalopathy remains a mystery since HIV-1
productively infects macrophage and Microglia
and only rarely infects neurons in the central nervous system.
Apoptosis is a mechanism which may account for the loss of neurons
in HIV-1 infected brain.
Putative toxic factors that result in neuronal cell death in HIV-1
infection include the regulatory protein Tat, since this protein is
known to be released from HIV-1
infected cells. Here we show that Tat induces cell death by
apoptosis in cultured human fetal neurons producing characteristic
morphological and biochemical features associated with apoptosis.
These findings suggest that Tat may play an important role as a
secreted, soluble neurotoxin in HIV-1
associated dementia
Persidsky Y, Buttini M, Limoges J, Bock P, Gendelman HE
(1997) An analysis of HIV-1-associated
inflammatory products in brain tissue of humans and SCID mice with
HIV-1 encephalitis.
J.Neurovirol. 3:401-416
Abstract: The human immunodeficiency
virus type 1 (HIV)-associated
dementia complex (ADC) is a neuroimmunological disorder fueled by
viral replication in mononuclear phagocytes (MP) (brain macrophages
and Microglia).
The elucidation of MP inflammatory factors involved in neurological
dysfunction is pivotal for unraveling pathogenic mechanisms and in
developing new therapies for this disease. Recent advances in animal
model systems for ADC and its associated encephalitis have provided
important insights into how virus-infected macrophages cause brain
injury. Indeed, the stereotactic inoculation of HIV
infected monocytes into the basal ganglia/cortex of mice with severe
combined immunodeficiency disease (SCID) results in pathological
features similar to those of human HIV-1
encephalitis (HIVE). We
used this SCID model to study the roles of macrophage secretory
factors in HIVE. The
expression of interleukin-1 (IL-1 beta, IL-6, IL-10), tumor necrosis
factors-alpha (TNF alpha), vascular endothelial growth factor
(VEGF), and adhesion molecules (E-selectin, intracellular cell
adhesion molecule (ICAM-1), and vascular cell adhesion molecule-1
(VCAM-1)) in encephalitic brains of mice and humans was evaluated by
semi-quantitative polymerase chain reaction (PCR). In SCID mice with
HIVE, human and mouse TNF
alpha, and mouse IL-6, VEGF, VCAM-1 and E-selectin were expressed at
high levels. These results paralleled, to a great extent, those in
HIVE brain tissues. Laser
scanning confocal microscopy performed to assess the associated
neuronal damage showed that microtubule associated protein-2 (MAP-2)
immunoreactive dendrites were significantly reduced in both the
ipsilateral and contralateral hemispheres of encephalitic mice.
These results demonstrate the importance of macrophage inflammatory
products in the pathogenesis of HIVE
and further validates this model of viral encephalitis in SCID mice
Samson M, LaRosa G, Libert F, Paindavoine P, Detheux M,
Vassart G, Parmentier M (1997) The second extracellular loop of CCR5
is the major determinant of ligand specificity. J.Biol.Chem.
272:24934-24941
Abstract: The chemokine receptor CCR5 binds
macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and
regulated on activation, normal T-cell expressed and secreted
(RANTES), and constitutes the major co-receptor allowing infection
of CD4(+) T lymphocytes, macrophages, and Microglial
cells by macrophage-tropic strains of human and simian
immunodeficiency virus. CCR5 is most closely related to CCR2b,
another chemokine receptor that responds to monocyte chemoattractant
protein (MCP)-1, MCP-2, MCP-3, and MCP-4. We have investigated by
mutagenesis the regions of CCR5 and CCR2b involved in the
specificity of binding and functional response to their respective
ligands. We demonstrate that the key region of CCR5 involved in its
specific interaction with MIP-1alpha, MIP-1beta, and RANTES, and its
subsequent activation, lies within the second extracellular loop
(and possibly the adjacent transmembrane segments). Conversely, the
NH2-terminal domain of CCR2b is responsible for the high affinity
binding of MCP-1, but is not sufficient to confer activation of the
intracellular cascades. Extracellular loops of the receptor, among
which the second loop plays a prominent role, are necessary to
achieve efficient signaling of the receptor. These data complement
our previous mapping of CCR5 domains functionally involved in the
fusion process with the human immunodeficiency virus envelope, and
will help in the development of agents able to interfere with the
early steps of viral infection
Seilhean D, Kobayashi K, He Y, Uchihara T, Rosenblum O,
Katlama C, Bricaire F, Duyckaerts C, Hauw JJ (1997) Tumor necrosis
factor-alpha, Microglia
and astrocytes in AIDS
dementia complex. Acta Neuropathol.(Berl) 93:508-517
Abstract:
The pathogenesis of HIV-associated
cognitive changes is poorly understood. Cytokines such as tumor
necrosis factor-alpha (TNF-alpha) have been postulated to contribute
to the mechanism of the neurological complications of HIV
infection. One of the effects of TNF-alpha is to induce astrocyte
proliferation in vitro. The purpose of this study was to look for a
correlation between the expression of TNF-alpha, astrogliosis and
the degree of cognitive impairment in 12 prospectively assessed AIDS
cases without focal brain lesion, 8 of whom were demented. They were
compared with 6 control patients without neurological disease.
Neuropathological examination showed myelin pallor in 5 of the 8
demented patients. TNF-alpha expression was detected by
immunohistochemistry in the midfrontal cortex, subcortical and deep
white matter, and basal ganglia. Not only perivascular macrophages
but also some Microglial
and endothelial cells were labeled. Most TNF-alpha-positive cells
were in close contact with glial fibrillary acidic protein-positive
astrocytes. They were more numerous than gp41-positive cells. Their
density increased with increasing cognitive impairment and in
parallel to the astrogliosis in the frontal cortex, basal ganglia
and deep white matter. These findings further support the hypotheses
that lesions of the deep white matter, driven by TNF-alpha, are
associated with cognitive alteration, and that indirect effects of
HIV infection in the brain
participate in the development of HIV-associated
dementia through a diffuse immune activation, mediated by cytokines
Silver B, McAvoy K, Mikesell S, Smith TW (1997) Fulminating
encephalopathy with perivenular demyelination and vacuolar
myelopathy as the initial presentation of human immunodeficiency
virus infection. Arch.Neurol. 54:647-650
Abstract: OBJECTIVE: To
study the neuropathologic features in a case involving a 22-year-old
woman in whom a fulminating encephalopathy developed as the initial
manifestation of human immunodeficiency virus (HIV)
infection. DESIGN: Case report. SETTING: Tertiary care hospital.
PATIENT: The patient presented with rapidly progressive mental
status, changes, cranial nerve abnormalities, and quadriplegia,
which led to her death 5 months later. Serologic tests for HIV
were initially indeterminate on Western blot analysis but were
positive 1 week later. METHODS: A complete autopsy, including
examination of the brain and spinal cord, was performed.
Paraffin-embedded sections of the brain and spinal cord were
examined using standard histologic staining procedures and
immunohistochemical techniques. RESULTS: Neuropathologic examination
revealed discrete foci of perivenular demyelination disseminated
throughout the brain and spinal cord, as well as severe vacuolar
myelopathy. Lesions typical of HIV
encephalitis were not present. Human immunodeficiency virus-infected
monocytes and Microglia
were observed in the vicinity of, but not restricted to, the
perivenular demyelinating lesions. No other infectious agents were
identified. CONCLUSIONS: The patient's acute encephalopathy was most
likely the direct result of a widespread demyelinating process
resembling acute disseminated encephalomyelitis. We suggest that the
perivenular demyelination may represent an autoimmune reaction,
possibly due to a nonspecific viral infection, occurring in the
setting of chronic immunosuppression secondary to HIV.
Although less likely, we cannot exclude the possibility that HIV
could have directly triggered an autoimmune response that caused the
acute disseminated encephalomyelitis-like lesions
Stephens EB, Galbreath D, Liu ZQ, Sahni M, Li Z, Lamb-Wharton
R, Foresman L, Joag SV, Narayan O (1997) Significance of macrophage
tropism of SIV in the macaque model of HIV
disease. J.Leukoc.Biol. 62:12-19
Abstract: Microglia,
alveolar macrophages, and Langerhans cells are representatives of
cells of macrophage lineage that are susceptible to infection with
HIV-1 and they play
important roles in the pathogenesis of AIDS
dementia, lymphoid interstitial pneumonia, and systemic viral
invasion from mucosal surfaces, respectively. In contrast,
elimination of CD4+ T cells with resultant development of
immunosuppression and AIDS
is thought to be reflective of the exclusive tropism of the virus
for CD4+ T cells. Examination of these concepts in macaques infected
with molecularly cloned strains of SIVmac suggested that all strains
of the virus are both macrophage- and lymphocyte-tropic and that all
aspects of pathogenesis including loss of CD4+ T cells are dependent
on infection in both cell types. However, viral clones that caused
productive lytic infection in macrophages were less virulent than
those which caused persistent nonproductive infection. The former
caused subclinical and even immunizing infections, whereas the
latter caused activation and productive infection in CD4+ T cells,
AIDS, and systemic
infection, even after inoculation of the virus on mucosal surfaces.
If these findings on SIVmac are relevant to HIV-1
disease, then demonstration that HIV-1
isolates are macrophage-tropic probably does not necessarily
correlate with their pathogenic potential
Strizki JM, Turner JD, Collman RG, Hoxie J, Gonzalez-Scarano
F (1997) A monoclonal antibody (12G5) directed against CXCR-4
inhibits infection with the dual-tropic human immunodeficiency virus
type 1 isolate HIV-1(89.6)
but not the T-tropic isolate HIV-1(HxB).
J.Virol. 71:5678-5683
Abstract: We used a monoclonal antibody
(12G5) directed against an extracellular domain of CXCR-4 to
investigate the role of this receptor in infection of immortalized
lymphoid cell lines, peripheral blood mononuclear cells (PBMCs), and
primary brain Microglia
with a dual-tropic strain of human immunodeficiency virus
(HIV-1(89.6)) and a
T-tropic strain (HIV-1(IIIB)).
Addition of antibody 12G5 to cells prior to and during infection
with HIV-1(89.6) inhibited
p24 production 100- to 10,000-fold in CEMx174 and 174-CD4 cells and
about 10-fold in PBMC cultures but had no activity against infection
of either monocyte-derived macrophages or brain Microglia.
In contrast, 12G5 had little or no effect on infection of CEMx174
cells with HIV-1(IIIB) or
HIV-1(HxB). To identify the
region of the HIV-1(89.6)
envelope that confers sensitivity to 12G5, we used chimeric
molecular clones. Chimeras containing the V3 loop region of
HIV-1(89.6) were inhibited
by 12G5 to the same degree as wild-type HIV-1(89.6)
whereas replication of those viruses containing the V3 loop of
HIV-1(HxB) was not
inhibited by the antibody. A similar pattern was seen in infections
of a U87 glioblastoma line that coexpresses CD4 and CXCR-4. Antibody
12G5 was also able to block fusion between HeLa-CD4 cells and
CEMx174 cells chronically infected with HIV-1(89.6)
but had no effect on fusion mediated by cells chronically infected
with HIV-1(IIIB). Taken
together, these results suggest that different strains of HIV-1
may interact with different sites on CXCR-4 or may have different
binding affinities for the coreceptor
Tanabe S, Heesen M, Yoshizawa I, Berman MA, Luo Y, Bleul CC,
Springer TA, Okuda K, Gerard N, Dorf ME (1997) Functional expression
of the CXC-chemokine receptor-4/fusin on mouse Microglial
cells and astrocytes. J.Immunol. 159:905-911
Abstract: The mRNA
for the seven-transmembrane-spanning G protein-coupled receptor
fusin/CXCR-4 is expressed in primary mouse astrocyte cultures and
the transformed mouse Microglial
cell line, N9. Cell surface expression of fusin in these cells was
confirmed by staining with a polyclonal anti-fusin Ab. The
functional capacity of this chemokine receptor was examined by
evaluating the calcium responses following stimulation of glial
cells with the CXC-chemokine, stromal-derived cell factor-1alpha
(SDF-1alpha). Both astrocytes and Microglial
cells mobilized calcium following stimulation with chemically
synthesized SDF-1alpha. SDF-1alpha- and carbachol-mediated calcium
responses of astrocytes were partially inhibited by treatment with
pertussis toxin (PTx), suggesting receptor coupling to a combination
of G alpha(i) and other G proteins. In contrast, the calcium
responses of Microglial
cells to SDF-1alpha were completely PTx sensitive, while responses
to carbachol stimulation were PTx resistant. The ability of
SDF-1alpha to induce glial cell migration was also examined.
Synthetic SDF-1alpha was a potent chemoattractant for mouse
Microglial
cells at ligand concentrations of 10 to 500 ng/ml; peak responses
were noted at 100 ng/ml. In contrast, astrocytes did not migrate
toward a gradient of SDF-1alpha. The failure of SDF-1alpha to induce
astrocyte migration was specific, as another chemokine, macrophage
inflammatory protein-1alpha, triggered astrocyte chemotaxis
Wingertsmann L, Chretien F, Authier FJ, Paraire F, Durigon M,
Gray F (1997) [Central nervous system lesions in the early stages of
HIV infection].
Arch.Anat.Cytol.Pathol. 45:106-117
Abstract: Early HIV-1
invasion of the central nervous system has been demonstrated by many
cerebrospinal fluid studies; however, most HIV-1
carriers remain neurologically unimpaired during the so-called
"asymptomatic" period lasting from seroconversion to
symptomatic AIDS.
Therefore, very few neuropathological studies have been conducted in
the early pre-AIDS stages,
and the natural history of central nervous system changes in HIV-1
infection remains poorly understood. Examination of brains of
asymptomatic HIV-1 positive
individuals who died accidentally and of rare cases with acute fatal
encephalopathy revealing HIV
infection, and comparison with experimental simian immunodeficiency
virus and feline immunodeficiency virus infections suggest that,
invasion of the CNS by HIV-1
occurs at the time of primary infection and induces an immunological
process in the central nervous system. This includes an inflammatory
T-cell reaction with vasculitis and leptomeningitis, and immune
activation of brain parenchyma with increased number of Microglial
cells, upregulation of major histocompatibility complex class II
antigens and local production of cytokines. Myelin pallor and
gliosis of the white matter are usually found and are likely to be
the consequence of opening of the blood-brain barrier due to
vasculitis; direct damage to oligodendrocytes by cytokines may also
be involved. These white matter changes may explain, at least
partly, the early cerebral atrophy observed, by magnetic resonance
imaging, in asymptomatic HIV-1
carriers. In contrast, cortical damage seems to be a late event in
the course of HIV-1
infection. There is no significant neuronal loss at the early stages
of the disease, no accompanying increase in glial fibrillary acid
protein staining in the cortex, and only exceptional neuronal
apoptosis. Although HIV-1
proviral DNA may be demonstrated in a number of brains, viral
replication remains very low during the asymptomatic stage of HIV-1
infection. This makes it likely that, although opening of the blood
brain barrier may facilitate viral entry into the brain, specific
immune responses including both neutralising antibodies and
cytotoxic T-lymphocytes, continuously inhibit viral replication at
this stage
Zenger E, Tiffany-Castiglioni E, Collisson EW (1997) Cellular
mechanisms of feline immunodeficiency virus (FIV)-induced
neuropathogenesis. Front Biosci. 2:d527-d537
Abstract: The high
incidence of neurologic dysfunction from human immunodeficiency
virus (HIV) infection has
heightened interest in neuropathogenesis of other lentiviruses,
including that associated with feline immunodeficiency virus (FIV).
Both HIV and FIV
efficiently enter the central nervous system and cause primary
neurological disease that is not attributable to opportunistic
infections or systemic disease. Cells in the brain infected by FIV
are similar to those observed in HIV
infection, both viruses infect macrophages, Microglia,
and astrocytes. Although substantial neuronal loss can occur in the
cortex of HIV- or
FIV-infected patients, most studies agree that neurons are not
infected and indirect mechanisms of neurotoxicity are postulated.
This review describes recent information on the neuropathogenesis of
FIV and how this information correlates with what is known about the
neuropathogenesis of HIV.
Although the pathogenesis of neurological dysfunction in HIV-
and FIV-infected patients is far from clear, it is becoming
increasingly evident that the relationship between lentivirus
presence in the brain and neurological signs is not straightforward
and cannot be explained by simple cytolytic infection. The observed
neurologic dysfunction is likely multifactorial and complex
involving an intricate web of subcellular pathways and neurotoxic
factors interacting with multiple cell types
Zheng J, Gendelman HE (1997) The HIV-1
associated dementia complex: a metabolic encephalopathy fueled by
viral replication in mononuclear phagocytes. Curr.Opin.Neurol.
10:319-325
Abstract: HIV
enters the brain soon after virus exposure but elicits profound
neurological deficits in infected humans years later usually during
progressive immunosuppression and the development of the acquired
immune deficiency syndrome. The neurological disease complex
associated with virus infection occurs in a large proportion of
infected patients and is commonly referred to as HIV-1
associated dementia complex. The neuropathogenesis of central
nervous system/viral infection revolves around mononuclear
phagocytes (brain macrophage/Microglial)
infection and immune activation in brain. Macrophages secrete
neurotoxic factors that elicit neuronal injury and inevitably death
leading to the constellation of cognitive and motor impairments
common during progressive disease. Neurotoxic factor production
requires virus entry and replication, the evolution/selection of
neurovirulent HIV-1 strains
and the production of viral and cellular immune factors injurious to
human neurons. Interestingly, neurological deficits, the HIV-1
associated neuropathology and viral replication disease are not
always associated. This has led to the notion that viral replication
induces the autocrine/paracrine production of cellular/viral factors
leading to a metabolic encephalopathy. Anti-retroviral and
anti-inflammatory therapies should prove increasingly beneficial for
treatment and, ultimately, reversal of HIV-1
associated dementia complex in the affected human host
Albright AV, Strizki J, Harouse JM, Lavi E, O'Connor M,
Gonzalez-Scarano F (1996) HIV-1
infection of cultured human adult oligodendrocytes. Virology
217:211-219
Abstract: The mechanism through which HIV-1
causes HIV dementia (HIVD)
is not well understood. Myelin pallor is a common pathological
finding in HIVD and could
be explained by a direct infection of oligodendrocytes or
interaction with HIV-1 gp
120. To determine if oligodendrocytes could be infected by HIV-1,
we purified oligodendrocytes from adult human brain tissues obtained
from temporal lobe resections. These cells were exposed to HIV-1
and infectivity was assayed by detection of p24gag antigen, PCR
amplification, and cocultivation with CD4+ cells. These results
indicate that HIV-1(IIIB
and BaL) and one of four primary isolates tested can infect
oligodendrocytes, resulting in the production of infectious virus.
Furthermore, in an experiment that mimics a potential in vivo
scenario, infected Microglia
were able to transmit virus to oligodendrocytes in a trans-well
culture system. These experiments indicate that oligodendrocyte
infection should be considered in studying the pathophysiology of
HIVD
Arribas JR, Storch GA, Clifford DB, Tselis AC (1996)
Cytomegalovirus encephalitis. Ann.Intern.Med. 125:577-587
Abstract:
PURPOSE: To review the pathologic and clinical features of and
establish the frequency of cytomegalovirus encephalitis in adults
and to review the methods available for diagnosis and treatment.
DATA SOURCE: MEDLINE search of all English-language articles from
January 1965 to August 1995. STUDY SELECTION: Articles dealing with
cytomegalovirus infection of the brain in adults. We also reviewed
all unselected autopsies of these populations to establish the
frequency of cytomegalovirus encephalitis in recipients of organ
transplants and in patients infected with the human immunodeficiency
virus (HIV). DATA
EXTRACTION: Epidemiologic and pathologic characteristics, clinical
manifestations, diagnostic methods, pathogenetic mechanisms, and use
of anticytomegalovirus treatments. DATA SYNTHESIS: Of 676 patients
receiving a diagnosis of cytomegalovirus encephalitis, 574 (85%)
were infected with HIV, 81
(12%) had other causes of immunosuppression, and 21 (3%) were
otherwise healthy. Cytomegalovirus encephalitis was confirmed during
autopsy in 12% of HIV-infected
patients and 2% of transplant recipients. The most common lesion was
Microglial
nodule encephalitis, but the clinical findings corresponding to this
pathologic entity are not well defined. In contrast, the pathologic
entity of cytomegalovirus ventriculoencephalitis, found almost
exclusively in patients with advanced HIV
infection, has distinct clinical features that allow recognition
even in patients with HIV
encephalopathy. Polymerase chain reaction has been shown to be
useful for diagnosis of cytomegalovirus encephalitis. CONCLUSIONS:
Cytomegalovirus encephalitis is an important opportunistic infection
in HIV-infected patients
but is rarely recognized in other groups. Cytomegalovirus
ventriculoencephalitis has emerged as a unique entity in patients
with advanced HIV
infection. Recent developments in diagnostic techniques allow early
recognition and may make more aggressive approaches to therapy
possible
Bagasra O, Lavi E, Bobroski L, Khalili K, Pestaner JP,
Tawadros R, Pomerantz RJ (1996) Cellular reservoirs of HIV-1
in the central nervous system of infected individuals:
identification by the combination of in situ polymerase chain
reaction and immunohistochemistry. AIDS
10:573-585
Abstract: OBJECTIVES: The majority of HIV-1-infected
individuals manifest a plethora of central nervous system (CNS)
diseases unrelated to opportunistic infections, including AIDS
dementia complex, encephalitis, and various other disorders of the
CNS. The present study sought to evaluate the cellular reservoirs
and expression patterns of HIV-1
in brain tissue to gain further understanding of HIV-1
neuropathogenesis. DESIGN: CNS tissue, obtained post-mortem from 22
patients with AIDS and four
HIV-1-seronegative
controls, was analyzed. METHODS: CNS samples were evaluated using a
combination of in situ DNA polymerase chain reaction (PCR), reverse
transcriptase (RT)-initiated in situ PCR, and immunohistochemistry.
By utilizing this triple-staining methodology, HIV-1
proviral DNA and HIV-1-specific
mRNA can be identified at the single cell level. RESULTS: HIV-1
was detected in all 22 AIDS
brain specimens and in none of the four brains from
HIV-1-seronegative
individuals. The most commonly infected cells in AIDS
brains were Microglia
cells and macrophages, but variable levels of HIV-1
infections were demonstrated in many of the major histological cell
types within the CNS, including neurons, microvascular endothelial
cells (MVEC) and astrocytes. The presence of HIV-1-infected
cells was not uniform with infected cells unevenly distributed
throughout the brain parenchyma. The degree of HIV-1
mRNA expression varied from 39-65% of the cells in the CNS harboring
HIV-1 provirus. Choroid
plexus and MVEC exhibited relatively high levels of productive
infection. CONCLUSION: These findings demonstrate that several cell
types in the CNS, in addition to Microglia
or macrophages, may become infected with HIV-1
in vivo with variable levels of HIV-1
mRNA expression. The diverse cellular reservoirs for HIV-1
in the CNS may be critically linked to the molecular mechanisms
involved in HIV-1
neuropathogenesis. In addition, in vivo infection of MVEC, and
possibly cells in the choroid plexus, may directly contribute to
penetration of the blood-brain barrier by HIV-1
Boelaert JR, Weinberg GA, Weinberg ED (1996) Altered iron
metabolism in HIV
infection: mechanisms, possible consequences, and proposals for
management. Infect.Agents Dis. 5:36-46
Abstract: The progression
of human immunodeficiency virus (HIV)
infection toward its more advanced stages is accompanied by
increasing body iron stores. Iron accumulates in macrophages,
Microglia,
endothelial cells, and myocytes. The iron burden is especially heavy
in bone marrow, brain white matter, muscle, and liver. Excess iron
potentially enhances oxidative stress, impairs several already
compromised immune defense mechanisms, and directly promotes the
growth of microbial cells. Thus, we hypothesize that the prevention
(or at least, reduction) of iron loading might slow the progression
of the infectious complications of HIV
infection, and perhaps indirectly, the HIV
infection itself. A twofold strategy is proposed, consisting of (a)
limitation of iron intake through the alimentary, parenteral, and
respiratory routes, and (b) possibly the use of iron chelator drugs
that could decrease the iron burden, redistribute the metal to the
erythroblasts, and suppress the growth of microorganisms. This
approach is still to be considered as hypothetical. However, the
available data suggest that there is an urgent need for careful
clinical studies to clarify the role of iron status on the course of
HIV infection
Bradl M, Linington C (1996) Animal models of demyelination.
Brain Pathol. 6:303-311
Abstract: Demyelination is a pathological
feature that is characteristic of many diseases of the central
nervous system (CNS) including multiple sclerosis (MS), sub-acute
sclerosing panencephalomyelitis (SSPE), metachromatic leukodystrophy
and Pelizaeus-Merzbacher disease. While demyelination is a
pathological end-point that is common to all of these diseases, the
cellular and molecular mechanisms responsible for this pathology are
very different . These range from genetic defects that affect lipid
metabolism in the leukodystrophies, cytopathic effects of viral
infection in SSPE to the action of immunological effector mechanisms
in MS and the viral encephalopathies. Irrespective of the initial
cause of myelin degradation, many of these disorders are associated
with some degree of CNS inflammation, as indicated by the local
activation of Microglia,
recruitment of macrophages or the intrathecal synthesis of
immunoglobulin. Many of these phenomena are now being duplicated in
animal models, providing not only new insights into the pathogenesis
of human demyelinating diseases , but also unexpected
interrelationships between the immune response in the CNS and the
pathogenesis of diseases such as Alzheimers disease and HIV
encephalopathy. Autoimmune mediated models of inflammatory
demyelinating CNS disease have proved particularly valuable in this
respect as they allow the effects of defined immune effector
mechanisms to be studied in the absence of CNS infection
Chiang CS, Powell HC, Gold LH, Samimi A, Campbell IL (1996)
Macrophage/Microglial-mediated
primary demyelination and motor disease induced by the central
nervous system production of interleukin-3 in transgenic mice.
J.Clin.Invest 97:1512-1524
Abstract: Activated
macrophage/Microglia
may mediate tissue injury in a variety of CNS disorders. To examine
this, transgenic mice were developed in which the expression of a
macrophage/Microglia
activation cytokine, interleukin-3 (IL-3), was targeted to
astrocytes using a murine glial fibrillary acidic protein fusion
gene. Transgenic mice with low levels of IL-3 expression developed
from 5 mo of age, a progressive motor disorder characterized at
onset by impaired rota-rod performance. In symptomatic transgenic
mice, multi-focal, plaque-like white matter lesions were present in
cerebellum and brain stem. Lesions showed extensive primary
demyelination and remyelination in association with the accumulation
of large numbers of proliferating and activated foamy
macrophage/Microglial
cells. Many of these cells also contained intracisternal crystalline
pole-like inclusions similar to those seen in human patients with
multiple sclerosis. Mast cells were also identified while
lymphocytes were rarely, if at all present. Thus, chronic CNS
production of low levels of IL-3 promotes the recruitment,
proliferation and activation of macrophage/Microglial
cells in white matter regions with consequent primary demyelination
and motor disease. This transgenic model exhibits many of the
features of human inflammatory demyelinating diseases including
multiple sclerosis and HIV
leukoencephalopathy
Di Stefano M, Wilt S, Gray F, Dubois-Dalcq M, Chiodi F (1996)
HIV type 1 V3 sequences and
the development of dementia during AIDS.
AIDS Res.Hum.Retroviruses
12:471-476
Abstract: The most frequent neurological complication
of AIDS is a dementia-like
syndrome. Power and collaborators (J Virol 1994; 68:4643-4649) have
reported an association between the clinical signs of AIDS
dementia and the amino acid composition of two positions (305 and
329) within the V3 region of HIV-1
strains amplified from brain tissue. Similarly, we analyzed position
305 in the V3 region of HIV-1
present in the brain or cerebrospinal fluid of 25 nondemented
subjects at different clinical stages of HIV-1
infection. Our results are, however, at variance with the findings
presented by Power and colleagues. Histidine, found to be common
among sequences derived from demented patients, was also present in
the majority (16 of 25) of nondemented patients analyzed by us. In
the hands of Power and colleagues, sequences derived from
nondemented patients contained proline at position 305. None of our
patients had proline in this position. We also asked the question
whether the presence of a specific amino acid at position 305 of the
V3 loop is linked to an increased capacity of HIV-1
isolates to infect primary Microglial
cells, the major target cell for HIV-1
infection in the brain. Primary HIV-1
isolates derived from blood and cerebrospinal fluid of five
patients, two asymptomatic and three AIDS
patients, were used to infect Microglia
cell cultures. Infection was monitored by syncytium formation and by
p24 antigen release in the culture supernatant. All but one of the
paired blood/CSF isolates replicated in human brain cultures.
Replication occurred independently from the amino acid present at
position 305 of the V3 region of the viral envelope. Our results
indicate that the majority of HIV-1
isolates, even derived during the asymptomatic stage, have the
capacity to infect Microglial
cells. The relevance of viral envelope sequences in determining
tropism for Microglial
cells and development of neurological symptoms remains an open
question
Fine SM, Angel RA, Perry SW, Epstein LG, Rothstein JD,
Dewhurst S, Gelbard HA (1996) Tumor necrosis factor alpha inhibits
glutamate uptake by primary human astrocytes. Implications for
pathogenesis of HIV-1
dementia. J.Biol.Chem. 271:15303-15306
Abstract: Human
immunodeficiency virus (HIV)
infection is commonly associated with neurological disease that
occurs in the apparent absence of extensive infection of brain cells
by HIV, suggesting that
indirect mechanisms account for neuropathogenesis in the CNS,
perhaps including changes in the normal neuroprotective functions of
astrocytes. To test this hypothesis, we examined the effect of the
pro-inflammatory cytokine, tumor necrosis factor alpha (TNFalpha),
produced by HIV-1-infected
macrophages and Microglia,
on glutamate transport by primary human fetal astrocytes (PHFAs). A
dose-dependent inhibition of high affinity glutamate uptake sites
was observed 12-24 h after addition of exogenous recombinant human
TNFalpha to PHFAs. This effect was specific since it was blocked by
a neutralizing monoclonal antibody directed against TNFalpha.
Furthermore, the inhibitory effect was reproduced by a monoclonal
antibody that is an agonist at the 55-kDa TNF receptor. These
results suggest that the neurotoxic effects of TNFalpha may be due
in part to its ability to inhibit glutamate uptake by astrocytes,
which in turn may result in excitotoxic concentrations of glutamate
in synapses
Gehrmann J (1996) Microglia:
a sensor to threats in the nervous system? Res.Virol.
147:79-88
Abstract: The parenchymal Microglia
are now believed to settle the CNS antenatally, being derived from a
bone marrow precursor cell. Based on developmental and
pathophysiological studies, at least four different types of
parenchymal Microglia
can be distinguished: (i) the amoeboid Microglia
which are mainly found perinatally in white matter areas, such as
the corpus callosum, i.e. the so-called "fountains of
Microglia",
(ii) the ramified, resting Microglia
in the adult CNS, (iii) the activated, non-phagocytic Microglia
found in areas of secondary reaction due to nerve transection and
(iv) the phagocytic Microglia,
found in areas of trauma, infection or neuronal necrosis. In
addition, there are perivascular cells enclosed in the basal lamina
which have a high turnover with a bone marrow precursor pool. While
the function of resting Microglia
is still largely unknown, it is clear from observations in
neuropathology that Microglia
are among the first cell types in the brain to respond to injuries.
Their reaction pattern to injury has been termed a graded response,
since the transformation of resting cells into phagocytes is under
strict control in vivo. Microglial
activation is a key cellular response in many infectious,
inflammatory, traumatic, neoplastic, ischaemic and degenerative
conditions in the CNS. In HIV
encephalitis, the Microglial
involvement is striking, and approximately 25% of Microglia
contain viral DNA or RNA. Based on natural homing mechanisms with
bone marrow precursor cells, HIV-infected
monocytes/macrophages may home at an early stage to the CNS
perivascular space and eventually spread the infection to resident
Microglia
in the CNS which may be difficult to reach by pharmacological
intervention. Further understanding of the mechanisms regulating
Microglial
proliferation and activation in vivo may help to develop therapies
targeting the potentially harmful Microglial
response in the injured CNS
Glass JD, Johnson RT (1996) Human immunodeficiency virus and
the brain. Annu.Rev.Neurosci. 19:1-26
Abstract: Human
immunodeficiency virus (HIV)
infects the nervous system in the majority of patients, causing a
variety of neurological syndromes throughout the course of the
disease. This review focuses on the effects of HIV
in the central nervous system, with an emphasis on HIV-associated
dementia. HIV-associated
dementia occurs in a subset of patients with AIDS;
it is unclear why these patients and not all patients develop the
disease. Several factors are likely to be involved in the
pathogenesis of HIV-associated
dementia, including neurotoxins released from the virus and/or
infected macrophages and Microglia,
immunologic dysregulation of macrophage function, and specific
genetic strains of HIV.
These factors, and their possible interactions, are discussed
Gray F, Scaravilli F, Everall I, Chretien F, An S, Boche D,
Adle-Biassette H, Wingertsmann L, Durigon M, Hurtrel B, Chiodi F,
Bell J, Lantos P (1996) Neuropathology of early HIV-1
infection. Brain Pathol. 6:1-15
Abstract: Early HIV-1
invasion of the central nervous system has been demonstrated by many
cerebrospinal fluid studies; however, most HIV-1
carriers remain neurologically unimpaired during the so called
"asymptomatic" period lasting from seroconversion to
symptomatic AIDS.
Therefore, neuropathological studies in the early pre-AIDS
stages are very few, and the natural history of central nervous
system changes in HIV-1
infection remains poorly understood. Examination of brains of
asymptomatic HIV-1 positive
individuals who died accidentally and of rare cases with acute fatal
encephalopathy revealing HIV
infection, and comparison with experimental simian immunodeficiency
virus and feline immunodeficiency virus infections suggest that,
invasion of the CNS by HIV-1
occurs at the time of primary infection and induces an immunological
process in the central nervous system. This includes an inflammatory
T-cell reaction with vasculitis and leptomeningitis, and immune
activation of brain parenchyma with increased number of Microglial
cells, upregulation of major histocompatibility complex class II
antigens and local production of cytokines. Myelin pallor and
gliosis of the white matter are usually found and are likely to be
the consequence of opening of the blood brain barrier due to
vasculitis; direct damage to oligodendrocytes by cytokines may also
interfere. These white matter changes may explain, at least partly,
the early cerebral atrophy observed, by magnetic resonance imaging,
in asymptomatic HIV-1
carriers. In contrast, cortical damage seems to be a late event in
the course of HIV-1
infection. There is no significant neuronal loss at the early stages
of the disease, no accompanying increase in glial fibrillary acid
protein staining in the cortex, and only exceptional neuronal
apoptosis. Although HIV-1
proviral DNA may be demonstrated in a number of brains, viral
replication remains very low during the asymptomatic stage of HIV-1
infection. This makes it likely that, although opening of the blood
brain barrier may facilitate viral entry into the brain, specific
immune responses including both neutralising antibodies and
cytotoxic T-lymphocytes, continuously inhibits viral replication at
that stage
Kibayashi K, Mastri AR, Hirsch CS (1996) Neuropathology of
human immunodeficiency virus infection at different disease stages.
Hum.Pathol. 27:637-642
Abstract: The authors studied the brains
of 471 adults infected with human immunodeficiency virus type 1
(HIV-1): 123 asymptomatic
carriers, 127 in an early stage of acquired immunodeficiency
syndrome (AIDS) with
pulmonary tuberculosis or bacterial infections, and 221 in fully
developed AIDS with
opportunistic infections or neoplasms. Lymphocyte infiltration of
the leptomeninges and of perivascular spaces occurred at all stages,
but the frequency was significantly higher in asymptomatic carriers.
Microglial
nodules appeared at all stages of disease; they were not an early
indicator of HIV
encephalitis (HIVE). The
incidence of HIVE was
unrelated to the stage of AIDS,
suggesting that HIVE occurs
before opportunistic infections and neoplasms. Drug abuse, such as
cocaine and opiates, may enhance HIV
replication and increase the incidence of HIVE
in the early stage of AIDS.
Opportunistic infections or lymphoma involved only the brain in
31.2% of persons with fully developed AIDS.
Conversely, opportunistic infections or neoplasms involved only
organs other than the brain in 55.7% of persons with fully developed
AIDS. In 13.1% of persons
with fully developed AIDS,
opportunistic infections or neoplasms involved the brain and other
organs. Multiple intracranial opportunistic infections and lymphoma
coexisted in 4.1% of persons with fully developed AIDS.
The authors identified cerebrovascular disease in 10.6% of
asymptomatic carriers, 7.1% of early AIDS,
and 5.0% of fully developed AIDS.
The observed sequence of abnormalities may be useful in
understanding the progression of HIV
disease in the brain
Kong LY, Wilson BC, McMillian MK, Bing G, Hudson PM, Hong JS
(1996) The effects of the HIV-1
envelope protein gp120 on the production of nitric oxide and
proinflammatory cytokines in mixed glial cell cultures. Cell
Immunol. 172:77-83
Abstract: Although the neurotoxicity induced
by the HIV envelope
protein, gp120, has been demonstrated to require the presence of
glial cells (Microglia/astrocytes),
the mechanisms for the gp120-induced neurotoxicity are not well
understood. Moreover, the neurotoxic potencies of gp120s obtained
from various HIV isolates
are different. Since nitric oxide (NO) and proinflammatory cytokines
(TNF-alpha, IL-1, IL-6) produced by glial cells have been involved
in the neuropathogenesis of various diseases, this study examined
the effects of gp120 obtained from two strains, HIV-1IIIB
and HIV-1SF2, of the HIV-1
virus on the production of NO, TNF-alpha, IL-1 alpha, IL-1 beta, and
IL-6 in murine primary mixed glial cell cultures. The glial cells
exposed to HIV-1IIIB gp120
released NO, TNF-alpha, and IL-6 in a dose-dependent manner, whereas
IL-1 alpha and IL-1 beta were undetectable. The cells exposed to
HIV-1SF2 gp120 increased
the release of IL-6 only. The gp120-induced effects were
significantly enhanced by priming glial cells with IFN-gamma. To
investigate the cellular sources and mechanisms of the gp120-induced
IL-6 production, in situ hybridization with mRNA for IL-6 was
performed in HIV-1IIIB
gp120- or HIV-1SF2
gp120-stimulated Microgliaenriched
or astrocyte-enriched cultures. HIV-1IIIB
gp120 or HIV-1SF2 gp120
induced the expression of IL-6 mRNA in both Microglia-enriched
and astrocyte-enriched cultures, indicating that both Microglia
and astrocytes produce IL-6, and that the transcriptional regulation
is involved in the gp120-induced IL-6 production. Taken together,
these results demonstrate that the production of NO, TNF-alpha,
IL-1, or IL-6 from glial cells is differentially regulated by
HIV-1IIIB gp120 and
HIV-1SF2 gp120. These
results may provide insights into the roles of NO and
proinflammatory cytokines in the neurotoxicity of gp120s and the
neuropathology of different strains of HIV-1
viruses
Lane JH, Sasseville VG, Smith MO, Vogel P, Pauley DR, Heyes
MP, Lackner AA (1996) Neuroinvasion by simian immunodeficiency virus
coincides with increased numbers of perivascular
macrophages/Microglia
and intrathecal immune activation. J.Neurovirol. 2:423-432
Abstract:
During peak viremia and initial antibody response, rhesus macaques
infected with pathogenic and nonpathogenic isolates of SIV show
distinct differences in viral load and tissue distribution. Animals
infected with pathogenic isolates of SIV invariably have virus in
the CSF and brain parenchyma by two weeks postinoculation, whereas
animals infected with nonpathogenic isolates do not. Mechanisms
underlying neuroinvasion by SIV and HIV
are unknown, but recruitment of latently infected mononuclear cells
from the peripheral circulation (Trojan horse theory) is frequently
proposed. Circulating monocytes, from which perivascular
macrophage/Microglia
are derived, are a likely vehicle for cell-associated transport of
virus across the blood-brain barrier. This transport and the
kinetics of perivascular macrophage/Microglial
turnover in the CNS likely depend on endothelial and leukocyte
adhesion molecules such as vascular cell adhesion molecule-1
(VCAM-1), which has previously been shown to be upregulated on
cerebrovascular endothelium in SIV encephalitis. To investigate the
role of peripheral monocyte recruitment into the perivascular
macrophage/Microglial
cell pool at the time of initial viral neuroinvasion, we examined
the temporal relationships among perivascular macrophage/Microglia
density, endothelial VCAM-1 expression and localization of viral
nucleic acid in the CNS of macaques acutely infected with pathogenic
and nonpathogenic molecular clones of SIV. The concentration of CSF
quinolinic acid, a marker of intrathecal immune and macrophage
activation, was examined concurrently. We found that significant
increases in the density of perivascular macrophages/Microglia
coincided with viral neuroinvasion and marked elevations in CSF
quinolinic acid. Furthermore, combined in situ hybridization and
immunohistochemistry demonstrated that infected perivascular cells
were macrophages/Microglia.
These findings provide evidence suggesting that neuroinvasion occurs
through an influx of infected monocytes which take up residence in
the CNS as perivascular macrophages/Microglia.
VCAM-1 expression, however, was not clearly correlated with these
events, thus its contribution to initial viral neuroinvasion is
unclear
Lane TE, Buchmeier MJ, Watry DD, Fox HS (1996) Expression of
inflammatory cytokines and inducible nitric oxide synthase in brains
of SIV-infected rhesus monkeys: applications to HIV-induced
central nervous system disease. Mol.Med. 2:27-37
Abstract:
BACKGROUND: Human immunodeficiency virus type 1 (HIV-1)
infection of the central nervous system (CNS) can lead to severe
impairments in cognition, behavior, and motor skills. The
mechanism(s) by which HIV-1
induces CNS disease are not well understood. Recent evidence
suggests that expression of inducible nitric oxide synthase (iNOS)
and nitric oxide (NO) may contribute to HIV-1-induced
neurologic disease. We sought to determine if these factors were
present in the CNS of rhesus monkeys with simian immunodeficiency
virus (SIV)-induced CNS disease. MATERIALS AND METHODS: Total NO
production in cerebral spinal fluid (CSF) from infected monkeys was
determined by measuring nitrite (NO2-) and nitrate (NO3-) (stable NO
degradation products) utilizing Greiss reagents. In situ
hybridization revealed iNOS, interferon-gamma (IFNgamma), and
interleukin 1 beta (IL-1 beta) mRNA in the brains of SIV-infected
monkeys. Microglia
were isolated from animals infected with SIV. Following stimulation
with LPS, induction of iNOS mRNA in isolated Microglia
was analyzed by reverse transcriptase-polymerase chain reaction.
RESULTS: Serial CSF samples from an SIV-infected monkey reveal
increased levels of NO2-/NO3-. In situ hybridization demonstrated
iNOS, IFN gamma, and IL-1 beta mRNAs in post-mortem brain tissue of
SIV-infected monkeys. Furthermore, stimulated Microglia
from an SIV-infected monkey could produce iNOS mRNA. CONCLUSIONS:
The presence of iNOS in the brain and NO2-/NO3- in the CSF indicates
that NO is produced in the CNS of SIV-infected monkeys. The data
suggest that iNOS and NO may be contributing to SIV-induced CNS
disease
Lee SC, Dickson DW, Casadevall A (1996) Pathology of
cryptococcal meningoencephalitis: analysis of 27 patients with
pathogenetic implications. Hum.Pathol. 27:839-847
Abstract: In
this autopsy series of cryptococcal meningoencephalitis (CME), the
authors analyzed neuropathologic lesions in 13 human
immunodeficiency virus (HIV)
and 14 non-HIV-related
cases. Most non-HIV
patients did not have immunosuppressive predisposing illness.
Analysis of pathological findings revealed significant differences
in the inflammatory response to CME in patients with and without HIV
infection. None of the acquired immunodeficiency syndrome (AIDS)
patients had granulomatous inflammation, whereas most
non-HIV-associated cases
had granulomas, supporting a role for cell-mediated immunity in CME.
Lymphocytic infiltrate in both groups consisted of T cells
(CD45RO+). In some non-HIV-associated
cases, CME was undiagnosed and untreated. In most HIV-associated
cases, CME had an encephalitic component, resulting in grossly or
microscopically visible accumulations of fungi within the brain
parenchyma, whereas in non-HIV-associated
cases, CME was often confined to the subarachnoid space and large
perivascular spaces (Virchow-Robin spaces). In non-HIV-associated
cases, yeast forms were fewer and showed a more limited
distribution. In contrast, many extracellular fungi were present in
many cases of HIV-associated
CME. The principal reactive cell in CME in AIDS
was brain macrophages and Microglia,
especially those in the perivascular and juxtavascular locations.
Reactive astrocytes were limited to large destructive lesions and
subpial regions. In several patients with HIV-associated
CME, large parenchymal cryptococcomas contained Crytococcus
neoformans (CN) with cell wall pigmentation, suggestive of melanin.
The authors suggest that in AIDS
patients altered immune functions allow CN to accumulate within the
brain, predominantly extracellularly, and that deficient
macrophage/Microglial
effector function may be responsible for the altered pathology. In
addition, coexisting CNS processes in HIV-associated
CME may contribute to the altered pathology. The authors conclude
that cryptococcal meningitis is not a disease limited to the
cerebrospinal fluid (CSF) space but affects the brain more
significantly than suspected. Therapeutic strategies that enhance
the effector function of glial cells at the CNS-CSF barrier may be
useful for improving the response to therapy
Lipton SA (1996) Similarity of neuronal cell injury and death
in AIDS dementia and focal
cerebral ischemia: potential treatment with NMDA open-channel
blockers and nitric oxide-related species. Brain Pathol.
6:507-517
Abstract: Using in vitro models, our laboratory in
collaboration with those of Pierluigi Nicotera (University of
Konstanz, Germany) and Stan Orrenius (Karolinska Institute) has
recently shown that fulminant insults to the nervous system from
excitotoxins or free radicals result in neuronal cell death from
necrosis, while more subtle insults result in delayed apoptosis.
Over the past dozen or so years, mounting evidence has suggested
that excitotoxins, such as glutamate, result in neuronal cell death
after stroke. More recent evidence has suggested that in addition to
necrotic cell death in the ischemic core, a number of neurons may
also undergo apoptosis. Thus, the hypothesis that intense injury
leads to necrosis while mild insult (perhaps in the penumbra) leads
to apoptosis may hold in focal cerebral ischemia. Another
neurological malady with mounting evidence for a pathogenesis that
is mediated at least in part by excitotoxins is HIV-1-associated
cognitive/motor complex (originally termed the AIDS
Dementia Complex and, for convenience, designated here AIDS
dementia). AIDS dementia
appears to be associated with several neuropathological
abnormalities, including giant cell formation by Microglia,
astrogliosis, and neuronal injury or loss. Recently, neuronal and
other cell injury in AIDS
brains has been shown to result in apoptotic-like cell death. How
can HIV-1 result in
neuronal damage if neurons themselves are only rarely, if ever,
infected by the virus? Experiments from several different
laboratories, including our group in collaboration with that of
Howard Gendelman (University of Nebraska Medical Center), have lent
support to the existence of HIV-
and immune-related toxins in a variety of in vitro and in vivo
paradigms. In one recently defined pathway to neuronal injury,
HIV-infected macrophages/
Microglia
as well as macrophages activated by HIV-1
envelope protein gp120 appear to secrete excitants/ neurotoxins.
These substances may include arachidonic acid, platelet-activating
factor, free radicals (NO. and O2.-), glutamate, quinolinate,
cysteine, cytokines (TNF-alpha, IL1-beta, IL-6), amines, and as yet
unidentified factors emanating from stimulated macrophages and
possibly reactive astrocytes. A final common pathway for neuronal
susceptibility appears to be operative, similar to that observed in
stroke and several neurodegenerative diseases. This mechanism
involves excessive activation of N-methyl-D-aspartate (NMDA)
receptor-operated channels, with resultant excessive influx of Ca2+
and the generation of free radicals, leading to neuronal damage.
With the very recent development of clinically-tolerated NMDA
antagonists, as discussed here, there is hope for future
pharmacological intervention
Makrigeorgi-Butera M, Hagel C, Laas R, Puschel K, Stavrou D
(1996) Comparative brain pathology of HIV-seronegative
and HIV-infected drug
addicts. Clin.Neuropathol. 15:324-329
Abstract: Early stages of
infection with human immunodeficiency virus (HIV)
were studied in HIV-seropositive
drug addicts. Since heroin users are immunocompromized even in the
absence of HIV infection,
the aim of the present study was to compare the morphological
alterations present in HIV-seronegative
and HIV-seropositive drug
addicts. A total of 60 cases (32 HIV-seronegative
subjects, 21 HIV-seropositive
patients without signs of acquired immunodeficiency syndrome (AIDS),
and 7 HIV-seropositive
patients with signs of AIDS)
were investigated macroscopically, histologically, and
immunohistochemically HIV-seronegative
patients presented more frequently with acute drug intoxication,
died at a significantly younger age than HIV-seropositive
patients, and were found to suffer more frequently from
alcohol-related changes. These results indicated that
HIV-seronegative and
HIV-seropositive patients
differed possibly in their drug consumption and also in their
general conditions of life. In accordance with previous reports
activated Microglia
and a diffuse astrogliosis in the white matter were detected at a
significantly higher frequency and found to be more severe in
HIV-seropositive subjects
than in HIV-seronegative
addicts. A lymphocytic meningitis was present in 6 of 21
HIV-seropositive patients
but in none of the HIV-seronegative
patients. Perivascular infiltrates consisting of lymphocytes and
macrophages were detected at similar frequencies in HIV-seronegative
and HIV-seropositive
patients but were significantly more severe in patients suffering
from lymphocytic meningitis or purulent encephalitis. Opportunistic
infections were only demonstrated in 2 AIDS
cases. In 10 of the HIV-seronegative
patients and in 3 of the HIV-seropositive
patients CD68-and Ham56-positive multinucleated cells were detected
scattered in the subarachnoidal space exclusively over the frontal
cortex
Masliah E, Ge N, Mucke L (1996) Pathogenesis of HIV-1
associated neurodegeneration. Crit Rev.Neurobiol. 10:57-67
Abstract:
A significant number of people infected with the human
immunodeficiency virus (HIV)
develop neurologic complications. The AIDS
dementia complex is frequently accompanied by HIV
encephalitis, which is characterized at the neuropathologic level by
loss of neuronal subpopulations in the neocortex, limbic system, and
basal ganglia in association with synaptic and dendritic damage,
astrogliosis, and formation of Microglial
nodules and multinucleated giant cells. Recent studies have shown
that the extent of neurodegeneration in this condition correlates
directly with the amount of HIV-1
antigen in the brain. HIV-1
infection of the brain could result in neurodegeneration via
neurotoxic effects of viral products (e.g., gp 120, Nef, Tat) and/or
via alterations in the expression of host factors. The latter may
include increased production of potentially detrimental factors such
as cytokines, excitotoxic amino acids, free oxygen radicals, and
bioactive lipid mediators as well as interference with the
production or action of neurotrophic/protective factors.
Derangements of the neuronal calcium homeostasis, lipid
peroxidation, and induction of programmed cell death (apoptosis) may
all play a role as final common pathogenetic pathways in
HIV-1-induced
neurodegeneration. Recent studies in transgenic mice
(over)expressing HIV- or
host-derived proteins in their central nervous system indicate that
distinct neuronal populations may differ in their susceptibility to
specific pathogenic factors. For example, glutamate-receptor-bearing
pyramidal neurons were particularly susceptible to neurodegeneration
promoted by HIV-1 products,
whereas interneurons were more sensitive to the neurotoxic effects
mediated by cytokines. For the design of effective treatments for
the HIV-1-associated
cognitive/motor complex, it will be important to determine whether
the neurologic deficits in this entity result from global neuronal
dysfunction or relate more specifically to the impairment of
distinct neuronal subpopulations. It will also be critical to
examine diverse in vitro and in vivo models to help decide which of
the many pathogenetic processes that may be at work in this complex
disease constitute the most promising therapeutic targets
Meyerhoff DJ, Weiner MW, Fein G (1996) Deep gray matter
structures in HIV
infection: a proton MR spectroscopic study. AJNR Am.J.Neuroradiol.
17:973-978
Abstract: PURPOSE: To evaluate the effects of human
immunodeficiency virus (HIV)
infection on proton metabolites in brain regions carrying the
heaviest HIV load. METHODS:
We used two-dimensional proton MR spectroscopy with a preselected
volume at the level of the third ventricle to measure
N-acetyl-aspartate (NAA) and metabolites containing choline (Cho),
and creatine (Cr) in the basal ganglia of eight cognitively impaired
subjects who were seropositive for HIV
and eight control subjects who were seronegative for HIV.
Results are expressed as metabolite ratios. RESULTS: In the thalamus
and lenticular nuclei, NAA/Cr was not different between the two
groups. NAA/Cho was decreased in both the thalamus and lenticular
nuclei of the HIV-positive
group compared with the HIV-negative
group. Cho/Cr tended to be increased in both the thalamus and
lenticular nuclei of the HIV-positive
group. CONCLUSIONS: The findings suggest no NAA differences between
groups, consistent with negligible neuron loss in the region of the
brain that carries the heaviest HIV
load. The trends toward increased Cho/Cr are consistent with
histopathologic findings of infiltration of subcortical gray matter
structures with foamy macrophages, Microglia,
and lymphocytes, or possibly with gliosis
Nottet HS, Flanagan EM, Flanagan CR, Gelbard HA, Gendelman
HE, Reinhard JF, Jr. (1996) The regulation of quinolinic acid in
human immunodeficiency virus-infected monocytes. J.Neurovirol.
2:111-117
Abstract: Quinolinic acid (Quin) is thought to underlie
cognitive and motor dysfunctions for a variety of neurological
disorders. Specifically, in human immunodeficiency virus
(HIV)-associated dementia,
Quin levels correlate with the degree of neurological dysfunction
observed in affected individuals. Since recent data from our
laboratories suggest that both HIV-1
infection and activation of brain macrophages are required for the
development of neurotoxicity we examined Quin production during
virus infection and immune activation. HIV-1
infection of monocytes induced low levels of Quin while
lipopolysaccharide (LPS) or interferon-gamma (IFN-gamma) activation
of the virus-infected cells elicited 10-fold higher levels. The
combined effects of LPS and IFN-gamma for Quin production in
HIV-infected monocytes was
identical to each factor added alone. Little or no Quin was detected
in unstimulated uninfected monocytes. LPS or IFN-gamma activation of
uninfected monocytes produced substantially higher levels of Quin
than found in similarly stimulated HIV-1-infected
monocytes. These results were at variance to the production of tumor
necrosis factor-alpha (TNF-alpha). Here, a 2-to 5-fold increase in
TNF-alpha levels were observed in culture fluids of LPS-activated
HIV-infected cells when
compared to similarly stimulated uninfected monocytes. The effect of
LPS-induced Quin production by HIV-infected
monocytes was not altered by primary human astrocytes. These data
suggest that Quin levels seen in HIV
dementia are a reflection of macrophage/ Microglial
activation seen during advanced clinical disease. These findings
could help explain, in part, why few HIV-1-infected
brain macrophages can give rise to significant neurological
impairments
Persidsky Y, Limoges J, McComb R, Bock P, Baldwin T, Tyor W,
Patil A, Nottet HS, Epstein L, Gelbard H, Flanagan E, Reinhard J,
Pirruccello SJ, Gendelman HE (1996) Human immunodeficiency virus
encephalitis in SCID mice. Am.J.Pathol. 149:1027-1053
Abstract:
The human immunodeficiency virus (HIV)
is neuroinvasive and commonly causes cognitive and motor deficits
during the later stages of viral infection. (referred to as HIV
dementia). The mechanism(s) for disease revolves around secretory
products produced from immune-activated brain macrophages/Microglia.
Recently, we developed an animal model system for HIV
dementia that contains xenografts of HIV-1-infected
cells inoculated into brains of mice with severe combined
immunodeficiency (SCID). This animal system was used to
quantitatively evaluate HIV-induced
neuropathology. Xenografts of HIV-1-infected
human monocytes (placed into the putamen and cortex of SCID mice)
remained viable for 5 weeks. HIV-1
p24 antigen expression in mouse brain was persistent. Progressive
inflammatory responses (including astrogliosis and cytokine
production), which began at 3 days, peaked at day 12. The range of
astrocyte proliferative reactions exceeded the inoculation site by >
1000 microns. Brains with virus-infected monocytes showed a > or
= 1.6-fold increase in glial fibrillary acidic protein (staining
distribution and intensity) as compared with similarly inoculated
brains with uninfected control monocytes. These findings paralleled
the accumulation and activation of murine Microglia
(increased branching of cell processes, formation of Microglial
nodules, interleukin (IL)-1 beta and IL-6 expression). An
inflammatory reaction of human monocytes (as defined by HLA-DR, IL-1
beta, IL-6, and tumor necrosis factor-alpha expression) and neuronal
injury (apoptosis) also developed after virus-infected monocyte
xenograft placement into mouse brain tissue. These data, taken
together, demonstrate that this SCID mouse model of HIV-1
neuropathogenesis can reproduce key aspects of disease
(virus-infected macrophages, astrocytosis, Microglial
activation, and neuronal damage). This model may serve as an
important means for therapeutic development directed toward
improving mental function in HIV-infected
subjects with cognitive and motor dysfunction
Sawaya BE, Rohr O, Aunis D, Schaeffer E (1996) Regulation of
human immunodeficiency virus type 1 gene transcription by nuclear
receptors in human brain cells. J.Biol.Chem.
271:22895-22900
Abstract: Infection of cells of the central
nervous system by the human immunodeficiency virus type-1 (HIV-1)
leads to HIV-1-associated
neuropathology. Recent studies have demonstrated the importance of
long terminal repeat (LTR) binding sites in determining the
pathogenicity of HIV. Here
we have investigated the presence and the functional role of
transcription factors that have the potential to interact, directly
or indirectly, with the nuclear receptor-responsive element in the
LTR of HIV-1, in different
human cell lines of the brain. Cotransfection experiments showed
that in oligodendroglioma TC-620 cells, the retinoic acid receptor
and the retinoid X receptor activate LTR-driven transcription in the
absence of ligand. Addition of all-trans- or 9-cis-retinoic acid
reverses this effect. In contrast, in astrocytoma, neuronal, and
Microglial
cells, no significant effect of the retinoid acid pathway was
detected. This retinoid response is mediated by distinct molecular
interactions in the lymphotropic LAI and the neurotropic JR-CSF
HIV-1 strains. Moreover,
retinoid receptors were found to antagonize the chicken ovalbumin
upstream promoter transcription factor- as well as the
c-JUN-mediated LTR transactivation. Our findings demonstrate the
importance of the retinoic acid signaling pathway and of
cross-coupling interactions in the repression of HIV-1
LTR gene expression
Schmidtmayerova H, Nottet HS, Nuovo G, Raabe T, Flanagan CR,
Dubrovsky L, Gendelman HE, Cerami A, Bukrinsky M, Sherry B (1996)
Human immunodeficiency virus type 1 infection alters chemokine beta
peptide expression in human monocytes: implications for recruitment
of leukocytes into brain and lymph nodes. Proc.Natl.Acad.Sci.U.S.A
93:700-704
Abstract: Two chemokine (chemoattractant cytokines)
beta peptides, macrophage inflammatory proteins 1 alpha and 1 beta
(MIP-1 alpha and MIP-1 beta), were induced in human monocyte
cultures following infection with the human immunodeficiency virus
type 1 (HIV-1). Induction
depended on productive viral infection: not only did the kinetics of
MIP-1 peptide induction closely follow those of viral replication,
but monocyte cultures inoculated with heat-inactivated virus or
infected in the presence of AZT failed to produce these chemokine
beta peptides. In addition, HIV
infection markedly altered the pattern of beta chemokine expression
elicited by tumor necrosis factor (TNF), itself a potent
proinflammatory cytokine upregulated during the development of AIDS.
Reverse transcription (RT)-PCR and RT-in situ PCR studies on brain
tissue from patients with AIDS
dementia demonstrated elevated MIP-1 alpha and MIP-1 beta mRNA
expression relative to comparable samples from HIV-1-infected
patients without dementia. Cells expressing chemokines in
HIV-1-infected brains were
identified morphologically as Microglia
and astrocytes. As MIP-1 alpha and MIP-1 beta are potent
chemoattractants for both monocytes and specific subpopulations of
lymphocytes, this dysregulation of beta chemokine expression may
influence the trafficking of leukocytes during HIV
infection. These data, taken together, suggest a mechanism by which
HIV-1-infected monocytes
might recruit uninfected T cells and monocytes to sites of active
viral replication or inflammation, notably the brain and lymph nodes
Shrikant P, Benos DJ, Tang LP, Benveniste EN (1996) HIV
glycoprotein 120 enhances intercellular adhesion molecule-1 gene
expression in glial cells. Involvement of Janus kinase/signal
transducer and activator of transcription and protein kinase C
signaling pathways. J.Immunol. 156:1307-1314
Abstract: It is well
established that the two major glial cells in the central nervous
system (CNS), astrocytes and Microglia,
are key participants in mediating the neurologic dysfunction
associated with HIV
infection of the CNS. In this study, we investigated the ability of
the major envelope glycoprotein of HIV,
glycoprotein 120 (gp120), to regulate intercellular adhesion
molecule-1 (ICAM-1) expression in glial cells, because ICAM-1 is
important in mediating immune responsiveness in the CNS,
facilitating entry of HIV-infected
cells into the CNS, and promoting syncytia formation. Our results
indicate that gp120 enhances ICAM-1 gene expression in primary rat
astrocytes, primary human astrocytes, a human astroglioma cell line
CRT, and primary rat Microglia.
The signal transduction events involved in gp120-mediated
enhancement of ICAM-1 appear to involve activation of both protein
kinase C and tyrosine kinase, because inhibitors of protein kinase C
and tyrosine kinase abrogate gp120-mediated ICAM-1 expression in
both astrocytes and Microglia.
Moreover, gp120 induces tyrosine phosphorylation of signal
transducer and activator of transcription (STAT-1 alpha) as well as
the Janus kinase (JAK2) in glial cells. We also demonstrate that
gp120-mediated ICAM-1 expression has functional significance, as it
enhances the ability of monocytic cells to bind to gp120-stimulated
human astrocytes in an ICAM-1/beta 2 integrin-dependent fashion.
These results provide new insights into how gp120 can influence the
involvement of glial cells in the pathogenesis of AIDS
dementia complex
Sopper S, Demuth M, Stahl-Hennig C, Hunsmann G, Plesker R,
Coulibaly C, Czub S, Ceska M, Koutsilieri E, Riederer P, Brinkmann
R, Katz M, ter M, V (1996) The effect of simian immunodeficiency
virus infection in vitro and in vivo on the cytokine production of
isolated Microglia
and peripheral macrophages from rhesus monkey. Virology
220:320-329
Abstract: Microglia
are the major target for human immunodeficiency virus (HIV)
infection within the central nervous system. Because only a few
cells are productively infected, it has been suggested that an
aberrant cytokine production by this cell population may be an
indirect mechanism leading to the development of neurological
disorders in HIV-infected
patients. Therefore we decided to study the secretion pattern of
several interleukins (IL) by Microglial
cells and peripheral blood macrophages isolated from uninfected and
simian immunodeficiency virus (SIV)-infected Rhesus monkeys. We
found that uninfected, unstimulated primate Microglia
produce more IL-6 and less TNF alpha than peripheral blood
macrophages, but generate comparable levels of IL-1 beta and IL-8.
After infection with SIV in vitro, synthesis of all cytokines tested
is increased compared to uninfected cultures and to peripheral blood
macrophages. Microglia
isolated from infected animals produce more IL-8 and TNF alpha than
the uninfected cultures and display a strongly increased capacity to
secrete TNF alpha upon stimulation with lipopolysaccharide. In
addition, production of IL-6 by in vivo-infected Microglia
increases with time in culture to very high levels despite the fact
that only a few cells contained replicating virus. These findings
clearly show that the cytokine production of Microglia
is impaired after SIV infection both in vitro and in vivo and that a
low level of viral replication is sufficient for these alterations
to occur. In conclusion, the results of this study further support a
possible role of cytokines in the pathogenesis of neuro-AIDS
Strizki JM, Albright AV, Sheng H, O'Connor M, Perrin L,
Gonzalez-Scarano F (1996) Infection of primary human Microglia
and monocyte-derived macrophages with human immunodeficiency virus
type 1 isolates: evidence of differential tropism. J.Virol.
70:7654-7662
Abstract: To ascertain whether viruses present at
the time of primary viremia can infect the central nervous system
and to determine if Microglial
tropism is distinct from tropism for monocyte-derived macrophages
(MDM), 27 human immunodeficiency virus type 1 (HIV-1)
isolates obtained from acutely infected individuals, as well as
laboratory strains, were assayed for their ability to replicate in
primary adult Microglial
cultures and in MDM. Most of the isolates replicated equally well in
both Microglia
and MDM, but several isolates replicated preferentially in one of
the two cell types, differing by as much as 40-fold in p24gag
production. This indicated that while MDM and Microglial
tropism overlap, a subset of isolates is particularly tropic for one
of the two cell types. One isolate was further adapted to Microglia
by 15 sequential passages, raising the peak p24 concentration
produced by 1,000-fold. In addition, the passaged virus induced
marked cytopathologic changes (vacuolization and syncytium
formation) in infected Microglial
cultures. Sequence comparison of the V3 loop of unpassaged and
multiply passaged virus revealed amino acid changes shown to be
associated with isolates from patients with HIV
dementia. Our data support the hypothesis that HIV-1
infection can be established in the central nervous system by
viruses present early in HIV
infection, that some of these viruses are particularly tropic for
Microglia,
and that adaptation in this cell type can result in the selection of
a pool of predominantly Microglia-tropic
(neurotropic) viruses
Sundar KS, Kamaraju LS, McMahon J, Bitonte RA, Gollapudi S, Wilson WH, Kong LY, Hong JS, Lee JE (1996) Endogenous opioids and HIV infection. Adv.Exp.Med.Biol. 402:53-57
Takahashi K, Wesselingh SL, Griffin DE, McArthur JC, Johnson
RT, Glass JD (1996) Localization of HIV-1
in human brain using polymerase chain reaction/in situ hybridization
and immunocytochemistry. Ann.Neurol. 39:705-711
Abstract: Human
immunodeficiency virus type 1 (HIV-1)
infects the brains of a majority of patients with the acquired
immunodeficiency syndrome (AIDS),
and has been linked to the development of a progressive dementia
termed "HIV-associated
dementia." This disorder results in severe cognitive,
behavioral, and motor deficits. Despite this neurological
dysfunction, HIV-1
infection of brain cells does not occur significantly in neurons,
astrocytes, or oligodendrocytes, but is restricted to brain
macrophages and Microglia.
To identify possible low-level or latent infection of other brain
cells, we combined the techniques of the polymerase chain reaction
with in situ hybridization for the detection of HIV
DNA, and used immunocytochemistry to identify the HIV-expressing
cells. In the 21 adult brains studied (15 AIDS
and 6 seronegative control brains), we found that polymerase chain
reaction/in situ hybridization was both sensitive and specific for
identifying HIV-infected
cells. In all brains, the majority of infected cells were
macrophages and Microglia.
In several brains, however, a substantial minority of cells
harboring HIV DNA were
identified as astrocytes. Neurons, oligodendrocytes, and endothelial
cells were not infected with HIV,
even in cases with HIV-associated
dementia. These findings confirm previous data regarding the
importance of macrophage/Microglial
infection, and essentially exclude neuronal infection in
pathogenetic models of HIV-associated
neurological disease. These data also demonstrate that latent or
low-level infection of astrocytes occurs in AIDS,
a finding that may be of importance in understanding HIV
neuropathogenesis
Vidal-Lampurdanes C, Pumarola-Sune T (1996) [The virus of
human immunodeficiency: virological characteristics, natural history
and physiopathology of the nervous system infection]. Rev.Neurol.
24:1563-1568
Abstract: Three phases are recognized in the natural
history of infection by the human immunodeficiency virus (HIV):
(a)an early or acute phase lasting several weeks, (b) an
intermittent or chronic phase, with active low-grade viral
replication, lasting several years and (c) the final stage or
crisis, which corresponds to the clinical phase of AIDS.
The virus may enter the nervous system at the time of
seroconversion. However the clinical picture of dementia appears
later, when there is marked immunodeficiency. HIV
enters the nervous system carried in the macrophages, and usually
infects the Microglia
but not the neurons. The physiopathology of dementia is not well
known. It is thought that neuronal dysfunction may be mediated by
viral proteins and cytokines synthetized by the infected cells and
toxic to the neurones
Westmoreland SV, Kolson D, Gonzalez-Scarano F (1996) Toxicity
of TNF alpha and platelet activating factor for human NT2N neurons:
a tissue culture model for human immunodeficiency virus dementia.
J.Neurovirol. 2:118-126
Abstract: A significant proportion of
HIV-1 infected individuals
develop a symptom complex consisting of dementia and motor deficits
termed HIV Dementia (HIVD)
or the AIDS Dementia
complex (ADC). The pathophysiology of this neurologic complication
is unclear, but neuronal injury and death may occur as a direct
result of the release of cytokines from HIV-1
infected Microglial
cells (Everall et al, 1991). To evaluate the utility of a human
neuronal cell line, NT2N, for studies of HIV-related
neuronal cytotoxicity, we studied cellular viability after exposure
to HIV-1 gp120, tumor
necrosis factor alpha (TFN alpha), platelet activating factor (PAF),
interleukin 1 beta (IL-1 beta), and interferon gamma (IFN gamma),
all of which have been implicated in previous publications as having
a role in HIVD (Brenneman
et al, 1988; Dreyer et al, 1990; Merrill et al, 1992; Gelbard et al,
1993). Neither gp 120 nor the cytokines IL-1 beta and IFN gamma
resulted in significant NT2N cell death. However, TNF alpha and PAF
were highly neurotoxic in this assay. Pentoxifylline, which inhibits
the effects of TNF alpha, had a significant protective effect. This
system provides an excellent substrate for the evaluation of
neurotoxicity and for the development of pharmacologic agents that
may be useful in HIV
dementia
Brew BJ, Rosenblum M, Cronin K, Price RW (1995) AIDS
dementia complex and HIV-1
brain infection: clinical-virological correlations. Ann.Neurol.
38:563-570
Abstract: To evaluate the presence and distribution of
central nervous system infection by human immunodeficiency virus
type 1 (HIV-1), we used
immunohistochemical methods to map the HIV-1
p24 core protein in the brains of 55 autopsied patients with
acquired immunodeficiency syndrome (AIDS).
In a subset of 40 of these patients who had undergone antemortem
neurological evaluation of the AIDS
dementia complex (ADC), we analyzed the relation between the
severities of the viral infection and clinical dysfunction. Viral
antigen was detected in macrophages and cells with morphological and
immunohistochemical characteristics of Microglia
as well as multinucleated cells. The distribution of
antigen-positive cells preferentially involved certain deep brain
structures, especially the globus pallidus, other basal ganglia
nuclei, and the central white matter. Overall, the presence and
frequency of infected cells were highly correlated with the
histological findings of multinucleated-cell encephalitis and in
general with the clinical ADC stage. However, infection was often
more limited than might be "anticipated" from the severity
of patients' clinical dysfunction: Only 61% of patients with at
least ADC stage 1 had detectable antigen and of these only
approximately 30% of the brain sections were antigen positive. These
results suggest a pathogenetic model of ADC where virus- or
cell-coded toxins amplify the effect of limited brain infection
Bubien JK, Benveniste EN, Benos DJ (1995) HIV-gp120
activates large-conductance apamin-sensitive potassium channels in
rat astrocytes. Am.J.Physiol 268:C1440-C1449
Abstract: Central
nervous system (CNS) involvement usually occurs in individuals
infected with human immunodeficiency virus type 1 (HIV-1).
Evidence is now accumulating that neurons and astrocytes may be
functionally compromised by exposure to viral components or cellular
factors released from HIV-1-infected
macrophages and/or Microglia.
We have previously reported that the HIV
coat protein gp120 stimulates Na+/H+ exchange in primary cultured
rat astrocytes, which, ultimately, results in the activation of a K+
conductance. In this report we characterize the electrophysiological
and biophysical properties of the channels responsible for the
gp120-induced increase in K+ conductance. These K+ channels had a
relatively large unitary conductance (147 pS), were not gated by
voltage, were sensitive to changes in H+ concentration at their
cytosolic face, were specifically inhibited by apamin, and were
insensitive to charybdotoxin and tetraethylammonium. The activation
of these channels by gp120 is referable to cellular alkalinization
subsequent to Na+/H+ exchange stimulation; gp120 failed to activate
these K+ channels in the absence of external Na+ or in the presence
of amiloride, an inhibitor of Na+/H+ exchange. Subsequent K+ loss
from the astrocyte into the restricted extracellular space
surrounding neurons can then lead to neuronal depolarization,
activation of voltage-sensitive Ca2+ channels, and, eventually, cell
death. Thus abnormal activation of astrocyte K+ channels by gp120
may contribute to the CNS pathophysiology associated with HIV-1
infection
Codazzi F, Menegon A, Zacchetti D, Ciardo A, Grohovaz F,
Meldolesi J (1995) HIV-1
gp120 glycoprotein induces [Ca2+]i responses not only in type-2 but
also type-1 astrocytes and oligodendrocytes of the rat cerebellum.
Eur.J.Neurosci. 7:1333-1341
Abstract: Cultures of cerebellar
cortex cells were exposed to the HIV-1
envelope glycoprotein, gp120, and investigated for cytosolic Ca2+
ion concentration ([Ca2+]i) changes by the fura-2 ratio videoimaging
technique while bathed in complete, Na(+)-free or Mg(2+)-free
Krebs-Ringer media. At the end of the [Ca2+]i experiments the cells
were fixed and immunoidentified through the revelation of markers
specific for neurons (microtubule associated protein-2), type-2
(A2B5) or all (glial fibrillary acidic protein) astrocytes,
oligodendrocytes (galactocerebroside) or Microglia
(F4/80 antibody). In complete medium, rapid biphasic (spike-plateau)
responses induced by gp120 (0.1-1 nM) were observed in a
subpopulation of type-2 astrocytes. In addition, slow but
progressive responses were observed in other type-2 cells and
oligodendrocytes, whereas type-1 astrocytes showed small responses,
if any, and granule neurons did not respond at all. Use of
Na(+)-free medium (a condition that blocked another gp120-induced
response, cytosolic alkalinization) resulted in an increase in
[Ca2+]i response that was appreciable not only in type-2 but also in
most type-1 astrocytes, possibly because of the inhibition of the
Na+/Ca2+ exchanger and the ensuing decrease in Ca2+ extrusion.
Granule neurons, including those in direct contact with responsive
astrocytes, remained unresponsive, even when the experiments were
carried out in Mg(2+)-free medium supplemented with glycine, a
condition that favors activation of the glutamatergic
N-methyl-D-aspartate (NMDA) receptor.(ABSTRACT TRUNCATED AT 250
WORDS)
Crowe SM (1995) Role of macrophages in the pathogenesis of
human immunodeficiency virus (HIV)
infection. Aust.N.Z.J.Med. 25:777-783
Abstract: There are a
number of machanisms by which HIV-infected
macrophages contribute to the pathogenesis of the Acquired
Immunodeficiency Syndrome (AIDS).
Macrophage-tropic strains of HIV
are present at the time of infection, and persist throughout the
course of infection, despite the emergence of T cell tropic
quasispecies. As HIV causes
chronic infection of macrophages with only minimal cytopathology,
these cells can provide an important viral reservoir in HIV-infected
persons. Macrophages are more susceptible to HIV
infection than freshly isolated monocytes. HIV-infected
macrophages can contribute to CD4 T lymphocyte depletion through a
gp120-CD4 dependent fusion process with uninfected CD4-expressing T
cells. Increasing data support the role of HIV-infected
macrophages and Microglia
in the pathogenesis of HIV-related
encephalopathy and AIDS-related
dementia through the production of neurotoxins. HIV
infection of macrophages in vitro results in impairment of many
aspects of their function. Reduced phagocytic capacity for certain
opportunistic pathogens, including Toxoplasma gondii and Candida
albicans, may be responsible for reactivation of these pathogens in
persons with advanced HIV
infection, although the mechanisms underlying reactivation of
infections and susceptibility to disease from new infections are
likely to be multifactorial. Our studies showing defective
phagocytosis and killing provide additional information that
contribute to our understanding of the pathogenesis of AIDS.
Studies of in vitro efficacy of potential antiretroviral therapies
should be performed in both primary lymphocyte and monocyte
cultures, given the importance of both of these cell populations to
HIV pathogenesis and their
differing biology
Dollard SC, James HJ, Sharer LR, Epstein LG, Gelbard HA,
Dewhurst S (1995) Activation of nuclear factor kappa B in brains
from children with HIV-1
encephalitis. Neuropathol.Appl.Neurobiol. 21:518-528
Abstract:
Human immunodeficiency virus type 1 (HIV-1)
infection of the central nervous system is associated with decreased
neuronal density in discrete areas of the brain. Neuronal loss may
occur via apoptosis, initiated by soluble neurotoxic factors
secreted from HIV-1
infected macrophages and Microglia.
To examine further the molecular events involved in HIV-1
neuropathogenesis, we assessed the activity of NF kappa B, an
inducible transcription factor involved in the activation of
multiple proinflammatory, and potentially neurotoxic, genes. NF
kappa B was analysed by immunocytochemistry using specific antisera
to the NF kappa B p. 50 and p. 65 subunits. Brains from children
with HIV-1 encephalitis and
progressive encephalopathy were found to contain increased numbers
of NF kappa B immunoreactive cells, relative to control brains
(HIV-1 negative, or HIV-1
positive without encephalitis). Double-labelling studies using
antibodies to CD68, or RCA-1 lectin, markers for cells of
monocyte/macrophage lineage, revealed an increase in the number of
Microglia
and macrophages with nuclear immunoreactivity for NF kappa B in
association with HIV-1
encephalitis. NF kappa B positive multinucleated giant cells were
also detected, as were cells which contained both NF kappa B and
HIV-1 antigen. In contrast,
the number of neurons and GFAP-positive astrocytes that were
immunoreactive for NF kappa B was approximately the same in all
groups of subjects. These data are consistent with the hypothesis
that persistent, high-level activation of NF kappa B may promote the
sustained production of neurotoxins by Microglia
and macrophages during HIV-1
encephalitis
Dubois-Dalcq M, Altmeyer R, Chiron M, Wilt S (1995) HIV
interactions with cells of the nervous system. Curr.Opin.Neurobiol.
5:647-655
Abstract: HIV
can invade the CNS, where it replicates principally in macrophages.
Yet, neurological disease is more often correlated with levels of
neurotoxins or tumor necrosis factor alpha than with viral
replication or specific viral determinants in brain. In experimental
systems, HIV glycoprotein
affects functions of uninfected Microglia
and astrocytes to eventually cause neuronal death. While the
cellular basis of cognitive and neurological dysfunction are
unravelled in the simian immunodeficiency virus model, the molecular
mechanisms of HIV
neurotoxicity are being studied in newly developed mouse models
Espey MG (1995) Apoptosis and HIV
neuropathogenesis. Med.Hypotheses 44:536-538
Abstract: A
consequence of HIV
infection may be neurological dysfunction secondary to the presence
of virus in the central nervous system (CNS). The CNS tropism of HIV
and the mechanisms that govern its dissemination are not well
defined. One view is that HIV
enters the brain through the diapedesis of infected monocytes from
blood into the perivascular space. HIV
may then spread to susceptible cells throughout parenchyma. An
alternate hypothesis is presented, which suggests that T lymphocyte
apoptosis may also participate in HIV
entry and dissemination in the brain. This is based on the following
observations: 1) T lymphocyte apoptosis may be a CNS-specific
mechanisms to control inflammation, 2) the most common circulating
reservoir of HIV is the T
lymphocyte, 3) uninfected macrophages recruited to phagocytize HIV
infected apoptotic T lymphocytes in vitro can become productively
infected, and 4) the predominant form of HIV
in the CNS is unintegrated. Aberrantly high levels of apoptosis in
HIV infected lymphocytes
within the CNS and subsequent recruitment and infection of
macrophages and Microglia
may be a novel component of HIV
neuropathogenesis
Gehrmann J, Matsumoto Y, Kreutzberg GW (1995) Microglia:
intrinsic immuneffector cell of the brain. Brain Res.Brain Res.Rev.
20:269-287
Abstract: Microglia
form a regularly spaced network of resident glial cells throughout
the central nervous system (CNS). They are morphologically,
immunophenotypically and functionally related to cells of the
monocyte/macrophage lineage. In the ultimate vicinity of the
blood-brain barrier two specialized subsets of macrophages/Microglia
can be distinguished: firstly, perivascular cells which are enclosed
within the basal lamina and secondly juxtavascular Microglia
which make direct contact with the parenchymal side of the CNS
vascular basal lamina but represent true intraparenchymal resident
Microglia.
Bone marrow chimera experiments indicates that a high percentage of
the perivascular cells undergoes replacement with bone
marrow-derived cells. In contrast, juxtavascular Microglia
like other resident Microglia
form a highly stable pool of CNS cells with extremely little
turnover with the bone marrow compartment. Both the perivascular
cells and the juxtavascular Microglia
play an important role in initiating and maintaining CNS autoimmune
injury due to their strategic localization at a site close to the
blood-brain barrier, their rapid inducibility for MHC class II
antigens and their potential scavenger role as phagocytic cells. The
constantly replaced pool of perivascular cells probably represents
an entry route by which HIV
gets access to the brain. Microglia
are the first cell type to respond to several types of CNS injury.
Microglial
activation involves a stereotypic pattern of cellular responses,
such as proliferation, increased or de-novo expression of
immunomolecules, recruitment to the site of injury and functional
changes, e.g., the release of cytotoxic and/or inflammatory
mediators. In addition, Microglia
have a strong antigen presenting function and a pronounced cytotoxic
function. Microglial
activation is a graded response, i.e., Microglia
only transform into intrinsic brain phagocytes under conditions of
neuronal and or synaptic/terminal degeneration. In T-cell-mediated
autoimmune injury of the nervous system, Microglial
activation follows these lines and occurs at an early stage of
disease development. In experimental autoimmune encephalomyelitis
(EAE), Microglia
proliferate vigorously, show a strong expression of MHC class I and
II antigens, cell adhesion molecules, release of reactive oxygen
intermediates and inflammatory cytokines and transform into
phagocytic cells. Due to their pronounced antigen presenting
function in vitro, activated Microglia
rather than astrocytes or endothelial cells are the candidates as
intrinsic antigen presenting cel of the brain. In contrast to
Microglia,
astrocytes react with a delay, appear to encase morphologically the
inflammatory lesion and may be instrumental in downregulating the
T-cell-mediated immune injury by inducing T-cell apoptosis.(ABSTRACT
TRUNCATED AT 400 WORDS)
Glass JD, Fedor H, Wesselingh SL, McArthur JC (1995)
Immunocytochemical quantitation of human immunodeficiency virus in
the brain: correlations with dementia. Ann.Neurol.
38:755-762
Abstract: The pathogenesis of human immunodeficiency
virus (HIV)-associated
dementia is unclear, and the underlying pathological substrate has
been a matter of debate. In a prospectively clinically characterized
population of acquired immunodeficiency syndrome (AIDS)
patients we investigated the relationship between the clinical
syndrome of HIV-associated
dementia and the presence and relative quantity of
immunocytochemical markers for HIV-1
(gp41 antibody), and for macrophages and Microglia
(HAM-56 antibody). Sections from the basal ganglia and frontal lobes
from the brains of 51 patients were studied, and the data were
stratified for severity of dementia (16 nondemented, 12 mildly
demented, 23 severely demented), rate of dementia progression,
duration of AIDS, use of
antiretrovirals, and several other demographic features. We found a
highly significant correlation between the degree of macrophage
staining and the severity of dementia but only a borderline
correlation between the presence and amount of gp41-positive cells
and dementia. Several nondemented patients showed abundant gp41
immunoreactivity, and some severely demented showed little to no
gp41 immunoreactivity. Other correlations with the immunostaining
data, including antiretroviral use, were not significant. We
conclude that the presence of macrophages and Microglia
is a better correlate with HIV-associated
dementia than is the presence and amount of HIV-infected
cells in the brain. These data support the concept that the
pathogenesis of HIV-associated
dementia is likely due to indirect effects of HIV
infection of the brain, possibly through the actions of macrophages
and Microglia
Hassine D, Gray F, Chekroun R, De Truchis P, Schouman-Claeys
E, Vallee C (1995) [CMV and VZV encephalitis in AIDS].
J.Neuroradiol. 22:184-192
Abstract: MATERIAL AND METHODS: Eighty
patients were followed up prospectively. Histological correlation
was obtained in 25 cases. All MRI examinations were performed on at
0.5 Tesla in T1-weighted sequences with and without gadolinium
injection, and in axial or frontal T2-weighted spin echo sequences.
Histological confirmation was obtained 30 days on average after the
last MRI examination. Immunohistochemical stainings were performed
in search of CMV, VZV, toxoplasma, HIV
antigen and lymphoma. RESULTS: CMV meningoencephalitis was found in
6 cases. In 3 of these it was manifested by atrophy, either isolated
or associated with high signal intensity punctiform areas. Histology
detected cortical or subcortical Microglial
nodules. In 2 cases MRI displayed abnormalities of subependymal
nodular signals without enhancement, associated with punctiform
abnormalities of subcortical signals. Histology showed subependymal
foci of necrosis and abnormalities of white matter. In one case, MRI
showed a ventriculitis confirmed by histology. VZV
meningoencephalitis was diagnosed in 2 cases. MRI displayed abnormal
basal ganglia related to meningitis (n = 1). All abnormalities were
confirmed at histology. CONCLUSION: Some images (ventriculitis,
infarction in basal ganglia, abnormal subependymal signal) would
suggest VZV and CMV encephalitis. Other images (abnormalities of
punctiform signals or atrophy) are not specific
Henin D, Gervaz E, Seilhean D (1995) [Pathologic anatomy of
cytomegalovirus encephalomyelitis and varicella-zona virus
encephalomyelitis]. J.Neuroradiol. 22:180-183
Abstract:
Cytomegalovirus (CMV) infection of the nervous system is frequent in
acquired immunodeficiency syndrome (AIDS)
and can be responsible for encephalitis, encephalomyelitis,
meningoradiculitis or polyradiculo-neuropathy. Encephalitis is
characterized at microscopy by its periventricular and cerebellar
location, and by the presence of cytomegalic cells, containing
intranuclear and/or intracytoplasmic inclusions, Microglial
nodules and necrotic foci. The virus can infect almost all types of
cells. Coexistence of CMV and HIV
has been observed in giant cells of macrophagic origin. It has been
suggested that the two viruses could act in synergy. The nervous
system is seldom infected by the varicella-zoster virus (VZV) in
AIDS. The infection can be
responsible for multifocal leukoencephalitis, ventriculitis,
vascular lesions associated or not with cerebral infarction, or with
meningomyeloradiculitis. In almost all cell types Cowdry's type A
intranuclear inclusions have been found. The virus can be
demonstrated by immunohistochemistry or in situ hybridization. VZV
antigens have been reported in the walls of vessels damaged by a non
inflammatory obliterating vasculopathy or by a granulomatous
angiitis. Coexistence of VZV and HIV
has been observed in giant cells of macrophagic origin, and synergy
between those two viruses has been suspected
Holliday J, Parsons K, Curry J, Lee SY, Gruol DL (1995)
Cerebellar granule neurons develop elevated calcium responses when
treated with interleukin-6 in culture. Brain Res.
673:141-148
Abstract: In humans, elevated levels of cytokines are
associated with several diseases (including HIV
infection and Down Syndrome) that result in developmental
abnormalities. Overexpression of interleukin-6 (IL-6) in the central
nervous system has been shown to cause extensive neuronal
abnormality in mice that becomes more evident with maturation.
However, it is difficult to separate direct effects of IL-6 on the
developing neurons of an intact animal from indirect effects
involving effects on other cell types that possess cytokine
receptors, such as Microglia
and astrocytes. We have found that IL-6 treatment of rat cerebellar
granule neurons developing in the absence of other cell types in
culture results in the persistence of large, depolarization or
neurotransmitter-induced calcium transients, that are normally
observed only in immature neurons. The cause of this appears to be
the persistence of a calcium-induced calcium release (CICR)
component of the calcium response to stimulation. This basic
abnormality in neuronal development may contribute to the
developmental abnormalities associated with human syndromes that
involve elevated cytokine levels
Ioannidis JP, Reichlin S, Skolnik PR (1995) Long-term
productive human immunodeficiency virus-1 infection in human infant
Microglia.
Am.J.Pathol. 147:1200-1206
Abstract: The course of human
immunodeficiency virus 1 (HIV-1)
infection in human infant Microglia
was studied using purified primary cultures of Microglia
derived from brain autopsy tissue. Previous in vitro studies have
used fetal or adult brain tissue. Important differences may exist
between brain tissues of different maturational ages with regard to
HIV-1 replication and other
neuropathogenic effects. Infant Microglia
were infected with four different strains of HIV-1
(JR-FL, JR-CSF, Ba-L, and IIIB). Productive infection was
demonstrated by p24 antigen production, immunocytochemistry, and
recovery of replication-competent virus from the supernatants of the
infected cultures. Multinucleated giant cells developed in culture
mimicking the neuropathological changes seen in the brains of
patients with HIV
encephalopathy. Productive infection was more readily established by
monocyte-tropic strains (JR-FL and Ba-L) of HIV-1
than by a lymphocyte-tropic strain (IIIB). p24 antigen production in
this system peaked at 47 to 51 days postinfection. Viral persistence
in giant cells was demonstrated by immunocytochemistry for the gp120
and gp41 viral antigens as late as 70 days postinfection. This in
vitro culture system, using infant Microglia
that support viral replication for more than 2 months, may provide a
useful model for studying the pathogenesis of progressive HIV
encephalopathy
Ishimoto S, Fujimura Y, Yamanaka T, Shimoyama T, Nishida S,
Matsuoka H, Nishikawa K, Yoshioka A, Narita N, Honda M, . (1995) [An
enzyme-linked immunosorbent assay determining anti-principal
neutralizing determinant antibodies using synthetic peptides deduced
from cDNA sequences of HIV-1
V3 loop domain]. Rinsho Ketsueki 36:193-199
Abstract: The V3
domain, one of the hypervariable regions of gp 120 in HIV-1
possesses principal type-specific neutralizing determinant (PND).
The V3 domain has the epitopes for class I major histocompatibility
antigens of cytotoxic-T lymphocyte and helper-T-lymphocyte
recognition sites, and also has major determinants for cell tropism
towards macrophage, Microglia,
and human brain-derived fibroblast. Therefore, establishment for the
assay of anti-PND antibodies in patients with HIV-1
infection appears to be important for the estimation on developing
AIDS in these patients. We
here describe a simple enzyme-linked immunosorbent assay (ELISA) for
the measurement of anti-PND antibodies found in Japanese
hemophiliacs. ELISA was performed using synthetic peptides, each 15
amino acid residues deduced from cDNA sequences of seven HIV-1
V3 domain mutants, which include 5 North-American and European
strains (IIIB, MN, RF, SC, and WMJ-2) and 2 African strains (Af1.
Con and Af2, Con). The specific antibody binding to each peptide was
determined after subtraction of the non-specific binding from the
total. In 49 control sera from healthy individuals with HIV-1
antibody negative, the absorbance (M +/- 1SD) at 405 nm was -0.002
+/- 0.064. Then, the cut off value was determined to be M + 4SD. In
48 hemophiliac sera with HIV-1
antibody negative, the absorbance was uniformly less than the cut
off value. However, among 44 hemophiliac sera with HIV-1
antibody positive, the anti-PND antibodies were detected in the
following frequencies; 2 for IIIB, 20 for MN, 1 for RF, 1 for Af1.
Con, and 5 for Af2. Con.(ABSTRACT TRUNCATED AT 250 WORDS)
Koka P, He K, Zack JA, Kitchen S, Peacock W, Fried I, Tran T,
Yashar SS, Merrill JE (1995) Human immunodeficiency virus 1 envelope
proteins induce interleukin 1, tumor necrosis factor alpha, and
nitric oxide in glial cultures derived from fetal, neonatal, and
adult human brain. J.Exp.Med. 182:941-951
Abstract: Although
Microglia
are the only cells found to be productively infected in the central
nervous system of acquired immunodeficiency disease syndrome (AIDS)
patients, there is extensive white and gray matter disease
nonetheless. This neuropathogenesis is believed to be due to
indirect mechanisms other than infection with human immunodeficiency
virus 1 (HIV-1). Cytokines
and toxic small molecules have been implicated in the clinical and
histopathological findings in CNS AIDS.
Previously, we have demonstrated in rodent glial cultures the
presence of biologically active epitopes of gp120 and gp41 that are
capable of inducing interleukin 1 and tumor necrosis factor alpha.
In this study, we map the HIV-1
envelope epitopes that induce nitric oxide, inducible nitric oxide
synthase, interleukin 1, and tumor necrosis factor alpha in human
glial cultures. Epitopes in the carboxy terminus of gp120 and the
amino terminus of gp41 induce these proinflammatory entities. In
addition, we compare HIV-1
infection and pathology in glial cells derived from human brain
taken at different states of maturation (fetal, neonatal, and adult
brain) in an effort to address some of the clinical and histological
differences seen in vivo. This study demonstrates that, in the
absence of virus infection and even in the absence of distinct viral
tropism, human glia respond like rodent glia to non-CD4-binding
epitopes of gp120/gp41 with cytokine and nitric oxide production.
Differences among fetal, neonatal, and adult glial cells'
infectivity and cytokine production indicate that, in addition to
functional differences of glia at different stages of development,
cofactors in vitro and in vivo may also be critical in facilitating
the biological responses of these cells to HIV-1
Lane TE, Buchmeier MJ, Watry DD, Jakubowski DB, Fox HS (1995)
Serial passage of Microglial
SIV results in selection of homogeneous env quasispecies in the
brain. Virology 212:458-465
Abstract: The pathogenic effects of
HIV include infection of
the central nervous system (CNS) which can result in cognitive and
motor dysfunction. Simian immunodeficiency virus (SIV) infection of
rhesus macaques provides an excellent model of HIV-induced
disease. We have achieved a reproducible infection of the CNS using
a stock of virus obtained by serial passage of Microglia-associated
SIV. Since the envelope genes of both HIV
and SIV encode determinants important in viral pathogenesis, and the
variability inherent in these viruses provides a molecular footprint
of viral quasispecies, we analyzed the viral env sequences resulting
from this serial passage. SIV env sequences were analyzed by direct
PCR amplification of DNA isolated from Microglia
from infected animals. Nucleotide sequence comparison reveals that
serial passage of Microglia-associated
SIV resulted in divergence from the donor stock of virus.
Furthermore, an enrichment of unique env quasispecies which is
maintained through the serial passage was found in the diseased
brains
Nath A, Hartloper V, Furer M, Fowke KR (1995) Infection of
human fetal astrocytes with HIV-1:
viral tropism and the role of cell to cell contact in viral
transmission. J.Neuropathol.Exp.Neurol. 54:320-330
Abstract:
Astrocyte cultures from human fetal brain were infected with human
immunodeficiency virus (HIV)
either as free virus or with a chronically infected lymphoblastoid
cell line and monitored for signs of infection. The lymphocytotropic
strains HIV3B and
HIVSF2(ARV-2) but not the
monocytotropic strain HIVAda-M
infected the human fetal astrocytes. The infected cells were
monitored by immunocytochemistry, detection of p24 antigen in the
supernatants and polymerase chain reaction amplification of the
proviral DNA. No morphological or cytopathic effects were seen in
these cells. Upon co-culture of astrocytes with a lymphoblastoid
cell line chronically infected with HIVSF2(ARV-2),
the lymphoblastoid cells readily adhered to the astrocytes as
determined by a 51Cr adhesion assay and by light and electron
microscopy. This cell to cell contact resulted in infection of
increased numbers of astrocytes. Similar adhesion of lymphoblasts to
Microglia
was not seen. Thus, astrocytes from human fetal brain can be
infected in vitro directly by lymphocytotropic strains of HIV
or by adherence to infected lymphoblastoid cells
Peterson PK, Gekker G, Hu S, Sheng WS, Molitor TW, Chao CC
(1995) Morphine stimulates phagocytosis of Mycobacterium
tuberculosis by human Microglial
cells: involvement of a G protein-coupled opiate receptor.
Adv.Neuroimmunol. 5:299-309
Abstract: Opiate-induced
immunosuppression has been implicated in the pathogenesis of
infections caused by a variety of microorganisms, including human
immunodeficiency virus (HIV).
Although effects of opiates on lymphocyte function have been studied
more extensively, morphine also has been shown to inhibit several
functional activities of mononuclear phagocytes (e.g. chemotaxis,
respiratory burst activity and phagocytosis). Opiate addiction has
been identified as a risk factor for clinical tuberculosis prior to
the HIV epidemic, and
macrophages are a key cell in the pathogenesis of Mycobacterium
tuberculosis. Thus, the hypothesis was tested in the present study
that morphine would suppress phagocytosis of M. tuberculosis by
human Microglial
cells, the resident macrophages of the brain. Contrary to this
hypothesis, treatment of human fetal Microglial
cell cultures with morphine (10(-8) M) was found to stimulate
phagocytosis of nonopsonized M. tuberculosis H37Rv. The stimulatory
effect of morphine was blocked by naloxone and the mu opiate
receptor selective antagonist beta-funaltrexamine. Also,
morphine-induced increase in phagocytic activity was markedly
inhibited by pertussis toxin and was unaffected by cholera toxin,
suggesting the mechanism of morphine's stimulatory effect on
Microglial
cell phagocytosis involves a Gi protein-coupled mu opiate receptor.
The results of this in vitro study support the concept that
exogenous and endogenous opioids play an immunomodulatory role
within the central nervous system through their interaction with G
protein-coupled receptors on Microglial
cells
Pulliam L, Moore D, West DC (1995) Human cytomegalovirus
induces IL-6 and TNF alpha from macrophages and Microglial
cells: possible role in neurotoxicity. J.Neurovirol.
1:219-227
Abstract: Human cytomegalovirus (HCMV) can frequently
infect the central nervous system (CNS) in the setting of
immunosuppression such as transplantation and infection with the
human immunodeficiency virus (HIV).
Our laboratory previously reported that HCMV infection of human
brain aggregates preferentially infected a Microglial/macrophage
(M/M) and caused a neuropathology that differed between strains and
could occur in the absence of antigen expression. We extended these
studies by infecting a human brain cell aggregate model with four
low passage clinical isolates of HCMV. Two patterns of cytopathology
emerged after infection; a lacy eosinophilic appearance or a glial
nodular formation concomitant with a decreased aggregate size. None
of the infections were positive for HCMV antigen; however, all were
positive for HCMV DNA. We also infected primary macrophages and
Microglial
cells with the same HCMV isolates. Microglial
cells were more susceptible to HCMV infection resulting in a lytic
infection. Production of potentially neurotoxic cytokines, IL-1,
IL-6 and TNF alpha, from HCMV-infected macrophages and Microglial
cells were evaluated to explain brain aggregate cytopathology.
Supernatants from HCMV-infected macrophages and Microglial
cells produced similar levels of TNF alpha (< 30 pg ml-1) but
showed strain and cell source variation in the production of IL-6;
Microglial
cultures produced > 4 fold higher levels. None of the
supernatants contained IL-1. Treatment of brain aggregates with
either IL-6 or TNF alpha resulted in morphologic alterations and/or
a decrease in size consistent with HCMV infection or supernatant
treatment
Ranki A, Nyberg M, Ovod V, Haltia M, Elovaara I, Raininko R,
Haapasalo H, Krohn K (1995) Abundant expression of HIV
Nef and Rev proteins in brain astrocytes in vivo is associated with
dementia. AIDS
9:1001-1008
Abstract: OBJECTIVE: To relate the expression of HIV
regulatory proteins and HIV-specific
mRNA in the brain cells of infected individuals with clinical
neurological disease. DESIGN: Formalin-fixed postmortem brain tissue
from 14 HIV-infected adult
patients, with previous repeated neurological and neuroradiological
examinations, was studied by immunohistochemical and molecular
biological methods. Samples from non-infected brains served as
controls. METHODS: Immunohistochemistry with monoclonal antibodies
(MAb) was combined with in situ RNA hybridization. Target cells were
identified with MAb to glial fibrillary acidic protein (GFAP;
astrocytes), CD68 (activated macrophages) and Ricinus communis
agglutinin (RCA-1; Microglia,
endothelial cells). For HIV,
a panel of MAb against HIV
Nef, Tat, Rev and Env proteins or probes specific for all classes of
mRNA (nef), for singly or non-spliced mRNA (env) and for non-spliced
mRNA (gag/pol) were used. RESULTS: Nef protein was detected in
subcortical or subpial astrocytes in seven out of 14 samples, and in
multinucleated giant cells in two cases. Gag/pol or env
mRNA-expressing astrocytes were detected in four cases. In four out
of five cases studied, HIV
Rev, but not Tat, was also expressed in astrocytes. Six out of the
seven patients with Nef-positive astrocytes had suffered from
moderate to severe dementia. The patient with most rapidly
progressing severe dementia showed extensive HIV
mRNA expression together with Nef and Rev expression in astrocytes.
CONCLUSION: In adult human brain, astrocytes are infected by HIV
and preferentially express HIV
Nef and Rev proteins but are also sometimes productively infected.
Astrocyte infection is associated with moderate to severe dementia
which agrees with recent knowledge on the housekeeping activities of
astrocytes and their eventual role in learning and memory
Seilhean D, Duyckaerts C, Hauw JJ (1995) [HIV
and dementia: neuropathology]. J.Neuroradiol. 22:161-162
Abstract:
Cognitive disorders associated with HIV
infection may be due to focal lesions (lymphoma, toxoplasmosis,
progressive multifocal leukoencephalitis, etc.), metabolic
encephalopathy (e.g. hepatic insufficiency) or psychiatric disorders
(depression). In the absence of such causes a "cognitive and
motor syndrome associated with HIV
infection" has been defined on clinical criteria (Working group
of the American Academy of Neurology, 1991). This syndrome is not
consistently associated with any specific lesion. Neither the
multifocal encephalitis of HIV
or CMV infection nor the diffuse leukoencephalopathy associated with
HIV are the only causes.
The existence of a neocortical neuronal loss has been suggested by
several retrospective studies, but our prospective study has not
shown cortical or subcortical atrophy. Measurement of neuronal
density in Brodmann's areas 4,9 and 40 has not revealed a
significant loss either global, by layer, or by column. The only
constant lesion was gliosis of the cortex and white matter. Neuronal
loss, therefore, is not indispensable to the occurrence of cognitive
disorders in AIDS. The
mechanism of dementia might be: dysfunction of cortical neurons
(dendritic abnormalities, virus/neurotransmitter competition);
subcortical dysfunction, as suggested by the high density of
Microglial
nodules in that region; white matter lesions which could be due to
abnormalities in the blood-brain barrier. The expression of cell
adhesion molecules (VCAM-1, VLA-4, ICAM-1 and LFA-1) by endothelial
cerebral cells is not significantly different in AIDS
patients, demented or not, and in patients with multiple sclerosis.
In contrast, the expression of VCAM-1 by astrocytes is significantly
increased in demented AIDS
patients compared with non demented ones.(ABSTRACT TRUNCATED AT 250
WORDS)
Sippy BD, Hofman FM, Wallach D, Hinton DR (1995) Increased
expression of tumor necrosis factor-alpha receptors in the brains of
patients with AIDS.
J.Acquir.Immune.Defic.Syndr.Hum.Retrovirol. 10:511-521
Abstract:
Tumor necrosis factor (TNF)-alpha has been shown to be increased in
brain tissue of AIDS
patients and may function as a mediator of cerebral damage. We
initiated a study to determine the cellular localization and degree
of protein and mRNA expression of the two specific TNF-alpha
receptors (TNF-Rs), p55 and p75, in brain tissues from AIDS
patients. Cerebral white matter obtained at autopsy from 13 AIDS
patients, 10 unhealthy controls, and 4 healthy controls was
evaluated. Double-label immunohistochemistry revealed prominent
up-regulation of p55 and p75 TNF-Rs on activated macrophages and
Microglial
cells in all AIDS patients;
no increased staining was found on astrocytes. Staining was most
prominent in patients with opportunistic infection of the brain and
in Microglial
nodules of patients with HIV
encephalitis. Brain tissues also showed increased expression of
interleukin (IL)-1 beta, IL-6, and TNF-alpha, cytokines known to
up-regulate the TNF-Rs. Increased staining for TNF-Rs was also found
in patients with multiple sclerosis, chronic cerebral edema, and
radiation necrosis but not in an asymptomatic HIV-positive
patient without AIDS.
Reverse transcriptase polymerase chain reaction performed on
adjacent sections from five AIDS
patients revealed up-regulation from normal for p55 in all patients
and for p75 in three patients. The up-regulation of both TNF-Rs in
AIDS suggests that
macrophages and Microglial
cells may be important in amplifying the TNF-alpha response
Spina CA, Guatelli JC, Richman DD (1995) Establishment of a
stable, inducible form of human immunodeficiency virus type 1 DNA in
quiescent CD4 lymphocytes in vitro. J.Virol. 69:2977-2988
Abstract:
Human immunodeficiency virus type 1 (HIV-1)
possesses the ability to establish a complete infection in
nondividing host cells. The capacity of HIV-1
to infect nondividing cells probably contributes significantly to
its pathology in vivo, as reflected by infection of peripheral T
lymphocytes, tissue macrophages, and Microglial
cells. However, the in vitro demonstration of the establishment of
stable HIV-1 infection in
quiescent T cells remains controversial. We have developed a primary
T-cell model of acute HIV-1
infection of quiescent CD4 lymphocytes that demonstrates the
development of a complete, reverse-transcribed form of virus that is
stable for over 10 days in culture. To ensure that our primary cell
culture was representative of a quiescent population, the CD4
lymphocyte targets were monitored for membrane expression of
activation antigens and for shifts in cell cycle from G0/G1 to S/G2
phase. The presence of viral DNA fragments reflecting progressive
reverse transcription was determined by PCR analysis. HIV
entered primary CD4 cells rapidly, but viral DNA accumulated slowly
in the resting cell cultures. DNA species containing regions of
full-length reverse transcription were not detected until 3 to 5
days after infection. In parallel with the appearance of complete
viral DNA, spliced RNA transcripts, predominantly of the nef
species, were detected by reverse transcriptase PCR amplification.
When infected CD4 cells were sorted on the basis of cell cycle
analysis of DNA content, the accumulation of a complete viral DNA
form was found to occur in both the purified G0/G1-phase cell subset
and the cell fraction enriched for the minor S-phase subset. In
contrast, spliced viral RNA products could be detected only in the
enriched S-phase cell fraction. These results demonstrate that HIV-1
can infect and establish a complete, stable form of viral DNA in
primary CD4 lymphocytes in vitro but is blocked from transcription
in the absence of cell activation. The findings are consistent with
in vivo data from HIV-infected
individuals that show the existence of viral DNA predominantly as a
stable, extrachromosomal form in T cells of the peripheral
circulation
Sundar KS, Kamaraju LS, Dingfelder J, McMahon J, Gollapudi S,
Wilson WH, Kong LY, Hong JS, Weiss JM, Lee JE (1995) beta-Endorphin
enhances the replication of neurotropic human immunodeficiency virus
in fetal perivascular Microglia.
J.Neuroimmunol. 61:97-104
Abstract: The effect of an endogenous
opiate, beta-endorphin, on the replication of HIV
was investigated in brain perivascular Microglia.
Beta-endorphin enhanced the synthesis of p-24 antigen and
transactivation of HIV
promoter. Dialysed culture supernatants of endorphin-treated
Microglia
re-activated latent HIV
infection. These culture supernatants showed elevated levels of
interleukin-1 beta, IL-6 and tumor necrosis factor alpha.
Sub-optimal concentration of beta-endorphin potentiated
GP-120-induced synthesis of these cytokines. Nalaxone reversed
beta-endorphin-induced, but not GP-120-induced, cytokine production
and enhanced HIV
replication. These results suggest that endogenous opiates may
contribute to the progression of AIDS
dementia complex
Tyor WR, Wesselingh SL, Griffin JW, McArthur JC, Griffin DE
(1995) Unifying hypothesis for the pathogenesis of HIV-associated
dementia complex, vacuolar myelopathy, and sensory neuropathy.
J.Acquir.Immune.Defic.Syndr.Hum.Retrovirol. 9:379-388
Abstract:
Neurological diseases associated with HIV
infection include dementia, vacuolar myelopathy, and sensory
neuropathy. Although in vitro studies suggest that other nervous
system cell types could harbor HIV,
immunohistochemical and in situ hybridization studies have indicated
that only macrophages/Microglia
are significantly infected in the central nervous system. In the
peripheral nervous system, even HIV-infected
macrophages are rare. Therefore, theories regarding the pathogenesis
of HIV-associated
neurologic disorders have centered around the elaboration of
substances that may be toxic to neurons, oligodendrocytes or myelin.
These potential toxins include HIV
proteins, cellular metabolites, and cytokines. In this review we
present evidence that there are large numbers of
macrophages/Microglia
present in the nervous system of patients with these diseases and
that they produce tumor necrosis factor (TNF)-alpha. The large
increase in macrophage activity late in HIV
infection may be due to the diminution in production by CD4-positive
T cells of cytokines such as interleukin (IL)-4 and IL-10 which are
inhibitors of macrophage activities. We hypothesize that
HIV-associated dementia
complex, vacuolar myelopathy, and sensory neuropathy are directly or
indirectly related to the increased numbers of macrophages found in
brain, spinal cord, and peripheral nerve. Future therapies may be
directed towards inhibition of macrophage functions
Williams KC, Hickey WF (1995) Traffic of hematogenous cells through the central nervous system. Curr.Top.Microbiol.Immunol. 202:221-245
Wilt SG, Milward E, Zhou JM, Nagasato K, Patton H, Rusten R,
Griffin DE, O'Connor M, Dubois-Dalcq M (1995) In vitro evidence for
a dual role of tumor necrosis factor-alpha in human immunodeficiency
virus type 1 encephalopathy. Ann.Neurol. 37:381-394
Abstract:
Microglial
cell activation, myelin alteration, and abundant tumor necrosis
factor (TNF)-alpha message have been observed in the brains of some
human immunodeficiency virus type 1 (HIV-1)-infected
and demented patients. We therefore used cultures of purified human
Microglia
and oligodendrocytes derived from adult human brain to examine the
role of TNF-alpha in HIV-1
encephalopathy. Human Microglia
synthesize TNF-alpha message and protein in vitro. When these cells
were infected with HIV-1
JrFL and maintained in the presence of TNF-alpha antibodies, soluble
TNF-alpha receptors, or the TNF-alpha inhibitor pentoxifylline,
viral replication was delayed or strongly inhibited. Both human
Microglia
and oligodendrocytes express the two TNF receptors, TNF-R1, which
has been implicated in cytotoxicity, and TNF-R2. While TNF-alpha may
enhance HIV-1 replication
in an autocrine manner, it is not toxic for Microglia.
In contrast, recombinant human TNF-alpha causes oligodendrocyte
death in a dose-dependent manner. In situ detection of DNA
fragmentation in some cells indicated that oligodendrocyte death may
occur by apoptosis. Addition of live Microglia
or medium conditioned by these cells also resulted in 30 to 40%
oligodendrocyte death, which was largely prevented by TNF-alpha
inhibitors. We propose that TNF-alpha plays a dual role in HIV-1
encephalopathy, enhancing viral replication by activated Microglia
and damaging oligodendrocytes. Thus, TNF-alpha inhibitors may
alleviate some of the neurological manifestations of acquired
immunodeficiency syndrome
Yeung MC, Pulliam L, Lau AS (1995) The HIV
envelope protein gp120 is toxic to human brain-cell cultures through
the induction of interleukin-6 and tumor necrosis factor-alpha. AIDS
9:137-143
Abstract: OBJECTIVE: To investigate the induction of
cytokines as a possible mechanism for the neurotoxicity of the HIV-1
envelope protein gp120. DESIGN: The gp120 protein was tested
directly on primary human brain cultures to examine its ability to
induce cytokines and its neurotoxicity on human neural cells because
gp120 is known to be toxic to rodent ganglion cultures, and neural
cells such as astrocytes and Microglia
produce cytokines when stimulated. METHODS: Primary cultures of
human brain cell aggregates, astrocytes and macrophages were exposed
to HIV-1 recombinant (r)
gp120SF2. Induction of cytokines was assayed by enzyme-linked
immunosorbent assay (ELISA) and reverse transcriptase polymerase
chain reaction (RT-PCR); neurotoxicity of rgp120SF2 and interleukin
(IL)-6 on human brain cultures was examined by electron microscopy.
RESULTS: ELISA and RT-PCR studies revealed that rgp120SF2 induced
IL-6 and tumor necrosis factor (TNF)-alpha in brain cultures; IL-6
could also be induced by TNF-alpha added to brain cultures. Both
IL-6 and TNF-alpha were upregulated in astrocytes and macrophage
cultures on rgp120SF2 treatment. Ultrastructural studies
demonstrated that IL-6 treatment for 72 h induced large cytoplasmic
vacuoles in neural cells with morphology consistent with neurons;
rgp120SF2 treatment for 7 days resulted in chromatin condensation
along the inner margins of nuclear envelopes of neural cells.
CONCLUSIONS: Our results demonstrated that HIV-1
rgp120SF2 can upregulate at least two known neurotoxic cytokines,
IL-6 and TNF-alpha, which may injure neural cells and contribute to
the neuropathology observed in AIDS
dementia patients
Yoshioka M, Bradley WG, Shapshak P, Nagano I, Stewart RV, Xin
KQ, Srivastava AK, Nakamura S (1995) Role of immune activation and
cytokine expression in HIV-1-associated
neurologic diseases. Adv.Neuroimmunol. 5:335-358
Abstract:
Central nervous system (CNS) involvement is common during human
immunodeficiency virus type-1 (HIV-1)
infection. The neurologic disease of the CNS most frequently
observed during acquired immunodeficiency syndrome (AIDS)
is HIV-1-associated
cognitive/motor complex or AIDS
dementia complex (ADC), which is most likely a direct consequence of
HIV-1 infection of the CNS.
The peripheral nervous system (PNS) is also affected in
HIV-1-infected individuals
and there are several features of immune- and cytokine-related
pathogenesis in both the CNS and PNS that are reviewed. Several
lines of evidence demonstrate aspects of immune activation in the
CNS and peripheral nervous system (PNS) of HIV-1-infected
individuals. The relative paucity of HIV-1
expression in contrast to widespread functional and pathologic
changes in the CNS and PNS of AIDS
patients, and the lack of evidence of productive infection of HIV-1
in neuronal cells in vivo lead to the possibility of indirect or
immunopathogenic mechanisms for HIV-1-related
neurologic diseases. Proposed mechanisms of neuronal and glial cell
damage are injury of oligodendrocytes by tumor necrosis factor-alpha
(TNF-alpha) released from activated macrophage/Microglia,
calcium-dependent excitoneurotoxicity induced by gp120 HIV-1
envelope protein, N-methyl-D-aspartate (NMDA) receptor-mediated
neurotoxicity by quinolinic acid (a product of activated
macrophages), cell injury by HIV-1-specific
cytotoxic T cells, and apoptosis of oligodendrocytes or neurons
triggered by interaction between cell surface receptors and HIV-1
gp120 protein. Common to those mechanisms is the dependence on
cellular activation with expression of proinflammatory cytokines
(TNF-alpha, interleukin-1). Amplification of activation signals
through the cytokine network by macrophage/astrocyte/endothelial
cell interactions, and cell-to-cell contact between activated
macrophages and neural cells by upregulation of adhesion molecules
dramatically enhances the toxic effect of macrophage products.
Expression of immunosuppressive cytokines such as interleukin-4,
interleukin-6, and transforming growth factor-beta is also increased
in the CNS and PNS of HIV-1-infected
patients. This may serve as neuroprotective and regenerative
mechanism against insults to nervous system tissue
(1994) Neuro-AIDS. Proceedings of a workshop. Portland, Maine, August 16-19, 1993. Adv.Neuroimmunol. 4:145-336
Benos DJ, Hahn BH, Bubien JK, Ghosh SK, Mashburn NA, Chaikin
MA, Shaw GM, Benveniste EN (1994) Envelope glycoprotein gp120 of
human immunodeficiency virus type 1 alters ion transport in
astrocytes: implications for AIDS
dementia complex. Proc.Natl.Acad.Sci.U.S.A 91:494-498
Abstract:
Infection by human immunodeficiency virus type 1 (HIV-1)
is often complicated by a variety of neurological abnormalities. The
most common clinical syndrome, termed acquired immunodeficiency
syndrome (AIDS) dementia
complex, presents as a subcortical dementia with cognitive, motor,
and behavioral disturbances and is unique to HIV-1
infection. The pathogenesis of this syndrome is poorly understood
but is believed to involve interactions among virally infected
macrophages/Microglia,
astrocytes, and neurons. In this study, we show that exposure of
primary rat and human astrocytes to heat-activated HIV-1
virions, or to eukaryotically expressed HIV-1
and HIV-2 envelope
glycoproteins (gp120) stimulates amiloride-sensitive Na+/H+
antiport, potassium conductance, and glutamate efflux. These effects
are blocked specifically by amiloride, an inhibitor of Na+/H+
antiport and by the selective removal of gp120 with immobilized
monoclonal antibody. As a result of modulation of astrocytic
function by gp120, the ensuing neuronal depolarization and glutamate
exposure could activate both voltage-gated and
N-methyl-D-aspartate-regulated Ca2+ channels, leading to increases
in intraneuronal Ca2+ and neuronal death. These findings implicate
the astrocyte directly in the pathogenesis of AIDS
dementia complex
Benos DJ, Hahn BH, Shaw GM, Bubien JK, Benveniste EN (1994)
gp120-mediated alterations in astrocyte ion transport.
Adv.Neuroimmunol. 4:175-179
Abstract: The pathogenesis of the
acquired immunodeficiency syndrome (AIDS)
dementia complex (ADC) is unknown. However, recent work indicates
that neurons and astrocytes are functionally compromised by exposure
to viral components or cellular factors released from HIV-1-infected
macrophages/Microglia.
We show that exposure of primary cultured rat astrocytes to the
major HIV envelope
glycoprotein gp120 results in alterations of ion and solute
transport that may contribute to neuronal cell injury
Benveniste EN (1994) Cytokine circuits in brain. Implications
for AIDS dementia complex.
Res.Publ.Assoc.Res.Nerv.Ment.Dis. 72:71-88
Abstract: This chapter
has summarized studies showing that cells of the immune system and
glial cells of the CNS use many of the same cytokines as
communication signals. Activated astrocytes and Microglia
are the principal sources of these cytokines in the CNS, although
oligodendrocytes are capable of expressing IL-1 and TGF-beta. There
is a complex circuitry of interactions mediated by cytokines,
especially in the event of blood-brain barrier damage and
lymphoid/mononuclear cell infiltration into the CNS. Infiltrating
activated macrophages produce cytokines such as IL-1, TNF-alpha, and
IL-6, which would trigger glial cells to produce their own
cytokines. The activation of astrocytes and Microglia
to secrete proinflammatory cytokines such as IL-1, TNF-alpha, IL-6,
and GM-CsF may contribute to the propagation of intracerebral immune
and inflammatory responses initiated by immune cells, as well as
enhancement of HIV-1
expression in the CNS. The cytokine cascades ongoing in the CNS
could ultimately be suppressed due to the presence of
immunosuppressive cytokines such as TGF-beta. Whether immune and
inflammatory responses within the CNS are propagated or suppressed
depends on a number of parameters, including (a) the activational
status of these cells, (b) cytokine receptor levels on glial and
immune cells, (c) the presence of cytokines with both
immune-enhancing and immune-suppressing effects (IFN-gamma, IL-1,
TNF-alpha, IL-6, TGF-beta, CsFs), (d) the concentration and location
of these cytokines in the CNS, and (e) the temporal sequence in
which a particular cell is exposed to numerous cytokines (see Fig.
1). The ultimate outcome of immunologic and inflammatory events in
the CNS, as well as HIV
expression, will be determined, in part, by an interplay of the
above parameters
Bernardo A, Patrizio M, Levi G, Petrucci TC (1994) Human
immunodeficiency virus protein gp120 interferes with beta-adrenergic
receptor-mediated protein phosphorylation in cultured rat cortical
astrocytes. Cell Mol.Neurobiol. 14:159-173
Abstract: 1. We have
previously shown that acute exposure to the HIV
coat protein gp120 interferes with the beta-adrenergic regulation of
astroglial and Microglial
cells (Levi et al., 1993). In particular, exposure to 100 pM gp120
for 30 min depressed the phosphorylation of vimentin and glial
fibrillary acidic protein (GFAP) induced by isoproterenol in rat
cortical astrocyte cultures. In the present study we have extended
our analysis on the effects of gp120 on astroglial protein
phosphorylation. 2. We found that chronic (3-day) treatment of the
cells with 100 pM gp120 before exposure to isoproterenol was
substantially more effective than acute treatment in depressing the
stimulatory effect of the beta-adrenergic agonist on vimentin and
GFAP phosphorylation. 3. Even after chronic treatment with gp120, no
differences were found in the levels and solubility of these
proteins. 4. Besides stimulating the phosphorylation of intermediate
filament proteins, isoproterenol inhibited the incorporation of 32P
into a soluble acidic protein of 80,000 M(r), which was only
minimally present in Triton X-100-insoluble extracts. 5. Treatment
of astrocytes with a phorbol ester or exposure to 3H-myristic acid
indicated that the acidic 80,000 M(r) protein is a substrate for
protein kinase C (PKC) and is myristoylated, thus suggesting that it
is related to the MARCKS family of PKC substrates. 6. Acute (30-min)
treatment with 100 pM gp120 totally prevented the inhibitory effect
of isoproterenol on the phosphorylation of the 80,000 M(r)
MARCKS-like protein. 7. Our studies corroborate the hypothesis that
viral components may contribute to the neuropathological changes
observed in AIDS through
the alteration of signal transduction systems in glial cells
Black R, Sager P (1994) Summary of workshop contributions.Third Workshop on NeuroAIDS. Adv.Neuroimmunol. 4:149-156
Bobryshev Y, Ashwell K (1994) Ultrastructural identification
of Ricinus communis agglutinin-1 positive cells in primary
dissociated cell cultures of human embryonic brain.
Arch.Histol.Cytol. 57:481-491
Abstract: While Ricinus communis
agglutinin 1 (RCA-1) can be used as a specific marker to study the
development and differentiation of Microglial
cells in human embryogenesis, little is known about the structural
heterogeneity and nature of RCA-1+ cells. To analyse the structural
peculiarities of RCA-1+ cells, we have used primary dissociated
cultures of human embryonic brain. These have been used as models
for investigating many of the aspects of central nervous system
(CNS) HIV infection. We
have shown that primary dissociated cultures from human embryos as
young as 10 weeks gestation contain RCA-1+ cells. The RCA-1+ cells
exist in two forms, those without (type I) and those with (type II)
processes. The former have a poorly developed ultrastructure, while
the latter have well developed ultrastructural features, such as
rough endoplasmic reticulum with short cisternae, abundant
ribosomes, mitochondria, lysosomes and vacuoles. Furthermore, some
of these cells with processes have well developed cytoskeletal
features. In this paper, the classification of RCA-1+ cells of
embryonic human brain is considered and their morphology compared to
Microglia
identified in rodent CNS
Climent C, DeVinatea ML, Lasala G, Ie SO, Velez R, Colon L,
Mullick FG (1994) Geographical pathology profile of AIDS
in Puerto Rico: the first decade. Mod.Pathol. 7:647-651
Abstract:
Postmortem histopathological changes in 100 adult patients with AIDS
who died in Puerto Rico from 1982 to 1991 were studied and
tabulated. Modes of HIV
transmission were reviewed. Patient ages ranged from 21 to 60 yr.
Gender composition for the patient group was 83 men (average age, 35
yr) and 17 women (average age, 39 yr). Sixty-eight of the patients
were injecting-drug users, 20 were homosexual and bisexual men,
seven were women who had had heterosexual contact with men at risk
for HIV, and one was a man
who had had heterosexual contact with prostitutes. Only one case was
linked to transfusions of blood. Twenty-seven men and seven women
were serologically tested for antibodies and all were HIV
seroreactive. The most common causes of infection and the frequency
of each were as follows: Pneumocystis carinii in 49 patients;
cytomegalovirus in 43; Toxoplasma gondii in 30; Candida species in
24; Histoplasma capsulatum in 18; Mycobacterium species in 14;
Cryptococcus species in eight; and Strongyloides stercoralis in six
patients. Infection by Schistosoma mansoni (10 patients) was
considered incidental because this trematode is endemic in Puerto
Rico. The lung was the organ most frequently infected by a single
microorganism: Pneumocystis carinii affected 49 patients. However,
Cryptococcus species was the microorganism that infected more body
systems: 20 different organs in eight patients. Nineteen patients
had Microglial
nodular encephalitis, 86 patients had lymphocyte depletion in the
spleen, and 58 had lymphocyte depletion in lymph node tissue.
Twenty-seven men had testicular maturation arrest and variable germ
cell loss. Three patients had malignant lymphoma, and two had
Kaposi's sarcoma.(ABSTRACT TRUNCATED AT 250 WORDS)
Donaldson YK, Bell JE, Holmes EC, Hughes ES, Brown HK,
Simmonds P (1994) In vivo distribution and cytopathology of variants
of human immunodeficiency virus type 1 showing restricted sequence
variability in the V3 loop. J.Virol. 68:5991-6005
Abstract: The
distribution, cell tropism, and cytopathology in vivo of human
immunodeficiency virus (HIV)
was investigated in postmortem tissue samples from a series of
HIV-infected individuals
who died either of complications associated with AIDS
or for unrelated reasons while they were asymptomatic. Proviral
sequences were detected at a high copy number in lymphoid tissue of
both presymptomatic patients and patients with AIDS,
whereas significant infection of nonlymphoid tissue such as that
from brains, spinal cords, and lungs were confined to those with
AIDS. V3 loop sequences
from both groups showed highly restricted sequence variability and a
low overall positive charge of the encoded amino acid sequence
compared with those of standard laboratory isolates of HIV
type 1 (HIV-1). The low
charge and the restriction in sequence variability were comparable
to those observed with isolates showing a non-syncytium-inducing
(NSI) and macrophage-tropic phenotype in vitro. All patients were
either exclusively infected (six of seven cases) or predominantly
infected (one case) with variants with a predicted
NSI/macrophage-tropic phenotype, irrespective of the degree of
disease progression. p24 antigen was detected by immunocytochemical
staining of paraffin-fixed sections in the germinal centers within
lymphoid tissue, although little or no antigen was found in areas of
lymph node or spleen containing T lymphocytes from either
presymptomatic patients or patients with AIDS.
The predominant p24 antigen-expressing cells in the lungs and brains
of the patients with AIDS
were macrophages and Microglia
(in brains), frequently forming multinucleated giant cells
(syncytia) even though the V3 loop sequences of these variants
resembled those of NSI isolates in vitro. These studies indicate
that lack of syncytium-forming ability in established T-cell lines
does not necessarily predict syncytium-forming ability in primary
target cells in vivo. Furthermore, variants of HIV
with V3 sequences characteristic of NSI/macrophage-tropic isolates
form the predominant population in a range of lymphoid and
nonlymphoid tissues in vivo, even in patients with AIDS
Gendelman HE, Lipton SA, Tardieu M, Bukrinsky MI, Nottet HS
(1994) The neuropathogenesis of HIV-1
infection. J.Leukoc.Biol. 56:389-398
Abstract: HIV
infection in brain revolves around productive viral replication in
cells of mononuclear phagocyte lineage, including brain macrophages,
Microglia,
and multinucleated giant cells [1-4]. Together, they are the
investigators for cellular and viral neurotoxic activities [5-10].
Several published reports show that viral and/or cellular products
produced from HIV-1-infected
macrophages injure neurons and induce glial proliferation during
advancing central nervous system (CNS) infection [11-18]. These
findings are supported by the apparent discrepancy between the
distribution and numbers of virus-infected cells and concomitant
brain tissue pathology [5, 19]. Whether these soluble factors are
indirectly responsible for neuronal damage remains undefined. The
identification and regulation of neurotoxins produced from
HIV-infected macrophages
are central to uncovering how HIV
mediates CNS disease. The authors who contributed to this work
represent laboratories with overlapping areas of expertise.
Broad-based complementary hypotheses regarding HIV
neuropathogenesis are now provided
Gendelman HE, Genis P, Jett M, Zhai QH, Nottet HS (1994) An
experimental model system for HIV-1-induced
brain injury. Adv.Neuroimmunol. 4:189-193
Abstract: The
pathological hallmark of HIV
infection in brain is productive viral replication in cells of
mononuclear phagocyte lineage including brain macrophages, Microglia
and multinucleated giant cells (Koenig et al., 1986; Wiley et al.,
1986; Gabuzda et al., 1986; Stoler et al., 1986). These cells
secrete viral and cell encoded neurotoxins that lead to neuronal
injury, glial proliferation and myelin pallor during advancing
disease (Genis et al., 1992; Giulian et al., 1990, 1993; Pulliam et
al., 1991). The apparent paradox between the distribution and
numbers of virus infected cells and brain tissue pathology support
indirect mechanisms for CNS damage (Epstein, 1993; Geleziunas et
al., 1992; Merrill and Chen, 1992; Michaels et al., 1988; Price et
al., 1988). First, brain macrophages and Microglia
can produce neurotoxins by secretion of viral proteins (for example,
gp120) (Dawson et al., 1991; Merrill et al., 1989; Lipton et al.,
1990; Lipton, 1993). Second, HIV
primes macrophages for immune activation to produce neurotoxins
including: cytokines (TNF alpha and IL-1 beta), eicosanoids:
quinolinate and nitric oxide (NO). Chronic immune stimulation
mediated by opportunistic infections and chronic interferon gamma
(IFN gamma) production (in and outside the CNS) continues the
process of macrophage activation leading to progressive neural
injury. The hyperresponsiveness of HIV-infected
macrophages to activation results in production of cellular factors
that activate uninfected macrophages. This suggests that
HIV-infected macrophages
are both perpetrators and amplifiers for neurotoxic activities
Kimura-Kuroda J, Nagashima K, Yasui K (1994) Inhibition of
myelin formation by HIV-1
gp120 in rat cerebral cortex culture. Arch.Virol.
137:81-99
Abstract: To study the role of HIV-1
gp120 in loss of myelin in HIV
encephalopathy, the binding of gp120 to various types of neural
cells and its effects on myelination were examined in rat primary
brain culture. Double-staining of cultured cells with gp120 and
specific antibodies for different neural cell types showed that
gp120 bound to most of the galactocerebroside (GalC)-positive
oligodendrocytes, a small population of type-2-like astrocytes and a
few small neurons. Gp120 did not bind to type-1-like astrocytes,
most neurons, or to macrophage/Microglia.
To assay myelination, cells were bathed in a myelination medium
containing chick embryo extract and high glucose, with or without
gp120. Seven days after the application, myelination in the culture
was observed morphologically and by staining with anti-myelin basic
protein (MBP) antibody, and was found to be significantly inhibited
by the addition of gp120 (50-100 nM). The processes of
oligodendrocytes were reduced in length and arborization relative to
the control, but MBP production by oligodendrocytes was unaffected.
These results show that gp120 can cause a functional disorder of
oligodendrocytes and thus could underlie the diffuse loss of myelin
sheaths of HIV
encephalopathy
Kleinschmidt A, Neumann M, Moller C, Erfle V, Brack-Werner R
(1994) Restricted expression of HIV1
in human astrocytes: molecular basis for viral persistence in the
CNS. Res.Virol. 145:147-153
Abstract: Besides macrophages and
Microglial
cells, cells of astroglial origin are thought to be targets of HIV1
in the brain. HIV1
infection of astroglial cells results in restricted production of
the virus. To analyse the molecular basis of this restricted
infection phenotype, we established a chronically HIV1-infected
low-producer astrocytoma cell line. These cells show only low levels
of mRNA encoding structural proteins, due to a cell-determined
blockage in the Rev/RRE regulatory axis. The low-producer state
could not be overcome by treatment with known stimulators of virus
expression such as phorbol ester,
(12-O-tetradecanoylphorbol-13-acetate), tumour necrosis factor alpha
or sodium butyrate. This indicates that the molecular mechanisms
involved in restricting virus production in astroglial cells differ
from those in latently infected T cells and monocytes
Kozlowski PB, Dambska M (1994) [Nervous system changes in
infants with HIV virus.
Neuropathological picture]. Neurol.Neurochir.Pol.
28:335-342
Abstract: The neuropathologic examination of
symptomatic perinatal HIV
infection was performed using a large group of cases from New York
Medical Centers. Macroscopic evaluation demonstrated many cases with
microencephaly and others with brain atrophy. Microscopically in a
part of them, as far as in others without microencephaly/atrophy
changes corresponding to HIV
encephalitis were found, including multinucleated giant cells,
Microglial
nodules and perivascular infiltrations. In other brains in which
inflammatory changes were minimal, myelin lesions were also observed
and the picture corresponded to the diagnosis of encephalopathy. In
addition lesions of cortico-spinal tracts, mineralization within the
basal ganglia and changes of vascular walls with secondary
parenchymal lesions were found. Opportunistic infections and
neoplastic changes were rare. The review demonstrated the picture of
neuropathological changes in pediatric cases that died of AIDS
Lipton SA (1994) HIV-related
neuronal injury. Potential therapeutic intervention with calcium
channel antagonists and NMDA antagonists. Mol.Neurobiol.
8:181-196
Abstract: Perhaps as many as 25-50% of adult patients
and children with acquired immunodeficiency syndrome (AIDS)
eventually suffer from neurological manifestations, including
dysfunction of cognition, movement, and sensation. How can human
immunodeficiency virus type 1 (HIV-1)
result in neuronal damage if neurons themselves are for all intents
and purposes not infected by the virus? This article reviews a
series of experiments leading to a hypothesis that accounts at least
in part for the neurotoxicity observed in the brains of AIDS
patients. There is growing support for the existence of HIV-
or immune-related toxins that lead indirectly to the injury or
demise of neurons via a potentially complex web of interactions
among macrophages (or Microglia),
astrocytes, and neurons. HIV-infected
monocytoid cells (macrophages, Microglia,
or monocytes), after interacting with astrocytes, secrete
eicosanoids, i.e., arachidonic acid and its metabolites, including
platelet-activating factor. Macrophages activated by HIV-1
envelope protein gp120 also appear to release arachidonic acid and
its metabolites. In addition, interferon-gamma (IFN-gamma)
stimulation of macrophages induces release of the glutamate-like
agonist, quinolinate. Furthermore, HIV-infected
macrophage production of cytokines, including TNF-alpha and
IL1-beta, contributes to astrogliosis. A final common pathway for
neuronal susceptibility appears to be operative, similar to that
observed in stroke, trauma, epilepsy, neuropathic pain, and several
neurodegenerative diseases, possibly including Huntington's disease,
Parkinson's disease, and amyotrophic lateral sclerosis. This
mechanism involves the activation of voltage-dependent Ca2+ channels
and N-methyl-D-aspartate (NMDA) receptor-operated channels, and,
therefore, offers hope for future pharmacological intervention. This
article focuses on clinically tolerated calcium channel antagonists
and NMDA antagonists with the potential for trials in humans with
AIDS dementia in the near
future
Lipton SA (1994) Neuronal injury associated with HIV-1
and potential treatment with calcium-channel and NMDA antagonists.
Dev.Neurosci. 16:145-151
Abstract: A substantial number of adults
and half of the children with acquired immunodeficiency syndrome
(AIDS) suffer from
neurological manifestations. Among the various pathologies reported
in brains of patients with AIDS
is neuronal injury and loss, although neurons themselves do not
appear to be infected by HIV-1.
There is growing support for the existence of HIV-
or immune-related toxins that lead indirectly to the injury or
demise of neurons via a potentially complex web of interactions
between macrophages (or Microglia),
astrocytes, and neurons. HIV-infected
monocytoid cells, especially after interacting with astrocytes,
secrete neurotoxic substances. Not all of these substances are yet
known, but they may include eicosanoids, platelet-activating factor,
quinolinate, cysteine, cytokines, and free radicals. Macrophages
activated by HIV-1 envelope
protein gp120 also appear to release similar toxins. Some of these
factors can lead to increased glutamate release or decreased
glutamate reuptake. A final common pathway for neuronal
suceptibility appears to be operative, similar to that observed in
stroke, trauma, epilepsy, and several neurodegenerative diseases,
possibly including Huntington's disease, Parkinson's disease, and
amyotrophic lateral sclerosis. This mechanism involves the
activation of voltage-dependent Ca2+ channels and
N-methyl-D-asparate (NMDA) receptor-operated channels, and therefore
offers hope for future pharmacological intervention. This review
focuses on clinically tolerated calcium channel antagonists and NMDA
antagonists with the potential for trials in humans with AIDS
dementia in the near future
Lipton SA (1994) AIDS-related
dementia and calcium homeostasis. Ann.N.Y.Acad.Sci.
747:205-224
Abstract: Approximately a third of adults and half of
children with acquired immunodeficiency syndrome (AIDS)
eventually suffer from neurological manifestations, including
dysfunction of cognition, movement, and sensation. Among the various
pathologies reported in the brain of patients with AIDS
is neuronal injury and loss. A paradox arises, however, because
neurons themselves are for all intents and purposes not infected by
human immunodeficiency virus type 1 (HIV-1).
This paper reviews evidence suggesting that at least part of the
neuronal injury observed in the brain of AIDS
patients is related to excessive influx of Ca2+. There is growing
support for the existence of HIV-
or immune-related toxins that lead indirectly to the injury or death
of neurons via a potentially complex web of interactions between
macrophages (or Microglia),
astrocytes, and neurons. Human immunodeficiency virus-infected
monocytoid cells (macrophages, Microglia,
or monocytes), especially after interacting with astrocytes, secrete
substances that potentially contribute to neurotoxicity. Not all of
these substances are yet known, but they may include eicosanoids,
that is, arachidonic acid and its metabolites, as well as
platelet-activating factor. Macrophages activated by HIV-1
envelope protein gp120 also appear to release arachidonic acid and
its metabolites. These factors can lead to increased glutamate
release or decreased glutamate reuptake. In addition, gamma
interferon (IFN-gamma) stimulation of macrophages induce release of
the glutamate-like agonist quinolinate. Human immunodeficiency
virus-infected or gp120-stimulated macrophages also produce
cytokines, including tumor necrosis factor-alpha and interleukin-1
beta, which contribute to astrogliosis. A final common pathway for
neuronal susceptibility appears to be operative, similar to that
observed in stroke, trauma, epilepsy, neuropathic pain, and several
neurodegenerative diseases, possibly including Huntington's disease,
Parkinson's disease, and amyotrophic lateral sclerosis. This
mechanism involves the activation of voltage-dependent Ca2+ channels
and N-methyl-D-aspartate (NMDA) receptor-operated channels, and
therefore offers hope for future pharmacological intervention. This
review focuses on clinically tolerated calcium channel antagonists
and NMDA antagonists with the potential for trials in humans with
AIDS dementia in the near
future
Lipton SA, Yeh M, Dreyer EB (1994) Update on current models
of HIV-related neuronal
injury: platelet-activating factor, arachidonic acid and nitric
oxide. Adv.Neuroimmunol. 4:181-188
Abstract: This review aims to
summarize recent work related to the pathogenesis and possible
treatment of neuronal injury in the acquired immunodeficiency
syndrome (AIDS), especially
with reference to potential neurotoxic substances released by
HIV-infected or
gp120-stimulated macrophages/Microglia.
Approximately a third of adults and half of children with AIDS
eventually suffer from neurological manifestations, including
dysfunction of cognition, movement, and sensation. Among the various
pathologies reported in brains of patients with AIDS
is neuronal injury and loss. A paradox arises, however, because
neurons themselves are for all intents and purposes not infected by
human immunodeficiency virus type 1 (HIV-1).
This paper reviews recent evidence suggesting that at least part of
the neuronal injury observed in the brains of AIDS
patients is related to excessive influx of Ca2+ after the release of
potentially noxious substances from HIV-infected
or gp120-stimulated macrophages/Microglia.
There is growing support for the existence of HIV-
or immune-related toxins that lead indirectly to the injury or
demise of neurons via a potentially complex web of interactions
between macrophages (or Microglia),
astrocytes, and neurons. HIV-infected
monocytoid cells (macrophages, Microglia
or monocytes), especially after interacting with astrocytes, secrete
substances that potentially contribute to neurotoxicity. Not all of
these substances are yet known, but they may include eicosanoids,
i.e. arachidonic acid and its metabolites, as well as
platelet-activating factor. Other candidate toxins include nitric
oxide (NO.), superoxide anion (O2.-), and the N-methyl-D-aspartate
(NMDA) agonist, cysteine. Similarly, macrophages activated by HIV-1
envelope protein gp120 also appear to release arachidonic acid and
its metabolites, and cysteine.(ABSTRACT TRUNCATED AT 250 WORDS)
Masliah E, Ge N, Achim CL, Wiley CA (1994) Cytokine receptor
alterations during HIV
infection in the human central nervous system. Brain Res.
663:1-6
Abstract: Cytokines are potent factors mediating
interactions between the immune and nervous systems. Cytokines
released by macrophages/Microglia,
the predominant immune cell within the brain, have been proposed to
modulate neuronal survival and death. In human immunodeficiency
virus-encephalitis (HIVE),
cytokines could modulate neurologic damage if nervous system cells
possessed appropriate receptors. We hypothesized that the
populations of neurons vulnerable to the toxic effects of cytokines
in HIVE might contain
specific receptors for these molecules. We examined the distribution
of cytokine receptors in the human brain utilizing
fluorescent-labeled cytokines combined with confocal laser
microscopy imaging. Phycoerythrin-conjugated interleukin-1 beta and
phycoerythrin-Avidin/biotin conjugated transforming growth factor
beta 1 labeled dendritic processes of neurons in the neocortex.
Labeling was abolished by pre-incubation with unlabeled cytokines.
In cases with moderate HIVE,
an average 35% increase in intensity of labeling was observed
compared to cases without HIVE
or with cases with severe HIVE.
The patterns of interleukin 2 labeling were not altered in HIVE.
These results suggest that neurons susceptible to cytokine-mediated
damage during the progression of HIVE
display abnormal patterns of cytokine receptor labeling
Morris CS, Esiri MM, Sprinkle TJ, Gregson N (1994)
Oligodendrocyte reactions and cell proliferation markers in human
demyelinating diseases. Neuropathol.Appl.Neurobiol.
20:272-281
Abstract: We have carried out immunocytochemical
reactions using antibodies to markers of oligodendrocytes,
astrocytes, Microglia
and proliferating cells (PCNA) in sections of human brain in a
variety of demyelinating conditions and human immunodeficiency virus
(HIV) infection. In the
acute phases of demyelinating diseases we found marked reactive
changes in oligodendrocytes with hyperplasia and an increased
cytoplasmic reaction using antibodies to enzymes involved in myelin
formation. Proliferative responses were implied by the hyperplasia
and the common finding of clusters of two or three adjacent
oligodendrocytes at sites of acute myelin damage. This was borne out
by studies using the PCNA antibody which gave negative reactions in
normal brain but positive reactions in acute demyelination. Double
staining for PCNA and cell markers showed that cells that had
entered the cell proliferation cycle were to be found among
astrocytes, Microglia/macrophages
and oligodendrocytes. In chronic demyelinating conditions, numbers
of oligodendrocytes were reduced and cells in the proliferative
cycle were not present, suggesting that the reactive potential of
oligodendrocytes or their precursors and their capacity to respond
to demyelination is limited
Nathanson N, Cook DG, Kolson DL, Gonzalez-Scarano F (1994) Pathogenesis of HIV encephalopathy. Ann.N.Y.Acad.Sci. 724:87-106
Patrizio M, Levi G (1994) Glutamate production by cultured
Microglia:
differences between rat and mouse, enhancement by lipopolysaccharide
and lack effect of HIV coat
protein gp120 and depolarizing agents. Neurosci.Lett.
178:184-189
Abstract: Glutamate release from rat and mouse
Microglia
subcultures grown in a serum-free medium was substantially greater
in the presence than in the absence of a physiological concentration
of glutamine (0.5 mM). Mouse Microglia
produced and released more glutamate than rat Microglia.
Glutamate accumulation in the medium increased with time and cell
density, which is consistent with the virtual absence of glutamate
reuptake. Lipopolysaccharide (LPS; 10-100 ng/ml), HIV
coat protein gp120 (0.1-10 nM), high K+ (35 mM) or ATP (150 microM),
did not affect glutamate release from cells maintained in serum-free
medium. In the presence of 1% dialyzed serum, however, LPS induced a
dose- and time-dependent increase in the accumulation of glutamate
in the medium, suggesting that, as in other cell types, serum
factors are required for LPS binding to its receptors
Peterson PK, Gekker G, Hu S, Chao CC (1994) Anti-human
immunodeficiency virus type 1 activities of U-90152 and U-75875 in
human brain cell cultures. Antimicrob.Agents Chemother.
38:2465-2468
Abstract: Antiviral activities of the reverse
transcriptase inhibitors U-90152 and 3'-azido-2',3'-dideoxythymidine
and the protease inhibitor U-75875 were compared in two culture
models of human immunodeficiency virus type 1 brain infection. In a
model involving acutely infected Microglial
cells, U-90152 was the most active, whereas in a model using
chronically infected promonocytes, U-75875 was the most active
Petito CK, Vecchio D, Chen YT (1994) HIV
antigen and DNA in AIDS
spinal cords correlate with macrophage infiltration but not with
vacuolar myelopathy. J.Neuropathol.Exp.Neurol. 53:86-94
Abstract:
Since the relationship between vacuolar myelopathy (VM) and HIV
infection of the spinal cord is unclear, we studied 74 cases of VM
in AIDS patients for
associated spinal cord and brain diseases, the presence of HIV
antigens (n = 54) and amplified DNA (n = 7) and serum levels of
vitamin B12 and folic acid (n = 6). Necrosis of the medial F.
gracilis was present in 14%, HIV
myelitis in 9%, cytomegalovirus myelitis in 3% and Microglial
nodules in 16%. HIV-immunoreactive
macrophages were encountered in 6% of VM cords; they were in regions
of gracile tract necrosis in two and in monocytes and multinucleated
cells in spinal gray matter in one. Amplified HIV
DNA was detected in 50% of cords and 70% of dorsal root ganglia
(DRG) of cases with moderate or severe VM and 63% of cords and 75%
of DRG in AIDS cases
without VM. Six of the eight spinal cords with HIV
DNA contained macrophages whereas all cords without HIV
DNA (n = 6) were normal or contained only rare macrophages. There
was no association between VM and HIV
myelitis or opportunistic infections of the CNS, but there was a
close association with HIV
encephalitis which occurred in 80% of severe VM, 33% of moderate VM
and 17% of mild VM. Vitamin B12 and folic acid levels were normal or
elevated in all six AIDS
with VM as well as in 12 AIDS
without VM; all had received prophylactic vitamin therapy prior to
death.(ABSTRACT TRUNCATED AT 250 WORDS)
Philippon V, Vellutini C, Gambarelli D, Harkiss G, Arbuthnott
G, Metzger D, Roubin R, Filippi P (1994) The basic domain of the
lentiviral Tat protein is responsible for damages in mouse brain:
involvement of cytokines. Virology 205:519-529
Abstract: The HIV
and visna lentiviruses induce an inflammatory reaction in the
central nervous system (CNS) of the infected hosts leading to
dysmyelination, demyelination, and neuronal loss. The basic domain
of the transactivating Tat protein has been involved in CNS damage.
Infusion of basic containing domain Tat peptides in the lateral
ventricle (systemic injection) or in the grey matter, i.e.,
hippocampus and thalamus (local injection), induced an inflammatory
process characterized by the formation of an edema and invasion of
macrophage accompanied by reactive astrogliosis. Control peptides
originating from either lentiviral proteins or irrelevant protein as
ovalbumin did not lead to any inflammatory reaction or cell death.
The inflammation led to the loss of ependymal cells in the lateral
ventricles and neurons in the grey matter. RNA extracted from the
Tat-injected hemisphere reacted with TNF-alpha, IL-1 alpha and beta,
and IL-6 probes. The macrophage/Microglia
inducible nitric oxyde synthase was also expressed. Blockade of
TNF-alpha by a pentoxifylline treatment led to the decrease of IL-1
and iNOS expression accompanied by a reduction of the volume of the
lesions indicating that the Tat-induced lesions might be mediated by
TNF production
Pulliam L, Clarke JA, McGuire D, McGrath MS (1994)
Investigation of HIV-infected
macrophage neurotoxin production from patients with AIDS
dementia. Adv.Neuroimmunol. 4:195-198
Abstract: The mechanism for
AIDS dementia may involve
the production of toxic cytokines. Since macrophage/Microglia
are the infected cells in the brain, we were interested in the
production of some of the same cytokines by HIV-infected
macrophages from patients with AIDS
dementia. HIV-infected
macrophages from 11 patients with AIDS
dementia were cultured and evaluated for p24, cytomegalovirus (CMV)
DNA, and the production of interleukin 6 (IL-6), tumor necrosis
factor alpha (TNF alpha) and other neurotoxic factors. The
percentage of HIV
macrophage infectivity did not correlate with the severity of
dementia nor did the presence of CMV. The production of IL-6 and an
unidentified neurotoxin did not correlate with HIV
macrophage infectivity suggesting that these soluble factors are
strain specific. Production of TNF alpha by HIV-infected
macrophages was relatively low (< 1-35 pg/ml) and may not be a
significant factor in toxicity
Reyes E, Mohar A, Mallory M, Miller A, Masliah E (1994)
Hippocampal involvement associated with human immunodeficiency virus
encephalitis in Mexico. Arch.Pathol.Lab Med. 118:1130-1134
Abstract:
The objective of the present study was to review the alterations of
the central nervous system (CNS) in a group of deceased Mexican
patients with acquired immunodeficiency syndrome; autopsies were
reviewed with a special emphasis on the damage to the hippocampal
formation. Of these 19 deceased patients with acquired
immunodeficiency syndrome, nine (47%) had opportunistic infections
in the CNS that were accompanied by human immunodeficiency virus
encephalitis (HIVE), three
(16%) had evidence of opportunistic infections in the brain without
HIVE, and two (11%) had
HIVE alone. All of the
patients who had presented with neurological and neurobehavioral
alterations had evidence of HIVE
and/or opportunistic infections in the CNS. Of these 19 patients, 11
(58%) had presented with evidence of HIVE
(with or without opportunistic CNS infections), as evidenced by the
presence of gp41-positive Microglial
cells in the basal ganglia, neocortex, and hippocampus. The
subiculum was the region that displayed the most abundant
infiltration by gp41-positive Microglial
cells. The percentage of cases of acquired immunodeficiency syndrome
with HIVE and/or CNS
opportunistic infections in our series was similar when compared
with that of other series in which similar methods of detection of
human immunodeficiency virus in the CNS were used. We conclude that
evidence of human immunodeficiency virus-associated lesions in the
hippocampal formation might in part explain the selective neuronal
alterations in this limbic structure, and we suggest that damage to
this circuitry might be in part involved in the cognitive
alterations in HIVE
Sinclair E, Gray F, Ciardi A, Scaravilli F (1994)
Immunohistochemical changes and PCR detection of HIV
provirus DNA in brains of asymptomatic HIV-positive
patients. J.Neuropathol.Exp.Neurol. 53:43-50
Abstract: The stage
of HIV infection at which
the virus enters the nervous system remains poorly understood.
Examination of brains of HIV-positive
non-AIDS patients often
shows lymphocytic meningitis, myelin pallor and gliosis, but no
immunohistochemical (IHC) evidence of the virus. In this study we
have examined a number of brains from HIV-positive
patients with (23) and without (8) AIDS
as well as brains from 5 HIV-negative
controls by morphological, morphometric, IHC and polymerase chain
reaction (PCR) methods in an attempt to establish at what stage of
the infection HIV can be
detected in the brain and to correlate its presence with the
pathological changes in the cortex. HIV-1
proviral DNA was found by PCR in the cortex of the majority of AIDS
and in 2 out of 8 non-AIDS
cases. Astroglial reaction was observed in the cortex of the
majority of AIDS brains but
not in most of the non-AIDS
brains which showed, in addition, a dramatic reduction of glial
fibrillary acidic protein staining around blood vessels; moreover,
in this group the density of Microglial
cells was higher than in the AIDS
group. These results show that: 1) HIV
proviral DNA can be found in the brains of HIV-positive
non-AIDS patients; 2) in
the same group there is an increase in density of Microglial
cells which 3) appears to be transient, since AIDS
brains without neuropathology show a lower density of these cells.
They also suggest that the status of 'immune reaction' existing in
AIDS may predate this
period.(ABSTRACT TRUNCATED AT 250 WORDS)
Stanley LC, Mrak RE, Woody RC, Perrot LJ, Zhang S, Marshak
DR, Nelson SJ, Griffin WS (1994) Glial cytokines as neuropathogenic
factors in HIV infection:
pathogenic similarities to Alzheimer's disease.
J.Neuropathol.Exp.Neurol. 53:231-238
Abstract: The mechanisms by
which human immunodeficiency virus (HIV)
infection provokes progressive neurodegeneration and dementia in
acquired immunodeficiency syndrome (AIDS)
remain obscure. In HIV-infected
(HIV+) individuals, we
found that the brain cells preferentially infected by HIV,
viz. the Microglia,
were abundant, activated, and intensely immunopositive for
interleukin-1 alpha (IL-1 alpha), an immune response-generated
cytokine that increases the synthesis and processing of beta-amyloid
precursor proteins (beta-APP) and promotes proliferation and
activation of astroglia. We also found an increase in the number of
activated astroglia expressing elevated levels of S100 beta, a
cytokine that increases intraneuronal calcium levels and promotes
excessive growth of neuronal processes (neurites). These glial
changes were accompanied by increased expression of beta-APP
immunoreaction product in neurons and overgrown (dystrophic)
neurites. In addition, some neurons contained monoclonal antibody
Tau-2 immunopositive, neurofibrillary tangle-like structures. Our
findings provide evidence that glial activation with increased
expression of IL-1 alpha and S100 beta may be important in the
neuropathogenesis of AIDS
dementia. We propose that HIV
infection promotes excessive Microglial
IL-1 alpha expression with consequent astrogliosis and increased
expression of S100 beta. Overexpression of these two cytokines may
then be involved in AIDS
neuropathogenesis by inducing gliosis, growth of dystrophic
neurites, and calcium-mediated neuronal cell loss in AIDS
Tabakoff B (1994) Alcohol and AIDS--is the relationship all in our heads? Alcohol Clin.Exp.Res. 18:415-416
Tillmann M, Krebs FC, Wessner R, Pomeroy SM, Goodenow MM,
Wigdahl B (1994) Neuroglial-specific factors and the regulation of
retrovirus transcription. Adv.Neuroimmunol. 4:305-318
Abstract:
Retroviruses have been implicated as causative agents of a variety
of human diseases including malignancy, immune system dysfunction,
and neurologic disorders. Despite the isolation of various
retroviral agents from patients suffering from malignant neoplasias
and neurologic disorders, only the human T-cell lymphotropic virus
type I (HTLV-I) and the human immunodeficiency virus (HIV)
have been definitively accepted as etiologic agents of human disease
(Hjelle, 1991; Gessain and Gout, 1992; Rosenblatt, 1993). Because of
their increasingly defined roles in disease progression, the
replication of HTLV-I and HIV
is an important focus for understanding the pathogenic processes
resulting from viral infection. Of particular interest are the
molecular mechanisms by which expression of retroviral genomes is
regulated by their regulatory units, the long terminal repeats
(LTR), in a manner specific to the cellular targets which they
infect
Toggas SM, Masliah E, Rockenstein EM, Rall GF, Abraham CR,
Mucke L (1994) Central nervous system damage produced by expression
of the HIV-1 coat protein
gp120 in transgenic mice. Nature 367:188-193
Abstract: Many
people infected with human immunodeficiency virus type 1 (HIV-1)
develop neurological complications that can culminate in dementia
and paralysis. The discrepancy between the severity of impairment
and the paucity of detectable HIV-1
within neurons has led to an intense search for diffusible virus-
and host-derived factors that might be neurotoxic (see ref. 2 for
review). The HIV-1 envelope
glycoprotein gp120 is an extracellular protein that is shed from
infected cells and so has the potential to diffuse and interact with
distant uninfected brain cells. Studies on cultured immature cells
suggest that gp120 induces neurotoxicity (reviewed in refs 2, 4),
and systemic injection of gp120 in neonatal rats and
intracerebroventricular injection in adult rats results in
deleterious effects on the brain. To assess the pathogenic potential
of gp120 in the intact brain, we have now produced gp120 in the
brains of transgenic mice and found a spectrum of neuronal and glial
changes resembling abnormalities in brains of HIV-1-infected
humans. The severity of damage correlated positively with the brain
level of gp120 expression. These results provide in vivo evidence
that gp120 plays a key part in HIV-1-associated
nervous system impairment. This model should facilitate the
evaluation and development of therapeutic strategies aimed at
HIV-brain interactions
Weis S, Neuhaus B, Mehraein P (1994) Activation of Microglia
in HIV-1 infected brains is
not dependent on the presence of HIV-1
antigens. Neuroreport 5:1514-1516
Abstract: The activation
pattern of Microglia
in the cerebral cortex of AIDS
patients with the neuropathological diagnosis of HIV-1
encephalitis was investigated by immunohistochemistry and
morphometry. The number of activated Microglial
cells in the grey and white matter of five cortical regions was
determined. In the grey and white matter of all cortical regions a
significant increase in the number of Microglial
cells was demonstrated in HIV-1
infected brains. Moreover, the activation of Microglia
was not correlated with the presence of HIV-1
antigen in the brain region. The data show a significantly increased
number of Microglia
in HIV-1 infected brains.
These activated Microglial
cells could, among others, be those cells producing cytotoxic
factors which, in turn, cause brain damage
Williams K, Ulvestad E, Antel J (1994) Immune regulatory and
effector properties of human adult Microglia
studies in vitro and in situ. Adv.Neuroimmunol. 4:273-281
Abstract:
Monocytes, macrophages, and brain Microglia
are the primary cell types most readily demonstrated to be infected
in CNS lesions of patients infected with HIV
(Koenig et al., 1986). Microglia
are implicated in mediating CNS immune regulation and neural tissue
injury associated with the AIDS-dementia
syndrome. This report describes the isolation and characterization
of Microglia
from the adult human central nervous system (CNS), and the
assessment of Microglial
immune accessory/effector functions, some of which might be altered
in CNS infectious and autoimmune diseases. In our studies we have
compared the in vitro properties of Microglia
with peripheral blood monocytes/macrophages, and with astrocytes, a
CNS cell type also implicated in contributing to immune regulatory
and effector functions. Additionally, we have compared phenotypic
features of resident Microglia
in situ with monocytes and macrophages that have infiltrated the CNS
during the course of CNS inflammation. Our results suggest that
adult human derived parenchymal Microglia
represent a unique cell of monocytic origin that can be
distinguished both in vitro and in situ from monocytes/macrophages
recently infiltrating into the CNS and from perivascular
macrophages/Microglial
cells. Our data demonstrate that parenchymal Microglia
express several immune accessory/adhesion molecules that can provide
second signals for CD4+T cell stimulation. Furthermore, Microglia
can synthesize cytokines and reactive oxygen species that may
augment ongoing pathology in the CNS of AIDS
patients. Infection of resident brain Microglia
could augment Microglial
immune accessory/effector functions possibly contributing to
pathology seen in HIV
dementia
Brinkmann R, Schwinn A, Muller J, Stahl-Hennig C, Coulibaly
C, Hunsmann G, Czub S, Rethwilm A, Dorries R, ter M, V (1993) In
vitro and in vivo infection of rhesus monkey Microglial
cells by simian immunodeficiency virus. Virology
195:561-568
Abstract: The observation that Microglial
cells in brain tissue are probably a major target for human
immunodeficiency virus (HIV)
infection has raised interest in the pathogenic role of this cell
population for the development of neuro-AIDS.
Since it is very difficult to obtain Microglia
from normal or diseased human brain we studied Microglial
cells isolated from fresh brain tissue of uninfected and simian
immunodeficiency virus (SIV) infected rhesus monkeys (Macacca
mulatta) in comparison to peripheral blood macrophages. Besides the
characterization of the phenotypes of these two cell populations, we
examined the replication of SIV in the cells in addition to the
effect of viral infection on the expression of cell surface
molecules. We found that Microglia
and macrophages support replication of the wild-type SIVmac251
strain as well as the infectious clone (SIV239). Infectious virus
was produced and a CPE developed. Isolated Microglial
cells from SIV-infected monkeys were latently infected independent
of the presence of neuropathological lesions and produced infectious
virus after 20-25 days in culture. In situ hybridization revealed
that only a small percentage of isolated Microglial
cells are productively infected in vivo, yet the majority of these
expressed MHC class II molecules. This indicated a state of
activation that is acquired in vivo. These findings indicate that
Microglia
are a prime target cell for SIV infection in CNS tissue
Dickson DW, Lee SC, Mattiace LA, Yen SH, Brosnan C (1993)
Microglia
and cytokines in neurological disease, with special reference to
AIDS and Alzheimer's
disease. Glia 7:75-83
Abstract: Microglia
are associated with central nervous system (CNS) pathology of both
Alzheimer's disease (AD) and the acquired immunodeficiency syndrome
(AIDS). In AD, Microglia,
especially those associated with amyloid deposits, have a phenotype
that is consistent with a state of activation, including
immunoreactivity with antibodies to class II major
histocompatibility antigens and to inflammatory cytokines
(interleukin-1-beta and tumor necrosis factor-alpha). Evidence from
other studies in rodents indicate that Microglia
can be activated by neuronal degeneration. These results suggest
that Microglial
activation in AD may be secondary to neurodegeneration and that,
once activated, Microglia
may participate in a local inflammatory cascade that promotes tissue
damage and contributes to amyloid formation. In AIDS,
Microglia
are the primary target of retroviral infection. Both ramified and
ameboid Microglia,
in addition to multinucleated giant cells, are infected by the human
immunodeficiency virus (HIV-1).
The mechanism of Microglial
infection is not known since Microglia
lack CD4, the HIV-1
receptor. Microglia
display high affinity receptors for immunoglobulins, which makes
antibody-mediated viral uptake a possible mechanism of infection. In
AIDS, the extent of active
viral infection and cytokine production may be critically dependent
upon other factors, such as the presence of coinfecting agents. In
the latter circumstance, very severe CNS pathology may emerge,
including necrotizing lesions. In other circumstances, HIV
infection of Microglia
probably leads to CNS pathology by indirect mechanisms, including
release of viral proteins (gp120) and toxic cytokines. Such a
mechanism is the best hypothesis for the pathogenesis of vacuolar
myelopathy in adults and the diffuse gliosis that characterizes
pediatric AIDS, in which
very little viral antigen can be detected
Dickson DW, Llena JF, Nelson SJ, Weidenheim KM (1993) Central
nervous system pathology in pediatric AIDS.
Ann.N.Y.Acad.Sci. 693:93-106
Abstract: Children with AIDS
frequently have neurological manifestations due to complications of
immunodeficiency or intrinsic effects of human immunodeficiency
virus type 1 (HIV-1) on the
central nervous system (CNS). The most common neurological disorders
not directly related to HIV-1
infection include cerebrovascular disease and lymphoma. Global
anoxic-ischemic and necrotizing encephalopathies are frequent, while
CNS hemorrhages and arteriopathies are less frequent. Opportunistic
CNS infections are uncommon, limited predominantly to monilial and
cytomegaloviral encephalitides. Only a few cases of CNS
toxoplasmosis have been reported in children. CNS lymphomas often
occur in the setting of systemic polymorphous, polyclonal B-cell
proliferations that have been associated with Epstein-Barr virus
infection. Intrinsic effects of HIV-1
on the CNS include microcephaly, diffuse gliosis, basal ganglia
mineralization, HIV
encephalitis, and corticospinal tract degeneration. Although viral
antigens can be detected in Microglia
and multinucleated cells in HIV
encephalitis, most of the CNS effects of HIV-1
infection cannot be attributed to detectable levels of viral
antigen, suggesting that the pediatric CNS is unusually susceptible
to low-level HIV-1
infection or to systemic effects of HIV-1
infection, possibly mediated by soluble factors, including the
inflammatory cytokines, interleukin-1 beta, and tumor necrosis
factor-alpha, which have been shown to be increased in serum and
cerebrospinal fluid of children with AIDS
Gosztonyi G, Schmidt V, Nickel R, Rothschild MA, Camacho S,
Siegel G, Zill E, Pauli G, Schneider V (1993) Neuropathologic
analysis of postmortal brain samples of HIV-seropositive
and -seronegative i.v. drug addicts. Forensic Sci.Int.
62:101-105
Abstract: Between 1987 and 1992 we performed
forensic-pathologic and neuropathologic examinations on 70 cases of
i.v. drug addicts who died of an overdose. In almost 25% of the
cases HIV-positivity was
revealed by serological examinations. In all the cases, irrespective
of the result of the serological examination, a diffuse, reactive
astrocytosis was the most prominent histologic alteration,
accompanied by more or less pronounced regressive changes of this
cell type in the deep layers of the white matter. Furthermore, also
in all the cases, a slight to moderate, reactive proliferation of
Microglia
could be assessed. In a few cases of the HIV-seropositive
group a lymphocytic meningitis, viz. meningoencephalitis was found;
these changes may indicate an early invasion of the central nervous
system (CNS) by the HIV. In
spite of these inflammatory alterations, in the latter cases no
HIV-specific antigens (p24
and gp41) could be demonstrated in the brain, most probably because
of the small number of infectious particles. In order to reveal the
earliest phase of invasion of the CNS by the HIV,
we performed a search for HIV-specific
nucleic acid sequences by the aid of the polymerase chain reaction
(PCR) in 8 HIV-seronegative
and 8 normal control cases. Although, most probably due to
contamination, also the control cases exhibited some PCR-signals,
these were more pronounced and appeared with more primer-pairs
within the group of HIV-seronegative
drug addicts. It is conceivable that HIV
penetrates the CNS and is harboured in it in latent form shortly
after the primary infection.(ABSTRACT TRUNCATED AT 250 WORDS)
Hawkins CP, McLaughlin JE, Kendall BE, McDonald WI (1993)
Pathological findings correlated with MRI in HIV
infection. Neuroradiology 35:264-268
Abstract: MRI forms an
important part of the assessment of patients with HIV-related
disease presenting with cerebral symptoms. Eleven formalin-fixed
brains were studied at 0.5 T using T2- and T1-weighted sequences. In
two cases of progressive multifocal leucoencephalopathy and one case
each of toxoplasmosis and lymphoma, the extent of white matter
abnormality seen on MRI corresponded broadly with that on
pathological examination. In general, however, histological changes
were more frequent than lesions on MRI. Cases in which abnormalities
were not seen with standard MRI included those with multiple
tuberculous granulomata, multinucleate giant cells, Microglial
nodules, perivascular cuffing and cytomegalovirus inclusions. A
common finding on MRI was punctate or patchy high signal in the
basal ganglia on T2-weighted scans, seen in six cases. Corresponding
histological changes included calcification of vessels with widened
perivascular spaces, and mineralised neurones
Kuchelmeister K, Bergmann M, Gullotta F (1993) Cellular
changes in the cerebellar granular layer in AIDS-associated
PML. Neuropathol.Appl.Neurobiol. 19:398-401
Abstract: Six cases
of AIDS-associated
progressive multifocal leukoencephalopathy (PML) exhibited peculiar
cellular changes in the cerebellar granular layer. These cells
without discernible cytoplasm showed hypochromatic nuclei about
twice as large as those of normal granule cells. They were
restricted exclusively to the granular layer and always surrounded
PML foci. An astrocytic, leukocytic or macrophage/Microglial
nature was largely excluded by immunocytochemistry. Human
immunodeficiency virus (HIV)
antigen p 24 could not be found in these cells and there was no
unequivocal detection of JC virus (JCV) DNA and no ultrastructural
evidence of papovavirus particles in them. They possibly represent
altered cerebellar granule cells abortively or latently infected
with JCV
Lacroix C, Vazeux R, Brousse N, Blanche S, Tardieu M (1993)
[A neuropathological study of 10 HIV-infected
children]. Rev.Neurol.(Paris) 149:37-45
Abstract: In 10 children
infected by HIV at birth,
who presented early and severe immunodeficiency encephalopathy, the
lesions observed in the central nervous system were different from
those found in adults. Using standard neuropathological techniques,
the main abnormalities were white matter palor and atrophy,
pyramidal tract demyelination, moderate perivascular inflammation,
numerous calcifications of blood vessels in basal ganglia, white
matter and occasional in the cortex, few opportunistic infections
including cytomegalovirus ventriculitis, polymorphonuclear
microabcessses and aspergillus abscesses; no toxoplasma was
detected. An 18-month-old girl presented with an angiocentric
lymphoproliferative disorder in central and peripheral nervous
system and muscle, with predominance of B cells. In most cases, low
levels of HIV replication
were detected in brain tissue, as demonstrated by the presence of
only few Microglial
nodules and giant cells, feeble detection of HIV
p24 and p17 antigens by immunocytochemistry, in situ hybridization
of HIV DNA and RNA and
polymerase chain reaction, despite severe clinical encephalopathy.
Zidovudine did not improve any patient. In children with severe AIDS
encephalopathy, HIV might
not be directly implicated in the central nervous system lesions: an
intermediate factor such as cytokines or another toxic substance
secreted by activated macrophages and/or lymphocytes, could induce
severe lesions in the central nervous system and minor pathology of
the peripheral nervous system and muscles
Lassmann H, Schmied M, Vass K, Hickey WF (1993) Bone marrow
derived elements and resident Microglia
in brain inflammation. Glia 7:19-24
Abstract: Infection of the
central nervous (CNS) system by the human immunodeficiency virus
(HIV) depends on the
migration of infected hematogenous cells into the brain. We thus
used quantitative light and electron microscopic immunocytochemistry
to study the homing and turnover of bone marrow derived cells in the
CNS in radiation bone marrow chimeras under normal conditions and in
experimental autoimmune encephalomyelitis (EAE) as an experimental
model of brain inflammation. Our studies suggest the following
conclusions. First, the central nervous system is continuously
patrolled by a small number of T-lymphocytes and monocytes.
Meningeal and perivascular monocytes are slowly replaced by
hematogenous cells under normal conditions, and this turnover is
accelerated in the course of inflammation. In contrast, resident
Microglia
represent a very stable cell pool, which in adult animals is only
exceptionally replaced by hematogenous cells, even after recovery
from severe brain inflammation. Second, although in
bone-marrow-chimeric animals resident Microglia,
astrocytes, and ependymal cells are not able to present antigen to
Lewis T-lymphocytes, the inflammatory reaction in EAE is
qualitatively and quantitatively similar in these animals compared
to fully histocompatible Lewis rats. Finally, resident Microglia
express the macrophage activation antigen ED1. Thus, Microglia
cells appear to function as effector cells in EAE lesions
Lee SC, Hatch WC, Liu W, Kress Y, Lyman WD, Dickson DW (1993)
Productive infection of human fetal Microglia
by HIV-1. Am.J.Pathol.
143:1032-1039
Abstract: Central nervous system disease is a
frequent finding in both pediatric and adult AIDS.
Microglia
have been shown to be the major target of HIV-1
infection in the central nervous system. However, studies in vitro
concerning susceptibility of human Microglia
to HIV-1 infection reported
conflicting results; Microglia
from adult brain showed productive infection by HIV-1,
whereas Microglia
from fetal brain did not. To investigate this further and to define
the possible mechanisms responsible for this difference, we prepared
highly purified human Microglial
cell cultures from fetuses of 16 to 24 weeks' gestation and exposed
them to monocytotropic (HIV-1
JR-FL and HIV-1 JR-CSF)
isolates of HIV-1. Culture
supernatants were examined for the presence of p24 antigen for a
4-week period after viral exposure. Concurrently, potential
cytopathic effects and cellular viral antigen expression (gp41 and
p24) were examined by light microscopy in combination with
immunocytochemistry. The results showed that human fetal Microglia
can be productively infected by HIV-1
as judged by p24 antigen capture assay, syncytia formation, and gp41
and p24 immunoreactivity of infected Microglia.
In addition, by electron microscopy, numerous viral particles
characteristic of HIV-1
were present both in the intracellular and extracellular
compartments. Uninfected cultures or astrocytes overgrown in the
Microglial
cultures did not show evidence of infection under identical
experimental conditions. These data demonstrate that human fetal
Microglia,
like their adult counterparts, are susceptible to HIV-1
infection in vitro and can support the production of virus
Levi G, Patrizia M, Agresti C, Petrucci T, Bernardo A (1993) Use of rat Microglial cells for the study of a possible mechanism of brain damage in AIDS. Clin.Neuropathol. 12:290-292
Levi G, Patrizio M, Bernardo A, Petrucci TC, Agresti C (1993)
Human immunodeficiency virus coat protein gp120 inhibits the
beta-adrenergic regulation of astroglial and Microglial
functions. Proc.Natl.Acad.Sci.U.S.A 90:1541-1545
Abstract: The
goal of our study was to assess whether the human immunodeficiency
virus (HIV) coat protein
gp120 induces functional alterations in astrocytes and Microglia,
known for their reactivity and involvement in most types of brain
pathology. We hypothesized that gp120-induced anomalies in glial
functions, if present, might be mediated by changes in the levels of
intracellular messengers important for signal transduction, such as
cAMP. Acute (10 min) exposure of cultured rat cortical astrocytes or
Microglia
to 100 pM gp120 caused only a modest (50-60%), though statistically
significant, elevation in cAMP levels, which was antagonized by the
beta-adrenergic receptor antagonist propranolol. More importantly,
the protein substantially depressed [by 30% (astrocytes) and 50%
(Microglia)]
the large increase in cAMP induced by the beta-adrenergic agonist
isoproterenol (10 nM), without affecting that induced by direct
adenylate cyclase stimulation by forskolin. Qualitatively similar
results were obtained using a glial fibrillary acidic protein
(GFAP)-positive human glioma cell line. The depression of the
beta-adrenergic response had functional consequences in both
astrocytes and Microglia.
In astrocytes we studied the phosphorylation of the two major
cytoskeletal proteins, vimentin and GFAP, which is normally
stimulated by isoproterenol, and found that gp120 partially (40-50%)
prevented such stimulation. In Microglial
cells, which are the major producers of inflammatory cytokines
within the brain, gp120 partially antagonized the negative
beta-adrenergic modulation of lipopolysaccharide (10 ng/ml)-induced
production of tumor necrosis factor alpha. Our results suggest that,
by interfering with the beta-adrenergic regulation of astrocytes and
Microglia,
gp120 may alter astroglial "reactivity" and upset the
delicate cytokine network responsible for the defense against viral
and opportunistic infections
Neuen-Jacob E, Arendt G, Wendtland B, Jacob B, Schneeweis M,
Wechsler W (1993) Frequency and topographical distribution of
CD68-positive macrophages and HIV-1
core proteins in HIV-associated
brain lesions. Clin.Neuropathol. 12:315-324
Abstract: We report
the neuropathological and immunohistochemical findings in the brains
of 14 AIDS patients with
HIV-related encephalopathy.
Clinically, half of the patients presented with severe AIDS
dementia complex including advanced psychomotor retardation and
behavioural dysfunction. These features correlated with striking
cerebral atrophy and subcortical lesions visible in CT and/or MRI
scans. In 7 cases early signs of impaired memory and concentration
and/or psychomotor slowing were apparent accompanied by subcortical
lesions in MRI scans and normal CCTs. In order to investigate the
topographical distribution of HIV-1-associated
features, in every case tissue samples from the frontal, temporal,
parietal, occipital cortex and subcortical white matter, the
hippocampus, basal ganglia, midbrain, pons, medulla oblongata and
cerebellum were studied. In all patients histological examination
disclosed the typical cellular constituents of HIV
encephalitis (n = 12) or leukoencephalopathy (n = 2). Antibodies
against lymphocyte subsets, CD68 antigen, myelin basic protein and
GFAP were used to characterize the phenotype of cells and to
highlight the white matter gliosis. The distribution and degree of
pathological features were analysed in a semiquantitative scale,
based on the number of CD68-positive cells, and disclosed great
interindividual differences concerning the affected brain regions
which only in part correlated with the severity of the clinical
picture. It is noteworthy, that the deep gray matter, in particular
putamen and thalamus, was involved in every case, independent from
the stage of the disease. In addition, quantity and topographical
distribution of HIV-1 core
protein p24 were studied by use of two monoclonal antibodies. It is
noteworthy, that the number of immunoreactive multinucleated giant
cells and Microglial
cells decreased gradually from the deep gray matter, especially
putamen and thalamus, and deep white matter to corpus callosum,
cerebellar white matter and subcortical cerebral white matter. The
topographical predilection of the deep gray matter even in cases
with early cognitive decline indicates that the basal ganglia are
affected early in the course of the disease. This observation
closely resembles the results of highly sensitive quantitative
neuropsychological tests which disclosed slowing and impaired
coordination of rapid extremity movements indicating basal ganglia
lesions even in early stages of HIV
dementia
Power C, Kong PA, Crawford TO, Wesselingh S, Glass JD,
McArthur JC, Trapp BD (1993) Cerebral white matter changes in
acquired immunodeficiency syndrome dementia: alterations of the
blood-brain barrier. Ann.Neurol. 34:339-350
Abstract: The cause
of acquired immunodeficiency syndrome (AIDS)
dementia, which is a frequent late manifestation of human
immunodeficiency virus (HIV)
infection, is unknown but radiological and pathological studies have
implicated alterations in subcortical white matter. To investigate
the pathological basis of these white matter abnormalities, we
performed an immunocytochemical and histological analysis of
subcortical white matter from AIDS
patients with and without dementia, from pre-AIDS
patients (asymptomatic HIV-seropositive
patients), and from HIV-seronegative
control subjects. Reduced intensity of Luxol fast blue staining,
designated "diffuse myelin pallor," was detected in 8 of
15 AIDS dementia patients,
3 of 13 AIDS nondemented
patients, and none of the pre-AIDS
patients (n = 2) or control subjects (n = 9). In contrast to Luxol
fast blue staining, sections stained immunocytochemically for myelin
proteins did not show decreased staining intensities in regions of
diffuse myelin pallor. In addition, neither demyelinated axons nor
active demyelination were detected in light and electron micrographs
of subcortical white matter from brains of patients with AIDS
dementia. An increase in the number of perivascular macrophages and
hypertrophy of astrocytes and Microglia
occurred in brain sections from HIV-infected
patients. These changes were not specific to dementia or regions of
diffuse myelin pallor and they occurred in both gray and white
matter. In contrast to the lack of myelin pathology in AIDS
dementia brains, significant accumulations of serum proteins in
white matter glia were detected in the brains of 12 of 12 patients
with AIDS dementia and 6 of
12 AIDS patients without
dementia. Serum protein-immunopositive cortical neurons were
detected in the frontal cortex of 11 of 12 patients with AIDS
dementia and 3 of 12 nondemented AIDS
patients. Seronegative control subjects showed minimal serum protein
immunoreactivity in both cortex and white matter. We conclude
therefore that alterations in the blood-brain barrier and not
demyelination contribute to the development of AIDS
dementia
Schielke E (1993) [HIV
encephalopathy--clinical aspects, neuropathology and pathogenesis].
Nervenarzt 64:83-90
Abstract: HIV
encephalopathy, which is probably primarily caused by human
immunodeficiency virus, is the most common neurological disorder in
HIV-infected patients and
is more frequent than opportunistic diseases of the central nervous
system. It is characterized most often by slowly progressing
cognitive impairment, psychomotoric slowing and increasing apathy.
The syndrome is found almost exclusively in the late stages of HIV
infection; its frequency in patients with full-blown AIDS
is estimated as being between 40 and 70%. Although numerous studies
have demonstrated alterations in the electrophysiological
parameters, cerebral perfusion and cerebrospinal fluid in many
asymptomatic patients, there are no reliable parameters that can
predict the risk of developing HIV
encephalopathy. Also, there is no sufficient correlation between the
extent of the frequent but mostly subtle neuropathological changes
and the clinical degree of the severity of the encephalopathy. The
mechanisms causing cerebral injury are poorly understood. Recent
studies indicate that the indirect effects of HIV
infection of the brain are the most important pathogenetic factors.
In particular, certain viral proteins and cytokines produced by
infected macrophages or activated Microglia
seem to induce neuronal dysfunction and finally loss of nerve cells
Bernton EW, Bryant HU, Decoster MA, Orenstein JM, Ribas JL,
Meltzer MS, Gendelman HE (1992) No direct neuronotoxicity by HIV-1
virions or culture fluids from HIV-1-infected
T cells or monocytes. AIDS
Res.Hum.Retroviruses 8:495-503
Abstract: Macrophages and
Microglia
are the principal target cells for human immunodeficiency virus
(HIV) in brain, and as
such, are likely participants in the neuropathology of HIV
infection. In a model system for this process, we found that fluids
from human monocyte cultures enhanced survival and differentiation
of the neurons in fetal rat brain explants. In contrast, fluids from
HIV-infected monocyte
cultures were strongly toxic to neurons and paradoxically enhanced
the proliferation of glial cells. Further, neuronotoxic activity in
these fluids was mediated through activation of NMDA binding
receptors on the neurons and was inhibited by any of several
different NMDA antagonists. Neuronotoxic activity was directly
related to contamination of the HIV
virus stock with Mycoplasma arginini and M. hominis. Pure cultures
of mycoplasma, bacterial lipopolysaccharide (LPS), or murine
recombinant tumor necrosis factor alpha (rTNF alpha) each induced
neuronotoxicity which exactly mirrored that induced by the
contaminated HIV stock. It
is likely that mycoplasma or components of the mycoplasma plasma
membrane stimulate TNF alpha production by the glial cells in the
brain explants. Indeed, careful depletion of glial cells in these
explants prevented mycoplasma or LPS-mediated neuronotoxicity. No
neuronotoxicity was evident with HIV-1
virus stock, HIV-1 gp120,
or culture fluids from HIV-infected
T cells or monocytes when these preparations were free of
contamination by mycoplasma and LPS. These findings suggest caution
in interpretation of those experiments in which similar
contamination has not been rigorously excluded
Brinkmann R, Schwinn A, Narayan O, Zink C, Kreth HW,
Roggendorf W, Dorries R, Schwender S, Imrich H, ter M, V (1992)
Human immunodeficiency virus infection in Microglia:
correlation between cells infected in the brain and cells cultured
from infectious brain tissue. Ann.Neurol. 31:361-365
Abstract: In
acquired immunodeficiency syndrome, the lesions of the central
nervous system in association with the human immunodeficiency virus
are thought to be related to an infection of Microglia,
although no studies are available in which cultured and
physiological characteristics of Microglia
cells infected in vivo have been examined. In this report, we used
brain tissue from a child dying of human immunodeficiency virus
infection and show that Microglia
cells were the main cell population being infected. Moreover,
isolated macrophage-like cells from fresh brain material revealed a
close resemblance to peripheral blood macrophages in their content
of surface and intracellular antigens. No virus particles or viral
antigens were produced by these cells during the first week of
cultivation. Productive infection was readily apparent, however, by
day 30. This finding illustrates the slow nature of the virus life
cycle in these cells and the minimal cytopathology that accompanied
the infection
Cornford ME, Holden JK, Boyd MC, Berry K, Vinters HV (1992)
Neuropathology of the acquired immune deficiency syndrome (AIDS):
report of 39 autopsies from Vancouver, British Columbia.
Can.J.Neurol.Sci. 19:442-452
Abstract: Neuropathological findings
from 39 acquired immune deficiency syndrome (AIDS)
autopsies of primarily neurologically symptomatic patients and 7
brain biopsies from AIDS
patients performed at St. Paul's Hospital, Vancouver, British
Columbia are reported. Autopsy findings included human
immunodeficiency virus-1 (HIV)-type
multinucleated giant cell (MNGC)-associated encephalitis seen in 17
patients, toxoplasmosis in 7 patients, and cytomegalovirus
encephalitis and/or Microglial
nodule-associated nuclear inclusions in brain parenchyma in 9
patients. Central nervous system lymphoma was identified in 11
autopsy patients and in 4 of 7 brain biopsies. Infectious processes
including HIV encephalitis
were seen in 10 of 11 autopsied patients with lymphoproliferative
lesions in the brain parenchyma, while 40% of patients without
lymphoma had HIV-type MNGC
or opportunistic infections. CNS lymphoma was not significantly
increased in incidence in patients with a clinical history of
zidovudine treatment, but increased duration of survival after the
diagnosis of AIDS was
associated with increased incidence of lymphoma in both untreated
and zidovudine-treated patients. Patients displaying HIV
MNGC within Microglial
nodules had a shorter mean duration of survival after diagnosis of
AIDS than those patients
with HIV encephalitis with
dispersed MNGC, white matter vacuolation, and gliosis
Epstein LG, Cvetkovich TA, Lazar E, Dehlinger K, Dzenko K,
del Cerro C, del Cerro M (1992) Successful xenografts of second
trimester human fetal brain and retinal tissue in the anterior
chamber of the eye of adult immunosuppressed rats. J.Neural
Transplant.Plast. 3:151-158
Abstract: Successful xenografting of
first trimester human fetal CNS tissue and retina has been reported
in the literature. We wished to test the feasibility of using the
anterior chamber of the rat eye to support the development of more
mature human fetal xenografts. Here we report on the successful
outcome of human brain and retinal transplants. Adult host rats
immunosuppressed with cyclosporin A accepted these xenografts and
supported their further development. Periodic examination of the
host eyes using a direct ophthalmoscope or an ophthalmic slit lamp
permitted direct visual monitoring of the health and growth of the
transplants. Histologically it was possible to identify neuronal,
macroglial, and Microglial
(macrophage) cell types within the grafts. Mitotic activity and
histogenetic differentiation took place. Blood vessels filled with
hematic cells were commonly present within the grafts. The walls of
these vessels prevented the leakage of horseradish peroxidase,
suggesting the presence of a functional brain-blood barrier in the
graft. These results indicate that it is possible to use a small
animal model to study normal and pathological phenomena on late
fetal human neural tissues. Our group has already taken advantage of
the model to achieve HIV
infectivity of fetal human brain outside the human body
Gray F, Lescs MC, Keohane C, Paraire F, Marc B, Durigon M,
Gherardi R (1992) Early brain changes in HIV
infection: neuropathological study of 11 HIV
seropositive, non-AIDS
cases. J.Neuropathol.Exp.Neurol. 51:177-185
Abstract: We examined
11 brains of human immunodeficiency virus (HIV)
seropositive cases who died from unnatural causes (10 intravenous
drug abusers who died from heroin overdose and 1 homosexual dead
from a gunshot injury); 10 brains of HIV
seronegative heroin addicts who died from overdose and 1
seronegative drug abuser who died from gunshot injury served as
controls. Complete postmortem examination did not show evidence of
acquired immune deficiency syndrome (AIDS)
or AIDS related complex.
Terminal changes including nerve cell ischemia, edema and diffuse
vascular congestion were observed in all cases. Perivascular pigment
deposition with macrophages was a constant finding in drug addicts
and was probably related to chronic intravenous injection. In
contrast, cerebral vasculitis was significantly more frequent and
marked in HIV seropositive
cases and was often associated with lymphocytic meningitis. Granular
ependymitis, myelin pallor with reactive astrocytosis and Microglial
proliferation were also more frequent and more severe in HIV
seropositive cases. Immunocytochemistry was negative for HIV
antigens. Our study further supports the view that early central
nervous system changes occur in HIV
infection
Hulette CM, Downey BT, Burger PC (1992) Macrophage markers in
diagnostic neuropathology. Am.J.Surg.Pathol. 16:493-499
Abstract:
It can be difficult to differentiate the cells of infiltrating
gliomas from macrophages associated with demyelinating lesions or
cerebral infarcts, especially in tissue with freezing artifact or
tissue that is technically suboptimal. We therefore sought to
identify a reliable immunohistochemical marker for central nervous
system macrophages that could be used on routinely processed tissue.
The reactions of commercially available markers [Ham-56, Mac 387,
CD68, CR3/43, DR alpha, lysozyme, CD16, and Ricinus communis
agglutinin-1 (RCA-1)] were studied in normal cerebellum, subacute
infarcts, viral encephalitis with Microglial
nodules, radiation necrosis, Alzheimer's disease, medulloblastoma,
T-cell lymphoma, oligodendroglioma, gliomatosis cerebri, and
microgliomatosis cerebri. We also performed a more extensive
investigation of Ham-56 with largely surgical material. We concluded
that (a) RCA-1 is a sensitive marker for Microglia,
either resting or responding to injury, but staining must be
interpreted carefully because endothelial cells and reactive
astrocytes frequently stain as well. This marker was useful in
highlighting focal inflammation in HIV
encephalitis. (b) CD68 is a specific marker for resting Microglia.
A case of microgliomatosis cerebri was intensely stained. (c) Ham-56
is a sensitive, specific (with the exception of endothelial cells),
and reliable marker of central nervous system macrophages in
routinely processed autopsy and surgical material. It is especially
useful in distinguishing the macrophages in demyelinating disease
and cerebral infarcts from neoplastic glial cells
Lipton SA (1992) Models of neuronal injury in AIDS:
another role for the NMDA receptor? Trends Neurosci.
15:75-79
Abstract: As many as two-thirds of patients with
acquired immunodeficiency syndrome (AIDS)
eventually suffer from neurological manifestations, including
dysfunction of cognition, movement and sensation. How can human
immunodeficiency virus type 1 (HIV-1)
result in neuronal damage if neurons themselves are not infected by
the virus? In this article Stuart Lipton reviews a series of
experiments from several different laboratories that offer related
hypotheses accounting for neurotoxicity in the brains of AIDS
patients. There is growing support for the existence of HIV-
or immune-related toxins that directly or indirectly lead to the
injury or demise of neurons via a potentially complex web of
interactions between macrophages (or Microglia),
astrocytes and neurons. However, a final common pathway for neuronal
susceptibility appears to be operative, similar to that observed
after stroke, trauma and epilepsy. This mechanism involves
voltage-dependent Ca2+ channels and NMDA receptor-operated channels,
and therefore offers hope for future pharmacological intervention
Masliah E, Achim CL, Ge N, DeTeresa R, Terry RD, Wiley CA
(1992) Spectrum of human immunodeficiency virus-associated
neocortical damage. Ann.Neurol. 32:321-329
Abstract: A spectrum
of neurocognitive defects, termed human immunodeficiency virus type
1 (HIV-1)-associated
cognitive/motor complex, has been described in patients with
acquired immunodeficiency syndrome (AIDS).
AIDS dementia complex (ADC)
is a severe form of this disease seen in 20 to 30% of terminally ill
patients. The etiology of this complex is distinct from commonly
observed opportunistic infections seen in brains of patients with
AIDS and has been
attributed to HIV infection
within the brain. At autopsy, the brains of patients with ADC
contain numerous HIV-infected
macrophages/Microglia
with prominent subcortical damage, together termed HIV
encephalitis. We retrospectively analyzed all 107 brains from a
three-year period (1988-1990) of AIDS
autopsies using immunocytochemistry to detect HIV.
Rather than breaking into distinct groups of HIV
encephalitis versus non-HIV
encephalitis, the specimens revealed a spectrum of severity of HIV
infection. Although only 16% of the brains showed the histological
hallmarks of HIV
encephalitis, more than 50% of the autopsies showed moderate to
severe HIV infection. In a
subset of 23 AIDS autopsies
during which short postmortem times and absence of significant
opportunistic infection permitted quantitative analysis of dendritic
and synaptic complexities, we identified a strong correlation
between neocortical dendritic and presynaptic damage and abundance
of HIV envelope protein in
the neocortical gray and deep white matter. This correlation
suggests that the presence of HIV-1
in the neocortex may be responsible by direct or indirect mechanisms
for dendritic and synaptic damage
Masliah E, Ge N, Achim CL, Hansen LA, Wiley CA (1992)
Selective neuronal vulnerability in HIV
encephalitis. J.Neuropathol.Exp.Neurol. 51:585-593
Abstract:
Recent studies of human immunodeficiency virus type 1 (HIV-1)
encephalitis have shown that in addition to well established white
matter damage, the neocortex shows thinning, loss of large neurons
and dendritic damage. In order to identify neuronal populations
affected in HIV
encephalitis and to determine how neuronal damage relates to the
severity of HIV infection
within the nervous system, we quantified parvalbumin (PV+) and
neurofilament (NF+) immunoreactive neurons in the frontal cortex and
hippocampus. We found that in the neocortex, the density of NF+ and
PV+ neurons was independent of severity of HIV
encephalitis, and therefore changes in these neuronal subsets did
not account for previously reported neuronal loss. However, neuritic
processes of PV+ neurons were fragmented, atrophic and in some cases
distended. In contrast to the frontal cortex, there was a trend
toward decreased density of PV+ neurons in the hippocampus which
only reached significance in the CA3 layer where there was a 50-90%
decrease in PV+ neurons. This decrease was closely correlated with
the severity of HIV
encephalitis. Double-label immunocytochemical analysis confirmed
neuritic damage to interneurons. These results suggest that HIV
encephalitis differentially involves specific subpopulations of
neurons. Since direct HIV
infection of neuronal cells was not detected, damage to PV+ cells
and fibers may be indirectly mediated by cytokines released by
HIV-infected Microglia
Matthiessen L, Marche C, Labrousse F, Trophilme D, Fontaine
C, Vedrenne C (1992) [Neuropathology of the brain in 174 patients
who died of AIDS in a Paris
hospital 1982-1988]. Ann.Med.Interne (Paris) 143:43-49
Abstract:
Between 1982 and 1988, 174 brains were systematically collected from
consecutive, autopsied AIDS
patients in a Parisian general hospital without neurology and
psychiatry departments. The data obtained under these conditions
provide reliable information on the frequency of central nervous
system (CNS) involvement in a non-selected population of AIDS
patients, most of whom were homosexuals (75.9%). One or several
lesions were observed in 148 cases (85%). HIV
encephalitis and/or leucoencephalopathy with multinucleated giant
cells was found in 33 cases (18.9%). Opportunistic infections were
identified in 91 patients (52.3%): toxoplasmosis (65 cases; 37.3%),
cytomegalovirus encephalitis (25 cases; 14.3%), cryptococcosis (9
cases; 5.8%), progressive multifocal leukoencephalitis (5 cases;
2.8%), candidosis (1 case) and tuberculosis (1 case). Neoplasias
were observed in 23 patients: primary (16 cases; 17.9%) or secondary
malignant non Hodgkin's large B-cell lymphoma (3 cas; 1.1%),
Kaposi's sarcoma (1 case) and glioma (3 cases; 1.1%). Non-specific
lesions (vasculitic, hemorrhagic, metabolic and especially
Microglial
nodules) were common. During the 6 years of study, the rate of CNS
involvement was constant. The number of toxoplasmosis cases per year
was stable, however, evolutive forms were more prevalent between
1982 and 1986, whereas treated inactive lesions were seen most
frequently thereafter. The opportunistic complications were often
associated and it should be noted that HIV
encephalitis was associated with one of several such infections in
85% of the patients. This high rate of association suggests that
these opportunistic infections may play a role in the pathogenesis
of HIV encephalitis
Peterson PK, Gekker G, Hu S, Schoolov Y, Balfour HH, Jr.,
Chao CC (1992) Microglial
cell upregulation of HIV-1
expression in the chronically infected promonocytic cell line U1:
the role of tumor necrosis factor-alpha. J.Neuroimmunol.
41:81-87
Abstract: Culture supernatants from lipopolysaccharide
(LPS)-treated murine Microglial
cells were found to markedly induce the expression of human
immunodeficiency virus (HIV)-1
in the chronically infected human promonocytic cell line U1 as
detected by measurements of HIV-1
p24 antigen release into U1 culture supernatants. Antibody to tumor
necrosis factor (TNF)-alpha had an inhibitory effect on the
induction of virus by Microglial
cell supernatants. Also, treatment of Microglia
with pentoxifylline, an inhibitor of TNF-alpha production, resulted
in suppressed amounts of TNF in the supernatants of LPS-treated
Microglia
and in a reduced stimulatory capacity of these supernatants on HIV-1
expression in U1 cells. These findings support the concept that
TNF-alpha production by glial cells plays a pathogenetic role in
HIV-1-associated brain
disease by promoting the expression of the virus in infected cells
Petito CK, Cash KS (1992) Blood-brain barrier abnormalities
in the acquired immunodeficiency syndrome: immunohistochemical
localization of serum proteins in postmortem brain. Ann.Neurol.
32:658-666
Abstract: Abnormalities in the blood-brain barrier
(BBB) may be important in mediating some of the tissue damage that
accompanies human immunodeficiency virus (HIV)
infection of the brain, as well as in facilitating viral entry into
the central nervous system. Accordingly, immunohistochemical
detection of fibrinogen (FIB) and immunoglobulin G (IgG) was used as
a marker of vascular permeability in formalin-fixed,
paraffin-embedded brains of patients with acquired immunodeficiency
syndrome (AIDS) who had HIV
encephalitis (HIVE) (n =
17) and those who did not have HIVE
(n = 16); nonimmunosuppressed patients served as control subjects (n
= 22). The sex ratios and postmortem intervals were similar in all
groups (p > 0.05), but the age of the two AIDS
groups were younger than the control group (43.2 and 40.9 versus
62.5 yr; p < 0.05). The two AIDS
groups had higher immunostaining for FIB and IgG than the control
group (p < 0.001 and p < 0.0001, respectively) but did not
differ from one another. Furthermore, the two AIDS
groups had a significantly higher incidence of combined
extravasation of both FIB and IgG, whereas the control group had a
significantly higher incidence of negative staining for both
proteins (p < 0.002). More than 95% of the Microglial
nodules of HIV were
negative for serum proteins; however, all focal lesions with tissue
necrosis, including lymphoma, opportunistic infections, and HIV
(rarely), contained extravasated serum proteins.(ABSTRACT TRUNCATED
AT 250 WORDS)
Scaravilli F, Sinclair E, Arango JC, Manji H, Lucas S,
Harrison MJ (1992) The pathology of the posterior root ganglia in
AIDS and its relationship
to the pallor of the gracile tract. Acta Neuropathol.(Berl)
84:163-170
Abstract: The spinal cord and the thoracic and lumbar
posterior root ganglia (PRGs) of 14 HIV-positive
men and 7 age- and sex-matched controls were studied by routine
histology, morphometric analysis of the number of nodules of
Nageotte (nN) and the diameters of sensory ganglion cells,
immunohistochemistry and in situ hybridization. In 7 patients (2 of
whom had evidence of cytomegalovirus ganglionitis) there were
increased numbers of nN and diffuse, mild infiltration with CD45R+ T
lymphocytes; no B lymphocytes were observed. Macrophages were
increased in number in all cases. Whenever more than one ganglion
was examined from the same patient, the appearances were similar in
all. There was no alteration in the distribution of ganglion cell
diameters. Changes in the spinal cord included vacuolar myelopathy
(5 cases), HIV myelitis (1
case), Microglial
nodules (3 cases) and pallor of the gracile tracts (GTP) in 7 cases,
in 6 of whom it co-existed with increased numbers of nN. Seven cases
had no abnormalities, except the increase in number of macrophages
in PRGs. In spite of a correlation between sensory nerve cell loss
and GTP our findings suggest that other mechanisms, such as 'dying
back' may contribute to the pathogenesis of GTP. Moreover, sensory
disturbances were found most commonly in association with nerve cell
loss; however, loss of sensory ganglion cells was not necessarily
associated with evidence of sensory impairment
Sharpless N, Gilbert D, Vandercam B, Zhou JM, Verdin E,
Ronnett G, Friedman E, Dubois-Dalcq M (1992) The restricted nature
of HIV-1 tropism for
cultured neural cells. Virology 191:813-825
Abstract: Infection
of the central nervous system by HIV-1,
the agent of AIDS, is
characterized by the presence of infected and giant Microglial
cells as well as astrocytosis, demyelination, and neuronal loss. To
determine whether cells of neuroectoderm origin can be infected by
HIV-1, we have inoculated
primary cultures derived from adult human brain with a lymphotropic
virus (LAV) or a neurotropic virus (Jr-FL) isolated from a patient
with AIDS dementia. While
Jr-FL invariably causes productive infection of cultured brain
Microglia,
neither astrocytes nor oligodendrocytes became productively infected
by these viral strains. Moreover, the cultured oligodendrocytes
develop a normal network of processes and express differentiation
antigens in the presence of an ongoing lytic infection of Microglial
cells. No HIV-1 proviral
DNA was detected in primary astrocyte cultures devoid of Microglial
after inoculation of either HIV-1
strain. Similarly, the neuronal cell line HCN-1 in its
differentiated state did not allow the virus to go through cycles of
reverse transcription and replication. LAV, however, was able to
replicate in undifferentiated HCN-1 cells. Thus, tropism of HIV-1
appears tightly restricted to only one type of differentiated cell
in the CNS, the Microglia
Sharpless NE, O'Brien WA, Verdin E, Kufta CV, Chen IS,
Dubois-Dalcq M (1992) Human immunodeficiency virus type 1 tropism
for brain Microglial
cells is determined by a region of the env glycoprotein that also
controls macrophage tropism. J.Virol. 66:2588-2593
Abstract:
Human immunodeficiency virus type 1 (HIV-1),
the agent of AIDS,
frequently infects the central nervous system. We inoculated adult
human brain cultures with chimeric viruses containing parts of the
env gene of a cloned primary isolate from brain tissue, HIV-1
JRFl, inserted into the cloned DNA of a T-cell-tropic strain. A
chimeric virus containing the carboxy-terminal portion of HIV-1
JRFl env did not replicate in these brain tissue cultures, while a
chimera expressing an env-encoded protein containing 158 amino acids
of HIV-1 JRFl gp120,
including the V3 loop, replicated well in brain Microglial
cells, as it does in blood macrophages. Infection of brain
Microglial
cells with such a chimera was blocked by an antibody to the V3 loop
of gp 120. Thus, env determinants in the region of gp120, outside
the CD4-binding site and comprising the V3 loop, are critical for
efficient viral binding to and/or entry into human brain Microglia
Sinclair E, Scaravilli F (1992) Detection of HIV
proviral DNA in cortex and white matter of AIDS
brains by non-isotopic polymerase chain reaction: correlation with
diffuse poliodystrophy. AIDS
6:925-932
Abstract: OBJECTIVE: (1) To determine whether detection
of HIV proviral DNA
sequences in the cerebral cortex correlates with the presence of
pathological changes in this region, believed to contribute to the
HIV-associated
cognitive/motor complex. (2) To compare the frequency with which HIV
infects cortical and subcortical regions of the brain. DESIGN: In
vitro studies on HIV
neurotoxicity suggest that HIV
may be involved in the pathogenesis of cortical damage, recently
defined as diffuse poliodystrophy (DPD) in AIDS.
Previous detection of HIV
antigen has localized HIV
more frequently to subcortical than to cortical regions. It is not
known whether HIV
preferentially infects subcortical tissues or if viral expression
varies in these two regions. METHODS: HIV
antigen and proviral DNA sequences were detected in anterior frontal
lobe tissues using immunohistochemistry (IHC) and the polymerase
chain reaction (PCR), respectively. DPD was assessed by staining
with antibodies against astrocytes (GFAP) and Microglia/macrophages
(HAM 56). RESULTS: HIV
proviral DNA was detected in nine out of 15 cortical samples and in
10 out of 15 white matter samples, whilst HIV
p24 antigen was localized to the cortex in three out of 15 and to
the white matter in seven out of 15 cases. DPD was found in 10
cases, although in five a different aetiology may have been
involved. However, DPD was present in eight out of the nine cases in
which HIV proviral DNA was
detected in the cortex. CONCLUSIONS: Using a non-isotopic PCR
method, HIV was detected in
the brains of more cases than would be expected on the basis of IHC
detection, and was present in the cortex as frequently as in the
white matter. HIV, together
with other factors, may contribute to the pathogenesis of DPD
Tyor WR, Glass JD, Griffin JW, Becker PS, McArthur JC, Bezman
L, Griffin DE (1992) Cytokine expression in the brain during the
acquired immunodeficiency syndrome. Ann.Neurol. 31:349-360
Abstract:
The pathogenesis of central nervous system (CNS) disease in acquired
immunodeficiency syndrome (AIDS)
is poorly understood but may be related to specific effects of the
immune system. Cytokines such as tumor necrosis factor and
interleukin-1 may have toxic effects on CNS cells and have been
postulated to contribute to the pathogenesis of the neurological
complications of human immunodeficiency virus (HIV)
infection. To characterize viral and immunological activity in the
CNS, frozen specimens taken at autopsy from the cerebral cortex and
white matter of HIV-seropositive
and -seronegative individuals were stained immunocytochemically for
mononuclear cells, major histocompatibility complex (MHC) antigens,
HIV, astrocytes, and the
cytokines interleukin-1 and -6, tumor necrosis factor-alpha and
-beta, and interferon gamma. Levels of soluble CD4, CD8, and
interleukin-2 receptor, as well as interferon gamma, tumor necrosis
factor-alpha, beta 2-microglobulin, neopterin, and interleukin-6 and
-1 beta were assayed in the cerebrospinal fluid and plasma of many
of these individuals during life. The HIV-seropositive
group included individuals without neurological disease, those with
CNS opportunistic infections, and those with HIV
encephalopathy. Perivascular cells, consisting primarily of
macrophages with some CD4+ and CD8+ T cells and rare B cells, were
consistently MHC class II positive. MHC class II antigen was also
present on Microglial
cells, which were frequently positive for tumor necrosis
factor-alpha. HIV p24
antigen, when present, was found on macrophages and Microglia.
Endothelial cells were frequently positive for interleukin-1 and
interferon gamma and less frequently for tumor necrosis factor and
interleukin-6. There were gliosis and significant increases in MHC
class II antigen, interleukin-1, and tumor necrosis factor-alpha in
HIV-positive patients
compared to HIV-negative
brains. Cerebrospinal fluid from most of the patients tested had
increased levels of tumor necrosis factor, beta 2-microglobulin, and
neopterin. There was no correlation in HIV-positive
individuals between levels of cytokines and the presence or absence
of CNS disease. These data indicate that there is a relative state
of "immune activation" in the brains of HIV-positive
compared to HIV-negative
individuals, and suggest a potential role for the immune system in
the pathogenesis of HIV
encephalopathy
Wiestler OD, Leib SL, Brustle O, Spiegel H, Kleihues P (1992)
Neuropathology and pathogenesis of HIV
encephalopathies. Acta Histochem.Suppl 42:107-114
Abstract: The
nervous system is frequently affected in patients with the acquired
immune deficiency syndrome (AIDS).
In addition to opportunistic CNS infections and cerebral lymphomas,
approx. 20% of the patients develop HIV-associated
encephalopathies. Two major histopathological manifestations are
observed. HIV
leukoencephalopathy (progressive diffuse leukoencephalopathy) is
characterized by a diffuse loss of myelin in the deep white matter
of the cerebral and cerebellar hemispheres, with scattered
multinucleated giant cells and Microglia
but scarce or absent inflammatory reaction. HIV
encephalitis (multinucleated giant cell encephalitis) is associated
with accumulations of multinucleated giant cells, inflammatory
reaction and often focal necroses. In some patients, both patterns
may overlap. In order to identify the HIV
genome in the CNS, brain tissue from 27 patients was analyzed for
the presence of HIV gag
sequences using the polymerase chain reaction (PCR) and primers
encoding a 109 base pair segment of the gag gene. Amplification of
HIV gag succeeded in all 5
patients with clinical and histopathological evidence for HIV
encephalopathy but was negative in the 20 AIDS
patients with opportunistic bacterial, parasitic and/or viral
infections or with cerebral lymphomas. These results strongly
suggest that the evolution of histopathologically recognizable
HIV-encephalopathies
closely correlates with the presence and/or tissue concentration of
HIV. Since there were no
cases with amplified HIV
DNA in the absence of HIV-associated
tissue lesions, we conclude that harboring and replication of HIV
in the CNS rapidly causes corresponding clinical and morphological
changes of HIV-associated
encephalopathies. In two children with severe HIV
encephalomyelitis, large amounts of HIV
gag and env transcripts were detected in affected areas of the brain
and spinal cord by in situ hybridization.(ABSTRACT TRUNCATED AT 250
WORDS)
Wiley CA, Johnson RT, Reingold SC (1992) Neurological
consequences of immune dysfunction: lessons from HIV
infection and multiple sclerosis. J.Neuroimmunol.
40:115-119
Abstract: In a recent workshop held on Sanibel Island,
Florida (18-21 January 1992), the two most common neuroimmunologic
diseases of young adults, multiple sclerosis (MS) and HIV
encephalopathy, were jointly discussed. The logic of assembling
investigators from these two fields was based not on an assumed
etiologic connection between MS and retroviral infection of the
central nervous system (CNS), but rather in the hope of uncovering
potential common pathogenic mechanisms, particularly as might relate
to trafficking of mononuclear cells into the central nervous system,
the distribution and function of macrophages and Microglia,
the structure and function of the blood-brain barrier, and the role
of cytokines released by activated cells. Multiple sclerosis is a
disease without a known etiologic agent or pathogenesis. While the
causative agent for HIV
leukoencephalopathy is known, the pathogenesis of the disease
remains entirely enigmatic (a topic covered by R. Johnson). This
meeting brought together two different groups of investigators to
compare and contrast the diseases and to share perspectives,
paradigms, and data with the aim of cross-fertilizing the
disciplines and generating healthy hybrids
Achim CL, Schrier RD, Wiley CA (1991) Immunopathogenesis of
HIV encephalitis. Brain
Pathol. 1:177-184
Abstract: HIV
infection leads to severe immunosuppression and in a sub-population
of patients, encephalitis. Whether systemic immunosuppression is
required for CNS infection is still unclear. However, latent
infection of monocytes/macrophages is an important mechanism by
which HIV escapes immune
surveillance and enters the CNS. Unlike other viral encephalitides,
HIV predominantly infects
macrophages/Microglia
and not neurons and glia. These cells produce retroviral proteins
and cytokines which may be neurotoxic. Despite significant MHC
expression within the CNS, there is a limited infiltration of immune
cells, possibly due to a defect in systemic immunity.
Anti-retroviral therapy by decreasing viral replication and
reversing immunosuppression, may arrest nervous system damage
Achim CL, Morey MK, Wiley CA (1991) Expression of major
histocompatibility complex and HIV
antigens within the brains of AIDS
patients. AIDS
5:535-541
Abstract: HIV
establishes a chronic infection in the central nervous system (CNS)
of AIDS patients. The
immunopathogenesis of this chronic encephalitis is unknown. Because
of the importance of major histocompatibility (MHC) class I and
class II antigens in modulating the immune response, we examined the
tissue expression of MHC molecules in relation to CNS damage and
expression of viral antigens. By immunocytochemical staining we
found that beta 2-microglobulin (beta 2M) expression is elevated in
all cases with signs of viral encephalitis. beta 2M was expressed at
high levels on endothelial cells, macrophages and possible
oligodendroglia within regions of histopathology. In histologically
normal regions elevated expression of beta 2M was noted only on
endothelial cells. MHC class II expression was elevated only in the
HIV encephalitis cases, and
was restricted to macrophages/Microglia
and occasional endothelial cells. When compared with other viral
encephalitides these findings suggest that the intra-CNS immune
response to HIV is
appropriate for viral presentation; however, the absence of
responsive systemic T cells may lead to chronic viral infection
Dickson DW, Mattiace LA, Kure K, Hutchins K, Lyman WD,
Brosnan CF (1991) Microglia
in human disease, with an emphasis on acquired immune deficiency
syndrome. Lab Invest 64:135-156
Abstract: In conclusion, there is
overwhelming evidence that within the CNS the primary sites of
active HIV-1 infection are
Microglia.
CNS infection may be related to the normal repopulation of the CNS
by monocytes (Microglial
turnover) that carry latent infection into the CNS. Activation of
viral infection may depend upon Microglial
differentiation, soluble factors (cytokines), and/or coexistent
infections. Infection of Microglia
may disturb the normal hemostatic balance that exists between
Microglia
and other glia, and between Microglia
and neurons, processes that are only recently being explored at the
molecular level. The impact that HIV
infection of Microglia
may have on synaptic integrity is unknown. Cytokines appear to be
prime candidates as mediators of some of the adverse effects of
Microglial
infection on other CNS cells, myelin and endothelial cells
Esiri MM, Morris CS, Millard PR (1991) Fate of
oligodendrocytes in HIV-1
infection. AIDS
5:1081-1088
Abstract: The brains of 22 HIV-1-infected
cases and 11 controls, matched for age and sex, were studied with
immunocytochemical reactions specific for oligodendrocytes,
astrocytes, Microglia
and HIV-1. In HIV-1
infection, mild degrees of myelin damage were associated with an
increase in oligodendrocyte numbers, a change that was reversed in
the presence of severe damage. Severity of myelin damage correlated
with the extent of astrocytic and Microglial
reactions expressed in a semi-quantitative manner. HIV-1
p24 antigen was detected in all cases with severe myelin damage and
a smaller proportion of cases with lesser degrees of myelin damage.
It is concluded that, in HIV-1
infection, oligodendrocytes undergo an initial reactive hyperplasia
which may represent an attempt to repair myelin damage
Geny C, Gherardi R, Boudes P, Lionnet F, Cesaro P, Gray F
(1991) Multifocal multinucleated giant cell myelitis in an AIDS
patient. Neuropathol.Appl.Neurobiol. 17:157-162
Abstract: A
19-year-old male intravenous drug abuser, was admitted to hospital
with a one-week history of lower limb weakness and urinary
retention. He was known to have been HIV-seropositive
for 3 years and had been treated for cerebral toxoplasmosis.
Neurological examination confirmed flaccid paraparesis with weak
ankle jerks and bilateral extensor plantar responses. There was no
obvious sensory deficit. Neurological examination was otherwise
normal. CSF contained 63 mg/dl protein and 10 leucocytes/mm3.
Myelography was normal. He died 1 month later from septic
peritonitis. Neuropathological examination showed chronic lesions of
toxoplasmosis in brain. Small necrotic foci with myelin loss,
proliferation of Microglia,
macrophages and multinucleated giant cells (MGC) were disseminated
in the whole spinal cord, mostly in the white matter, but the brain
was spared. Immunohistochemistry demonstrated p24 and p17 HIV
antigens in macrophages, MGC and Microglial
cells. These lesions resemble those of so called 'multifocal giant
cell encephalitis'. The present case demonstrates that HIV-related
multifocal inflammatory changes may be restricted to the spinal cord
and may be a cause of myelopathy in AIDS
patients
Gray F, Chimelli L, Mohr M, Clavelou P, Scaravilli F, Poirier
J (1991) Fulminating multiple sclerosis-like leukoencephalopathy
revealing human immunodeficiency virus infection. Neurology
41:105-109
Abstract: A 66-year-old French homosexual man and a
42-year-old Brazilian man with no known risk factors for HIV
infection developed headaches, asthenia, and neurologic episodes of
abrupt onset. CT showed multiple hypodense, nonenhancing lesions.
Serology for HIV was
positive. They died respectively 2 months and 1 month after onset of
the illnesses. Autopsy in both cases showed multiple,
well-demarcated, demyelinating foci in the white matter of the
cerebral hemispheres, brainstem, and cerebellum with histologic
features characteristic of recent plaques of multiple sclerosis.
There were no multinucleated giant cells or Microglial
nodules. Immunostaining for HIV
was negative. Although a random coincidence of MS and HIV
infection cannot be ruled out, the close temporal relationship
between the 2 disorders suggests a possible etiologic association
Gray F, Haug H, Chimelli L, Geny C, Gaston A, Scaravilli F,
Budka H (1991) Prominent cortical atrophy with neuronal loss as
correlate of human immunodeficiency virus encephalopathy. Acta
Neuropathol.(Berl) 82:229-233
Abstract: A 25-year-old homosexual
AIDS patient presented with
progressive cognitive, motor and behavioral disturbances consistent
with HIV encephalopathy. CT
scans demonstrated progressive diffuse brain atrophy. Neuropathology
showed predominant cortical changes including severe neuronal loss
corroborated by morphometry. Only minimal changes were found in the
white matter and basal ganglia. Immunocytochemistry for HIV
stained occasional Microglial
cells more markedly in the cerebral cortex. This suggests that HIV
infection of the brain may cause predominant cortical nerve cell
loss, and that HIV
encephalopathy is not necessarily due to white matter lesions
Gray F, Geny C, Lionnet F, Dournon E, Fenelon G, Gherardi R,
Poirier J (1991) [Neuropathologic study of 135 adult cases of
acquired immunodeficiency syndrome (AIDS)].
Ann.Pathol. 11:236-247
Abstract: The central nervous system was
examined in 135 adult AIDS
patients who died between August 1982 and December 1990. Twenty two
brains showed non-diagnostic changes including Microglial
nodules, discrete myelin pallor with reactive astrocytosis,
mineralization of blood vessels and granular ependymitis. In 105
brains with specific changes, toxoplasmosis was the most frequent
finding (55 cases) manifested by multifocal necrotic lesions or
diffuse pseudo-encephalitic process. Other opportunists included
cytomegalovirus (21 case), progressive multifocal
leukoencephalopathy (1 cases), cryptococcosis (6 cases),
mycobacterium avium intracellulaire (2 cases), varicella-zoster
virus (2 cases), aspergillosis (1 case) and multiple bacterial
microabscesses (1 case). Multinucleated giant cells were found in 52
cases. In 40 cases, they were widely disseminated throughout the
brain and in 39 cases, they were associated with diffuse or
multifocal white matter changes. Fifteen cases had a cerebral
lymphoma, 9 hepatic encephalopathy, 1 centropontine myelinolysis and
1 focal pontine leukoencephalopathy. Three cases had a cerebral
haemorrhage due to disseminated intravascular coagulation,
antithrombin therapy and amyloid angiopathy. Spinal changes in 13
cases included vacuolar myelopathy (7 cases), HIV
myelitis (1 case) and ganglio-radiculitis (1 cases), cytomegalovirus
myelo-radiculitis (1 case) secondary spread from a lymphoma (1 case)
and spinal infarcts due to disseminated intravascular coagulation (1
case). These lesions were frequently atypical and various
combinations of all these pathologies were encountered in the same
brain, sometimes in the same area and occasionally in the same cell.
Chronological variations in the incidence of some complications
could be related to changes in treatment
Hassan NF, Campbell DE, Rifat S, Douglas SD (1991) Isolation
and characterization of human fetal brain-derived Microglia
in in vitro culture. Neuroscience 41:149-158
Abstract: Human
brain Microglia
may play a central role in immunopathogenesis of CNS diseases
including HIV infection,
multiple sclerosis and Alzheimer's disease. In order to investigate
the possible relationship between Microglia
and the mononuclear phagocyte system, human brain Microglia
were isolated from 14-18-week-old fetal brains, and maintained in in
vitro culture. Enriched fetal brain Microglia
were stained for different monocyte/macrophage and glial cell
markers. Fresh dissociated brain cells lacked macrophage surface
markers. Isolated Microglial
cells stained positive for complement receptor C3bi, Class II [human
leukocyte antigen-DR (HLA-DR)] antigen and with the lectin Ricinus
communis. Microglia
also share several functional properties with monocyte/macrophages,
which include generation of superoxide anion and histochemically
demonstrable intracellular acid phosphatase and non-specific
esterase. Primary human dissociated brain cultures were maintained
in culture for at least 28 weeks. Although Microglia
were not observed above the astrocyte cell layer after 5 weeks in
culture, Microglia-like
cells appear below the astrocyte layer after 12 weeks in culture.
These cells stained positive for non-specific esterase and displayed
oxidative burst activity upon activation with phorbol myristate
acetate. Thus, we have successfully isolated an enriched population
of Microglia
from human fetal brain and have demonstrated that these cells
possess markers and properties which are characteristics of
mononuclear phagocytes
Ho KL, Gottlieb C, Zarbo RJ (1991) Cytomegalovirus infection
of cerebral astrocytoma in an AIDS
patient. Clin.Neuropathol. 10:127-133
Abstract: Association of
glioma with AIDS is
unusual. Cytomegalovirus (CMV) infection of glioma has not been
documented in AIDS or
non-AIDS patients. We
present the case of a 37-year-old homosexual, HIV
positive man who had a history of pneumocystis pneumonia and died of
disseminated CMV infection and an anaplastic astrocytoma (5 x 5 x 4
cm) of the left temporal lobe. Part of the tumor was severely
infected by CMV as demonstrated by immunohistochemical stain.
Intranuclear and intracytoplasmic CMV inclusions were present in the
cytomegalic cells whose astrocytic nature was identified by
immunostain for GFAP. CMV-bearing cells were scattered throughout
the astrocytoma but were rarely seen outside the tumor. CMV-bearing
endothelial cells were seen in several capillaries within the tumor.
Microglial
nodules were scattered within the tumor and some contained
CMV-infected cells. Many multinucleated giant cells (MNGC) with
circularly arranged small nuclei were present in the infected area
of the tumor and some showed fusion with cytomegalic cells. MNGC
were absent outside the tumor. CMV ependymitis was not seen. The
findings suggest that a) astrocytoma cells are permissive to CMV
infection, b) that they may be more susceptible to CMV infection and
replication than normal brain tissue, and c) the hyperplastic
endothelia and abnormal blood brain barrier of the astrocytoma may
facilitate the entry of CMV itno the tumor
Imamura K, Suzumura A, Sawada M, Marunouchi T, Takahashi A
(1991) [Functional and immunohistochemical studies of cultured rat
Microglia].
Rinsho Shinkeigaku 31:127-134
Abstract: We studied functional and
immunohistochemical characteristics of cultured rat Microglia.
Unstimulated Microglia
did not proliferate. Microglia
stimulated with LCM (L929 conditioned medium: colony stimulating
factor-1) had proliferative activity and increased acid phosphatase
activity. LPS (lipopolysaccharide) and IFN gamma (interferon-gamma)
but did not affect proliferative activity. Immunohistochemically,
RCA-1 lectin and GS-1 lectin, which react to beta-D-galactose and
alpha-D-galactose respectively, strongly reacted to the cytoplasm
and membrane of unstimulated Microglia.
After stimulation with LCM, Microglia
elongated processes and decreased response to these lectins. On the
other hand, Microglia
stimulated with LCM showed increased reactivity to monoclonal
antibody of vimentin. Microglia
stimulated with LPS had round shape and had response to these
lectins and vimentin. Microglia
stimulated with IFN gamma had adhesive activity and weakly stained
with these lectins but not with vimentin. ED-1 (monoclonal antibody
of rat monocytes/macrophages) reacted to unstimulated and stimulated
Microglia.
In flow cytometry, unstimulated Microglia
expressed OX-18 (MHC class I) and W3/25 (CD4) antigen. After
stimulation with IFN gamma, Microglia
were induced to express these antigens. CD4 antigen is a marker of
helper/inducer T cells and thought to be a receptor of HIV.
The results that Microglia
had CD4 antigen which was further induced with IFN gamma are
important to investigate infection of the CNS with HIV.
OX-6 (Ia) antigen was induced with IFN gamma. This indicates that
the Microglia
plays a central role in the CNS immune reaction. These
characteristics of cultured rat Microglia
provide useful informations to investigate the pathogenesis of the
CNS disorders
Jordan CA, Watkins BA, Kufta C, Dubois-Dalcq M (1991)
Infection of brain Microglial
cells by human immunodeficiency virus type 1 is CD4 dependent.
J.Virol. 65:736-742
Abstract: In the central nervous system of
AIDS patients, human
immunodeficiency virus (HIV)
infects primarily Microglia,
a cell type of bone marrow origin. Moreover, Microglial
cells isolated from adult human brain support the replication of
macrophage-adapted strains of HIV
type 1 (HIV-1) (B.A.
Watkins, H.H. Dorn, W.B. Kelly, R.C. Armstrong, B. Potts, F.
Michaels, C.V. Kufta, and M. Dubois-Dalcq, Science 249:549-553,
1990). To determine whether the CD4 receptor, which is expressed in
brain, mediates the entry of HIV-1
in Microglial
cells, we analyzed CD4 transcript expression in cultured Microglia
using highly sensitive polymerase chain reaction detection of cDNAs
synthesized from RNA. With this method, CD4 transcripts could be
detected in cultured Microglia--as
well as in various human brain regions and cultured macrophages used
as positive controls--along with transcripts for the LDL and Fc
receptors which are characteristic of cells of the macrophage
lineage. We then attempted to block viral entry into Microglial
cells using anti-CD4 antibodies or soluble CD4 (sCD4), which
recognize binding sites on CD4 and HIV-1
glycoprotein gp120, respectively. Cultures were pretreated with
blocking antibodies (Leu-3a, OKT4A) or virus was preincubated with
sCD4 prior to infection with HIV-1
strain AD87(M) or BaL. With either viral strain, these treatments
resulted in the prevention of infection or significant and
dose-dependent reduction in the number of infected cells and in the
levels of reverse transcriptase or p24 antigen released in the
medium. Thus, brain-derived Microglial
cells, which are the primary target of HIV-1
infection in the brain, express the CD4 receptor and this receptor
is effectively used for viral entry in vitro
Kure K, Llena JF, Lyman WD, Soeiro R, Weidenheim KM, Hirano
A, Dickson DW (1991) Human immunodeficiency virus-1 infection of the
nervous system: an autopsy study of 268 adult, pediatric, and fetal
brains. Hum.Pathol. 22:700-710
Abstract: The central nervous
system (CNS) of 221 adults and 31 infants or children with the
acquired immunodeficiency syndrome (AIDS)
was examined with immunocytochemistry for infectious agents and for
human immunodeficiency virus-1 (HIV-1)
antigen (gp41). Since the major risk factor in this population was
intravenous drug abuse, there were more female and pediatric
patients than in other neuropathology autopsy series. Although
children had a different spectrum of pathologic changes, including
less frequent opportunistic infections, women did not differ from
men in terms of types or incidence of opportunistic infections,
vascular disease, neoplasia, and subacute AIDS
encephalitis (SAE). Subacute AIDS
encephalitis was detected in 26% of adult and 48% of pediatric
brains. Immunocytochemical analysis of 100 adult and 20 pediatric
brains revealed gp41 immunoreactivity in 78% and 40%, respectively.
Virtually all adult brains with SAE had gp41 immunoreactivity in
macrophages and Microglia.
Even brains with no significant pathology had frequent gp41
immunoreactivity, especially in the basal ganglia. In pediatric
brains, including cases with SAE, gp41 immunoreactivity was less
abundant, suggesting the possibility of latent infection or viral
clearance. Spinal cords with vacuolar myelopathy or corticospinal
tract degeneration had only rare gp41-positive cells. Brains from 16
aborted fetuses from HIV-1-seropositive
women were all negative for gp41 immunoreactivity, but 12 brains
were positive for HIV-1 by
the polymerase chain reaction. These results may indicate that HIV-1
infection in fetal brains is below the limits of detection of
immunocytochemistry. The differences noted between adults and
children suggest that adults more often have productive CNS HIV-1
infection
Lipton SA (1991) HIV-related
neurotoxicity. Brain Pathol. 1:193-199
Abstract: The central
nervous system manifestations of AIDS
were originally thought to consist solely of white matter lesions,
but recent evidence has shown that a substantial degree of neuronal
loss can also occur. This review presents evidence for HIV-related
toxic factors that may account at least in part for this
newly-recognized neuronal injury. One potential neurotoxin is the
HIV-1 envelope glycoprotein
gp-120 or a fragment of this molecule. This coat protein is shed by
the virus and potentially released from HIV-infected
immune cells. In tissue culture experiments on rodent neurons, gp120
produces an early rise in intracellular calcium concentration and,
subsequently, delayed-onset neurotoxicity. In addition, HIV-infected
macrophages or Microglia
release as yet undefined toxic factor(s) that kill rodent, chick,
and human neurons in vitro. It is as yet unknown if one of these
macrophage toxic factors might represent a gp120 fragment, or
alternatively, if gp120, in the absence of HIV-1
infection, might be capable of activating macrophages to release
these toxic factor(s). In at least some neuronal cell types,
gp120-induced neurotoxicity can be prevented by antagonists of
L-type voltage-dependent calcium channels or by antagonists of
N-methyl-D-aspartate (NMDA, a subtype of glutamate receptor).
Degradation of endogenous glutamate also protects neurons from
gp120-related neuronal injury, suggesting that gp120 and glutamate
are both necessary for neuronal cell death as synergistic effectors.
Antagonists acting at the other types of glutamate receptors
(non-NMDA antagonists) are ineffective in affording protection from
gp120.(ABSTRACT TRUNCATED AT 250 WORDS)
Peudenier S, Hery C, Ng KH, Tardieu M (1991) HIV
receptors within the brain: a study of CD4 and MHC-II on human
neurons, astrocytes and Microglial
cells. Res.Virol. 142:145-149
Abstract: We have investigated the
level of expression of CD4 and MHC-II antigens on CNS cells and
compared it to that on monocytes. MHC-II antigens were expressed
spontaneously on cultured astrocytes and monocytes, whereas they
were detected only after IFN gamma stimulation of Microglial
cells. In vitro, CD4 receptor was present on monocytes but not on
neurons, astrocytes or Microglial
cells. In normal brain, CD4 antigen was expressed on perivascular
Microglial
cells, a specialized Microglia
expressing monocytic markers, whereas in HIV1-infected
brain, CD4+ cells were numerous and scattered throughout the whole
parenchyma. These CD4+ macrophages may be HIV1-infected
monocytes which have crossed the blood-brain barrier after
infection, or perivascular Microglial
cells infected by HIV1-infected
blood lymphocytes or five virions
Poutiainen E, Haltia M, Elovaara I, Lahdevirta J, Iivanainen
M (1991) Dementia associated with human immunodeficiency virus:
subcortical or cortical? Acta Psychiatr.Scand. 83:297-301
Abstract:
Two different types of dementia and corresponding neuropathological
findings of patients with human immunodeficiency virus (HIV)
infection are presented. In one case, "subcortical"
dementia with slow movements and mental processes as well as
problems in active recall but without focal defects corresponded to
diffuse leukoencephalopathy. In another case, "cortical"
dementia with impaired abstraction and memory as well as several
focal defects corresponded to Microglial
nodules in cortical and in deep grey matter, with only a mild
diffuse leukoencephalopathy. Thus, in contrast to earlier
interpretations, subcortical dementia does not appear to be the only
form of dementia in HIV-infected
patients, and cortical dysfunction may also occur
Pulliam L (1991) Cytomegalovirus preferentially infects a
monocyte derived macrophage/Microglial
cell in human brain cultures: neuropathology differs between
strains. J.Neuropathol.Exp.Neurol. 50:432-440
Abstract:
Cytomegalovirus (CMV) has been shown through pathologic examination
to infect many cell types of the brain; however, neuropathology
specific for CMV has been difficult to prove in the absence of
classic cytomegalic cells or demonstration of CMV antigens. In an
effort to further understand CMV infection of brain tissue, a human
brain cell aggregate system was infected with several strains of
CMV. Different neuropathologic changes were observed that were
related to CMV strain and multiplicity of infection. These changes
were consistent with those considered characteristic for human
immunodeficiency virus (HIV)
infection, including a nodular and multinucleated giant cell
formation. By electron microscopy, only a few cells throughout the
aggregates demonstrated intranuclear virions. These cells were
identified by ultrastructural morphology as either monocyte derived
macrophages or Microglial
cells (M/M). Antigen expression was observed in these cells with and
without neuropathologic changes. Infection progressed in either a
diffuse fulminant manner or a more focal cell to cell spread. These
studies demonstrate that CMV selectively infects M/M in normal human
brain cultures and suggests differences in neuropathology based on
multiplicity of infection and strain variation
Schlote W (1991) [HIV
encephalopathy]. Verh.Dtsch.Ges.Pathol. 75:51-60
Abstract: The
early manifestation of HIV
infection of the brain, HIV
encephalitis, is due to the invasion of HIV
infected mono- and multinuclear macrophages into the brain tissue
and cerebrospinal fluid. These cells are intensely PAS reactive,
auto-fluorescent and express the macrophage antigen CD68. They
clearly prefer the white matter of cerebral hemispheres, corpus
callosum and internal capsule. Lymphocytic infiltrates and
Microglial
nodules are additional, unspecific changes. HIV
encephalopathy following HIV
encephalitis is patho-anatomically characterized by brain tissue
damage. Its clinical correlate is so-called AIDS
dementia complex. It presumably is caused by neurocytotoxic and
myelinotoxic factors released by activated macrophages and/or by
shedding HIV retrovirus
proteins. HIV
encephalopathy includes leukoencephalopathy, diffuse poliodystrophy,
disseminated basal ganglia damage and brain atrophy. In some cases,
granulomatous angiitis may occur
Stoltenburg G, Schmidt S, Marzheuser S, Herbst H, Spiegel H,
Unger M (1991) [The central nervous system of infants born to
HIV-positive mothers--
neuropathology, immunohistochemistry in in situ hybridization].
Verh.Dtsch.Ges.Pathol. 75:191-194
Abstract: The central nervous
system (CNS) of 12 fetuses from
human-immunodefiency-virus-seropositive mothers was investigated.
Postconceptional ages ranged between 15 and 21 weeks. 3 preterm
infants born to HIV
positive mothers whose survival ranged from 6 hours to 6 months were
included in the study. In all cases, the development of the CNS was
macroscopically normal. The microscopic examination showed many
ectopic neurons indicating disturbances of normal neuronal
migration. As a regular finding there was a significant increase in
Microglia
in all areas of the CNS but no Microglial
nodules were found. In all cases haematogenous monocytes were
scattered in the perivascular space of the cerebral parenchyma as
well as in the chorioid pexus. The virus-antigen p24 could neither
be detected immunohistochemically in the paraffin sections nor in
the frozen material of the brain or by in-situ-hybridization. In
contrast, in five of the cases investigated the placenta showed
macrophages, socalled Hofbauer cells with p24-associated antigen
Tornatore C, Nath A, Amemiya K, Major EO (1991) Persistent
human immunodeficiency virus type 1 infection in human fetal glial
cells reactivated by T-cell factor(s) or by the cytokines tumor
necrosis factor alpha and interleukin-1 beta. J.Virol.
65:6094-6100
Abstract: Human immunodeficiency virus type 1
(HIV-1) infection of the
brain has been associated with a severe dementing illness in
children and adults. However, HIV-1
antigens are most frequently found in macrophages and Microglial
cells. To determine the extent of susceptibility of neuroglial cells
to infection, the HIV-1
genome was introduced into cells cultured from human fetal brain
tissue. Astroglial cells rapidly transcribed the viral genome
producing high levels of p24 protein and infectious virions which
peaked two to three days posttransfection. Thereafter HIV-1
genome expression progressively diminished and a persistent phase of
infection developed during which neither virus nor viral proteins
could be demonstrated by immunodetection methods. Cocultivation with
CD4+ T cells at any time during the persistent infection resulted in
resumption of p24 synthesis and virus multiplication. The release of
persistence did not require direct cell-cell contact between the
glial and T cells, since separation of the two cell types across a
permeable membrane resulted in a delayed but similar resumption of
p24 synthesis and virus multiplication. The persistently infected
glial cells could also be stimulated to produce viral p24 protein if
either tumor necrosis factor alpha or interleukin-1 beta was added
to the medium without T cells present. These results suggest that
astrocytes may serve as an undetected reservoir for HIV-1
and disseminate the virus to other susceptible cells in the brain
upon triggering by some cellular or biochemical signal
Vazeux R (1991) AIDS
encephalopathy and tropism of HIV
for brain monocytes/macrophages and Microglial
cells. Pathobiology 59:214-218
Abstract: HIV
induces severe dementia in about 20% of adult AIDS
patients. In children HIV-infected
at birth, the incidence of specific neurological complications is
still higher since severe encephalopathy occurs in almost all
children who develop an early and severe immunosuppression. In all
cases, the brain monocytes/macrophages and the Microglial
cells are the only cells which replicate HIV
in the central nervous system (CNS) of these patients, and the
appearance of neurological symptoms seems induced by an interaction
between HIV-infected
macrophages with neurons and glial cells. AIDS
encephalopathy is related to two properties of HIV:
to the viral tropism for monocytes/macrophages/Microglial
cells, which allow the brain infection, and to HIV
tropism for CD4+ lymphocytes responsible for the appearance of
immunosuppression, which trigger viral dissemination in the CNS.
However, childhood encephalopathy is not always associated with HIV
replication in the CNS at the time of death, and mild dementia in
HIV-infected adults were
described without signs of HIV
replication in autopsy CNS samples. Those findings suggest that
persistent, productive viral infection is not required for the
development of HIV
encephalopathy. Therefore, if the relationship between HIV
CNS infection and AIDS
encephalopathy in adults and children is clearly demonstrated, the
pathogenesis of the neurological disease and the kinetics of HIV
replication in the CNS are unclear. In addition, the very high
incidence of AIDS
encephalopathy in children could be related to HIV
infection of Microglia
which is differentiating in fetal or newborn brain
Aksamit AJ, Gendelman HE, Orenstein JM, Pezeshkpour GH (1990)
AIDS-associated progressive
multifocal leukoencephalopathy (PML): comparison to non-AIDS
PML with in situ hybridization and immunohistochemistry. Neurology
40:1073-1078
Abstract: We studied brain sections from 10 patients
with the acquired immunodeficiency syndrome (AIDS)
and progressive multifocal leukoencephalopathy (PML) by in situ
hybridization with a biotin-labeled JC virus (JCV) DNA probe and by
immunohistochemistry using antibody against the JCV capsid antigen.
We compared the results with brain sections studied in the same
fashion from 10 PML patients without AIDS.
The pathology of JCV infection in AIDS
was similar to non-AIDS PML
except for minor differences in degree. AIDS-associated
pathologic material showed a greater tendency toward necrosis and a
higher density of JCV-infected cells. Replication of JCV was
restricted to glial cells in all tissue studied. Bizarre astrocytes
were less frequent in the AIDS
patients, and perivascular inflammatory cells were more frequent. We
could not demonstrate JCV in macrophages or Microglial
cells known to harbor HIV
infection. In situ hybridization with nonradioactive probes serves
as a useful technique for the confirmation of PML in AIDS
Budka H (1990) Human immunodeficiency virus (HIV)
envelope and core proteins in CNS tissues of patients with the
acquired immune deficiency syndrome (AIDS).
Acta Neuropathol.(Berl) 79:611-619
Abstract: Frequency, cellular
tropism and relation to pathology of productive infection with human
immunodeficiency virus (HIV)
in human central nervous system (CNS) were studied. Serial sections
of formol-fixed and paraffin-embedded CNS tissues from 70 patients
(69 with acquired immune deficiency syndrome, AIDS)
were immunolabeled with monoclonal antibodies against HIV
antigens (Ags) p17, p24, and gp41. Additional and double
(immuno)stains were used to identify cell types and opportunistic
infectious agents. HIV Ags
were detected in 52 cases; they were restricted to cells with
characteristics of Microglia
or macrophages. Anti-gp41, anti-p24, and anti-p17 labeled 50, 33,
and 15 cases, respectively. Immunoreactivity for core proteins
predominated in mature macrophages and Microglia
of fully developed lesions; additional immunoreactivity for gp41 was
seen in Microglia
adjacent to, or unassociated with, histopathological lesions.
Multifocal and/or diffuse lesions previously suggested as HIV
induced because of characteristic histopathology, consistently
contained large numbers of cells with HIV
Ags (33 cases), confirming their HIV
specificity. Isolated labeled Microglia
without associated pathology, found in seven brains, presumably
represent the earliest stage of productive CNS infection by HIV.
Lesions of opportunistic infections contained no (34 cases), few (16
cases), or many (4 cases) cells with HIV
Ags. These data do not suggest transactivation of local HIV
production by opportunistic agents as a frequent event in vivo.
Development of specific HIV
histopathology appears correlated with the number of productively
infected cells
Chrysikopoulos HS, Press GA, Grafe MR, Hesselink JR, Wiley CA
(1990) Encephalitis caused by human immunodeficiency virus: CT and
MR imaging manifestations with clinical and pathologic correlation.
Radiology 175:185-191
Abstract: To determine the computed
tomographic (CT) and magnetic resonance (MR) imaging manifestations
of central nervous system (CNS) infection by the human
immunodeficiency virus (HIV),
the authors analyzed the results of imaging of the CNS in 24
patients with HIV
encephalitis confirmed at autopsy. Careful pathologic correlation
demonstrated that neither CT nor MR imaging enabled detection of
Microglial
nodules with multinucleated giant cells, the hallmark of HIV
encephalitis seen in all 24 affected patients. The most common
abnormality observed on images of the CNS was atrophy, demonstrated
in 18 patients. Demyelination and vacuolation of white matter tracts
accompanying severe HIV
infection caused hypoattenuation on CT scans and hyperintensity on
T2-weighted MR images. These lesions had no mass effect. MR imaging
was more sensitive than CT in the detection of lesions caused by HIV
or other superimposed infectious agents. Although it is often
difficult to attribute any radiologic appearance to a single
etiologic agent in patients with acquired immunodeficiency syndrome,
the combination of atrophy and symmetric, periventricular or diffuse
white matter disease suggests HIV
encephalitis
Ciardi A, Sinclair E, Scaravilli F, Harcourt-Webster NJ,
Lucas S (1990) The involvement of the cerebral cortex in human
immunodeficiency virus encephalopathy: a morphological and
immunohistochemical study. Acta Neuropathol.(Berl)
81:51-59
Abstract: The encephalopathy resulting from direct
infection of the brain by human immunodeficiency virus (HIV),
which correlates clinically with the AIDS
dementia complex, has been reported as being localized to the white
matter where it induces myelin loss, gliosis and perivascular
infiltration by mononuclear macrophages and multinucleated giant
cells. Damage to the cortical grey matter in HIV
encephalopathy was investigated in nine randomly selected
HIV-positive cases with or
without clinical or morphological evidence of encephalopathy and in
five age-matched controls, using routine histology and
immunohistochemical methods [glial fibrillary acidic protein (GFAP),
Microglia
and HIV antibodies].
Increased numbers of GFAP-expressing astrocytes and Ricinus communis
agglutinin 1-120-expressing Microglial
cells were found in all the HIV-positive
cases (including asymptomatic) and their severity could be
correlated with the severity of the encephalopathy in the white
matter; the increase in number of cells expressing GFAP was diffuse
and the intensity of the staining higher than that of Microglial
cells. The subpial region was the most severely involved. It is
suggested that involvement of the cortical grey matter is more
common in HIV infection
than previously suspected and that clinical evidence of a dementing
process in AIDS is not
necessarily due only to white matter lesions
Giampalmo A, Buffa D, Quaglia AC (1990) [AIDS
pathology: various critical considerations (especially regarding the
brain, the heart, the lungs, the hypophysis and the adrenal glands].
Pathologica 82:663-677
Abstract: Our studies on pathology of AIDS
point to four major conclusions. 1) The brain is often directly
affected by the HIV
infection (with the characteristics of subacute Microglial
encephalitis with pathognomonic multinucleated giant cells) and then
by opportunistic infections such as Cytomegalovirus, Herpes-virus,
Papova-virus JC (with progressive multifocal leucoencephalopathy),
Mycobacterium tuberculosis, Toxoplasma gondii, Cryptococcus
neoformans, Candida albicans and Aspergillus fumigatus;
opportunistic neoplasms (i.e. B cell lymphoma mostly pluricentric)
could also developed. 2) The heart is frequently involved as well;
perivascular sclerosis and myocytolysis are the hallmarks of a
peculiar cardiomyopathy. 3) In the lung viral, bacterial, fungal an
protozoan severe infections are frequently present: common are those
caused by Cytomegalovirus and Pneumocystis carinii. Frequently thin
fibrotic interalveolar septa are observed (with consequent
alteration of hematosis). 4) Adrenal (most frequently) and pituitary
may display necrotic-hemorragic areas (in adrenals chiefly due to
Cytomegalovirus). These may be extensive enough to explain the
occurrence of clinical syndromes of endocrine insufficiency
Kure K, Lyman WD, Weidenheim KM, Dickson DW (1990) Cellular
localization of an HIV-1
antigen in subacute AIDS
encephalitis using an improved double-labeling immunohistochemical
method. Am.J.Pathol. 136:1085-1092
Abstract: Among 102 brains
obtained from patients with acquired immune deficiency syndrome
(AIDS), 34 cases with
subacute AIDS encephalitis
were characterized by immunohistochemistry using an antibody that
binds to a human immunodeficiency virus-1 (HIV-1)
envelope glycoprotein, gp41. This glycoprotein was detected in
mononucleated and/or multinucleated cells in 90% of adult and 50% of
pediatric brains with subacute AIDS
encephalitis. In addition, many gp41-positive cells with bipolar or
multipolar processes were found in 10 cases, and these cells
occurred most frequently in the basal ganglia and internal capsule.
The phenotype of the gp41-positive cells was determined using an
improved double-labeling immunohistochemical technique that employed
beta-galactosidase and peroxidase conjugated reagents. Cell-type
specific markers for double-labeling included: Ricinus communis
agglutinin-1 (RCA-1) for macrophages and Microglia;
Ulex europaeus agglutinin-1 for endothelium; anti-glial fibrillary
acidic protein (GFAP) for astrocytes; anti-amyloid precursor protein
for neurons; and anti-leukocyte common antigen for leukocytes.
Results of double-immunostaining revealed that gp41-positive cells
of all morphologic types, including cells with bipolar or multipolar
processes, were double-labeled with RCA-1, but not with markers for
astrocytes, neurons, or endothelia. These findings support the
contention that HIV-1
infection of the CNS is predominantly restricted to cells of the
macrophage/Microglia
lineage
Kure K, Weidenheim KM, Lyman WD, Dickson DW (1990) Morphology
and distribution of HIV-1
gp41-positive Microglia
in subacute AIDS
encephalitis. Pattern of involvement resembling a multisystem
degeneration. Acta Neuropathol.(Berl) 80:393-400
Abstract: Among
100 brains from patients with acquired immunodeficiency syndrome
(AIDS), 33 brains (21
adults and 12 children) with histological evidence of subacute AIDS
encephalitis were immunostained with one of the most sensitive
antibodies to HIV-1
antigen, anti-gp41. Twenty-six (20/21 adults, 6/12 children) of the
33 brains showed pg41 positivity. Brains from children had fewer
gp41-positive cells than brains from adults. The distribution of
gp41-positive cells was characteristic. They were frequently
detected and most numerous in the globus pallidus (medial greater
than lateral). Although gp41-positive cells were prevalent, fewer
were detected in the corpus striatum and thalamus. Of infratentorial
areas involved, the ventral midbrain, especially the substantia
nigra, and the dentate nucleus contained many positive cells. Lower
levels of infections, often patchy, were noted in the cerebral and
cerebellar white matter and pontine base. Gp41-positive cells were
rarely seen in the cerebral cortex, medulla, spinal cord,
leptomeninges, choroid plexus, ependyma, subependymal areas and
endothelia. Besides immunoreactive macrophages and multinucleated
cells, gp41-positive Microglia
with various morphological alterations were abundant in the deep
cerebral gray matter, ventral midbrain and dentate nucleus. Most of
these Microglia
were undetectable with conventional histological methods. We discuss
the significance of the distribution of HIV-1-infected
cells, especially Microglia,
with respect to cellular tropism and involvement of deep gray matter
nuclei in a pattern reminiscent of a multisystem atrophy
Lang W, Probst A, Miklossy J, Deruaz JP, Pizzolato GP,
Schaffner T, Gessaga E, Kleihues P (1990) [Nervous system pathology
in AIDS: results of a
collaborative autopsy study from Switzerland].
Schweiz.Rundsch.Med.Prax. 79:562-568
Abstract: Neuropathological
lesions were studied in a consecutive autopsy series of 206 cases,
comprising 61% of all patients who died of AIDS
in Switzerland between April 1981 and December 1988. Central nervous
system involvement was found in 84% of the patients, and 17% showed
multiple concomitant intracerebral lesions. Among the non-viral
opportunistic infections, cerebral toxoplasmosis was most frequent
(24%), whilst among the viral opportunistic infections,
cytomegalovirus (CMV) encephalitis was most frequent (7%). A nodular
encephalitis consisting of disseminated Microglial
nodules without morphological or immunocytochemical evidence of CMV
occurred in 13.5% of the patients. The majority of these cases
showed evidence of extracerebral CMV infection. Progressive
multifocal leukoencephalopathy (PML) was observed in 6% of the
patients and was associated with widespread tissue destruction and
cyst formation. HIV
encephalopathy occurred in 38 patients (18%) and showed two
characteristic morphological patterns: progressive diffuse
leukoencephalopathy (PDL) and multifocal giant cell encephalitis
(MGCE). PDL was observed in 22 patients and was characterized by a
diffuse demyelination and gliosis of the white matter with little
inflammatory infiltrates and scattered multinucleated giant cells
which were immunoreactive to HIV
antigens. MGCE was found in 16 patients and was characterized by
clusters of macrophages, lymphocytes, and HIV-immunoreactive
multi-nucleated giant cells. In our view, PDL and MGCE represent two
opposite variants of HIV-induced
encephalopathies with numerous intermediate manifestations
Smith TW, DeGirolami U, Henin D, Bolgert F, Hauw JJ (1990)
Human immunodeficiency virus (HIV)
leukoencephalopathy and the microcirculation.
J.Neuropathol.Exp.Neurol. 49:357-370
Abstract: We studied the
brains of three patients with acquired immune deficiency syndrome
(AIDS), all of whom
developed subacutely progressive dementia unassociated with
opportunistic infection or neoplasm in the central nervous system.
Computed tomographic (CT) scans of the head revealed cortical
atrophy, ventricular dilation, and diffuse hypodensity of the
centrum semiovale. On microscopic examination, the cerebral and
cerebellar white matter in all cases showed diffuse and focal,
angiocentric regions of myelin pallor, focal vacuolization, and
extensive gliosis. Variable axonal loss and axonal spheroids were
evident. The microvasculature showed striking changes, including
mural thickening, increased cellularity, and enlargement and
pleomorphism of endothelial cells with variable numbers of
macrophages and multinucleated giant cells (MNGC), which often
contained hemosiderin pigment. Human immunodeficiency virus type 1
(HIV-1) antigens were
identified immunocytochemically within perivascular macrophages and
MNGC and in some Microglial
cells. We suggest that the morphologic abnormalities of the
microcirculation may be associated with an alteration of the
blood-brain barrier. The increased vascular permeability could
contribute to damage and loss of the white matter including both
myelin and axons, and result in subcortical cerebral atrophy. The
HIV-1 infected cells
present in relation to the microvasculature may play a role in
mediating the vascular injury
Vazeux R, Cumont M, Girard PM, Nassif X, Trotot P, Marche C,
Matthiessen L, Vedrenne C, Mikol J, Henin D, . (1990) Severe
encephalitis resulting from coinfections with HIV
and JC virus. Neurology 40:944-948
Abstract: We observed 3 cases
of progressive multifocal leukoencephalopathy (PML) among frozen CNS
samples obtained at autopsy from 102 adult AIDS
patients. In 2 patients, PML was associated with severe HIV
encephalitis. In those 2 cases, the areas of extensive JC-induced
demyelination were massively infiltrated by HIV
infected macrophages/Microglial
cells with evidence for localized increase of HIV
encephalitis in PML lesions. Using immunohistochemistry and in situ
hybridization, we demonstrated that each virus infects, in a latent
or productive fashion, different CNS cell populations. Therefore,
the extension of HIV
encephalitis could not be related to an intracellular
transactivation of 1 virus by the other. However, the results are
consistent with dissemination of viral infection by the recruitment
of HIV-infected macrophages
to damaged areas of the brain. This phenomenon might be generalized
to other pathogens that are frequently associated with HIV
CNS infection. Early detection and treatment of opportunistic CNS
lesions could be important to prevent extension of HIV
encephalitis
Watkins BA, Dorn HH, Kelly WB, Armstrong RC, Potts BJ,
Michaels F, Kufta CV, Dubois-Dalcq M (1990) Specific tropism of
HIV-1 for Microglial
cells in primary human brain cultures. Science 249:549-553
Abstract:
Human immunodeficiency virus (HIV)
frequently causes neurological dysfunction and is abundantly
expressed in the central nervous system (CNS) of acquired
immunodeficiency syndrome (AIDS)
patients with HIV
encephalitis or myelopathy. The virus is found mostly in cells of
the monocyte-macrophage lineage within the CNS, but the possibility
of infection of other glial cells has been raised. Therefore, the
effects of different HIV-1
and HIV-2 strains were
studied in primary cultures of adult human brain containing
Microglial
cells, the resident CNS macrophages, and astrocytes. These cultures
could be productively infected with macrophage-adapted HIV-1
isolates but not with T lymphocyte-adapted HIV-1
isolates or two HIV-2
isolates. As determined with a triple-label procedure, primary
astrocytes did not express HIV
gag antigens and remained normal throughout the 3-week course of
infection. In contrast, virus replicated in neighboring Microglial
cells, often leading to their cell fusion and death. The death of
Microglial
cells, which normally serve immune functions in the CNS, may be a
key factor in the pathogenesis of AIDS
encephalitis or myelopathy
Arndt R, Keeser D (1989) [Impairment of the immune system by
HIV infection]. Z.Hautkr.
64:353-8, 363
Abstract: CD4 + T-helper lymphocytes are the main
target cells in HIV
infection. Since CD4 molecules are not restricted to T-cells but
also found on monocytes, macrophages, follicular dendritic cells,
Langerhans cells, and Microglial
brain cells, these cells might be affected, too, by HIV.
HIV binds via the gp 120
envelope protein to the 67 KD CD4 membrane protein. Patients with
HIV infection show distinct
autoimmunological reactions against the cells of their immune
system. Autoantibodies directed against CD4 cells seem to be
responsible for the extent of the immune deficiency and are,
therefore, of prognostic value. Aside from CD4+ cell depletion, the
functional impairment of the T-cell system plays an important part
in the progress of the disease. Patients with depressed
gamma-interferon production after stimulation with antigens are at a
risk for AIDS-related
opportunistic infections. Polyclonal production of immunoglobulins
and impaired stimulation of B-cells are characteristic for B-cell
dysfunction. NK-cell dysfunction depends on reduced production of
IL-2 and altered gamma-interferon production of T-cells infected
with HIV
Budka H (1989) Human immunodeficiency virus (HIV)-induced
disease of the central nervous system: pathology and implications
for pathogenesis. Acta Neuropathol.(Berl) 77:225-236
Abstract:
Significant contributions from many different groups during the last
2 or 3 years have characterized relatively uniform neuropathological
changes of the CNS in AIDS
patients. They feature human immunodeficiency virus (HIV)-induced
multinucleated giant cells as a histopathological hallmark and HIV
demonstrable by electron microscopy, immunocytochemistry, and in
situ hybridization. Unfortunately, a varying and confusing
terminology is used to designate these changes which have been
reported in surprisingly different incidences. Focal lesions have a
microgranulomatous appearance and were designated as multifocal
giant cell encephalitis or subacute encephalitis, which may be
confused with the nodular encephalitis caused by cytomegalovirus.
For some authors, the latter designation also covers characteristic
diffuse white matter changes which have been termed progressive
diffuse leukoencephalopathy by others, and which may overlap with
focal lesions. Pathological features of these HIV-induced
syndromes and other data do not support a major cytopathic effect of
HIV on neural cells;
rather, they suggest secondary pathogenetic events involving the
predominant cell type in the lesion, the
monocyte/macrophage/Microglia.
However, low-level, latent, and persisting HIV
infections of neural cells cannot be excluded at present; the CNS
may then serve as an early infected virus reservoir. A detailed
correlation of clinical symptoms and stage of the infection to
neuropathological changes is currently lacking but urgently needed.
The presence of the HIV-receptor
(CD4) molecule on brain cells is controversial; similarly, a
putative cross-reaction of HIV
proteins with trophic substances and transmitters needs to be
substantiated
Dickson DW, Belman AL, Park YD, Wiley C, Horoupian DS, Llena
J, Kure K, Lyman WD, Morecki R, Mitsudo S, . (1989) Central nervous
system pathology in pediatric AIDS:
an autopsy study. APMIS Suppl 8:40-57
Abstract: The
neuropathologic findings of brains and spinal cords removed at
autopsy from 26 infants and children with AIDS
is described; in two cases, only the spinal cords were available.
The most common finding in the brains was dystrophic calcification
of blood vessels of all calibers in the basal ganglia and deep
cerebral white matter (21 og 24 cases). The next most frequent
finding was subacute encephalitis (SE) (15 of 24 cases) with
Microglial
nodules and multinulceated giant cells. Immunocytochemical and in
situ hybridization studies showed HIV
antigen or genetic sequences only in the brains of cases with SE.
Multinucleated giants cells (MGC) were the most frequent cells with
reaction products. MGC were labeled with ricinus lectin (RCA), but
not with leukocyte common antigen (LCA) or glial fibrillary acidic
protein. Many cells in Microglial
nodules were labeled with RCA, but not LCA; cells in the
perivascular compartment were labeled with LCA, but not RCA.
Corticospinal tract degeneration was noted in 15 of 20 spinal cords.
In six cases tract degeneration was consistent with delayed
myelination, and the remaining cases had axonal injury consistent
with Wallerian degeneration. Opportunistic infections were rare
(three cases). Central nervous system lymphoma occurred in three
children and was the most common mass lesion. In two cases lymphoma
occurred in the setting of a systemic polyclonal immunoproliferation
possibly related to Epstein-Barr virus infection. Cerebrovascular
accidents were noted in seven cases. Two cases had hemorrhage
associated with immune thrombocytopenia; one hemorrhage was
catastrophic. Two children had large vessel arteriopathy with
multiple encephalomalacias. Two children had a necrotizing
encephalopathy with encephalomalacia and vascular changes suggestive
of a mitochondrial cytopathy.(ABSTRACT TRUNCATED AT 250 WORDS)
Grafe MR, Wiley CA (1989) Spinal cord and peripheral nerve
pathology in AIDS: the
roles of cytomegalovirus and human immunodeficiency virus.
Ann.Neurol. 25:561-566
Abstract: We examined spinal cords, nerve
roots, or peripheral nerves of 27 patients who died with acquired
immunodeficiency syndrome (AIDS)
for the presence of cytomegalovirus (CMV) and human immunodeficiency
virus (HIV) by
immunoperoxidase techniques in paraffin-embedded tissue. Vacuolar
myelopathy was seen in 8 of 26 spinal cords (31%) and Microglial
nodules were seen in 13 (50%). All of the patients with lateral
column vacuolar myelopathy showed severe brain pathology. HIV
antigens had been detected in the brains of 15 (55%) of the 27
patients but were detected in only 3 (11%) of 26 spinal cords and
were not localized to regions of vacuolar myelopathy. This suggests
that the vacuolar myelopathy may be due to a remote or indirect
effect of HIV or other
infectious agent. CMV antigens were detected in none of the patients
who showed vacuolar myelopathy but were detected in 2 of the 13 with
Microglial
nodules. Focal nerve root or peripheral nerve inflammation was seen
in 7 patients; 4 had CMV antigens and none had HIV
antigens. CMV appears to be an important cause of inflammatory
peripheral neuropathy in AIDS
patients
Gullotta F, Kuchelmeister K, Masini T, Ghidoni P, Cappricci E
(1989) [The morphology of HIV
encephalopathy]. Zentralbl.Allg.Pathol. 135:5-13
Abstract:
Reported in this paper are postmortem findings recorded from the
central nervous system of 51 HIV
carriers, among them 43 with clinically manifest AIDS.
Opportunistic infections and tumours were established in 24 cases,
including toxoplasmosis, cytomegaly, progressive multifocal
leucoencephalopathy, and lymphomas. Findings obtained from 5
patients were restricted to unspecific alterations. No pathological
findings at all were recordable from 8 HIV
carriers without AIDS.
So-called subacute Microglial
encephalitis (SME) was detected in 26 cases. SME was found to
provide for the morphological substrate of genuine HIV
encephalopathy. It was characterised by occurrence of mononuclear
and even multinucleated cells which were macrophages and obviously
served as virus carriers. Multinucleated cells are pathognomonic of
HIV encephalopathy. No
unambiguous evidence has so far been produced to primary invasion of
neurons or glial cells by HI viruses
Hirano A (1989) [Neuropathology of AIDS:
Montefiore experience]. Rinsho Shinkeigaku 29:1546-1549
Abstract:
From September 1982 to December 1988 113 cases of AIDS
have been autopsied and the brains examined at Montefiore Medical
Center. Findings in four areas were presented; 1. Opportunistic
infections In approximately one third of cases there were
opportunistic infections which were often the cause of death.
Cryptococcus, cytomegalovirus and toxoplasma were the three most
common infections followed by papovavirus (progressive multifocal
leukoencephalopathy) and herpes zoster. Tuberculosis, aspergillosis,
histoplasmosis and infection with mycobacterium avium-intracellulare
infection were found in only one case each. 2. Malignant lymphoma
Both primary and metastatic lymphomas were seen in almost 10% of the
cases. 3. HIV encephalitis
This conclusion is regarded as the pathological substrate of "AIDS
dementia complex" described by the neurologists. In general, it
was characterized by cerebral atrophy and diffuse pallor of the
white matter with gliosis. The basal ganglia and other areas of the
CNS were also often involved. Histologically, there was perivascular
infiltration of lymphocytes, macrophages and multinucleated giant
cells. Microglial
nodules were commonly seen. Electron microscopic and other
techniques demonstrates the HIV
virus within macrophages and multinucleated cells. 4.
Cerebrovascular lesions These lesions are known in AIDS
but their high frequency is not generally appreciated unless a
careful search for microinfarcts is made. Microinfarcts were found
in approximately 1/3 of our cases
Kure K, Park YD, Kim TS, Lyman WD, Lantos G, Lee S, Cho S,
Belman AL, Weidenheim KM, Dickson DW (1989) Immunohistochemical
localization of an HIV
epitope in cerebral aneurysmal arteriopathy in pediatric acquired
immunodeficiency syndrome (AIDS).
Pediatr.Pathol. 9:655-667
Abstract: A 6-year-old boy with
acquired immunodeficiency syndrome (AIDS)
developed aphasia and quadriplegia 3 months before his death.
Cerebral vascular ectasia and multiple cerebral infarcts were noted
on premortem radiological studies. Postmortem evaluation revealed
diffuse aneurysmal dilatation of the circle of Willis associated
with fresh and organizing thrombi, destruction of the elastic
lamina, and marked intimal fibroplasia. Multiple cerebral infarcts
and subacute AIDS
encephalitis with basal ganglia calcification were also present.
Immunohistochemistry with a monoclonal antibody (anti-gp41) to human
immunodeficiency virus (HIV)
demonstrated positively stained cells in the arterial wall of the
circle of Willis and in the cerebral parenchyma. Double
immunostaining demonstrated that gp41-positive cells in the circle
of Willis were also positive for a macrophage marker or
leukocyte-common antigen, but not with an endothelial marker. Some
macrophages or Microglia
in the cerebrum were also colabeled with anti-gp41. These results
suggest that HIV may be
directly involved in vascular pathology associated with pediatric
AIDS
Lantos PL, McLaughlin JE, Schoitz CL, Berry CL, Tighe JR
(1989) Neuropathology of the brain in HIV
infection. Lancet 1:309-311
Abstract: The brains of 26 patients
infected with the human immunodeficiency virus (HIV)
were examined post mortem. All patients were men, aged 20-67 years
(mean 38.8). 13 (50%) were homosexual, 3 (12%) were bisexual, 8
(31%) were haemophiliac, 1 was both an intravenous drug addict and
homosexual, and 1 denied belonging to any risk group. Only 3 (12%)
brains were normal, whereas 23 (88%) showed abnormalities that
varied in severity and complexity. 11 were affected by more than one
disease. In addition to neoplasms, opportunistic infections, and
vascular lesions, 6 cases of HIV
encephalitis were found, characterised by multinucleate giant cells
which indicate the presence of HIV.
Microglial-macrophage
nodules (nodular encephalitis) occurred in 5 cases. Cerebral
pathology differed between risk groups: all 6 patients with HIV
encephalitis were homosexuals, whereas vascular lesions were more
common in haemophiliacs. These observations have fundamental
implications for clinical practice and indicate the importance of
neuropathological examination in AIDS
Pfister HW, Einhaupl KM, Wick M, Fateh-Moghadam A, Huber M,
Schielke E, Goebel FD, Matuschke A, Heinrich B, Bogner JR, . (1989)
Myelin basic protein in the cerebrospinal fluid of patients infected
with HIV. J.Neurol.
236:288-291
Abstract: The major pathological abnormalities of HIV
encephalopathy are infiltrates of macrophages, multinucleated giant
cells, Microglial
nodules and demyelination. Elevated myelin basic protein (MBP)
levels in the cerebrospinal fluid (CSF) provide a marker for central
nervous system demyelination. The purpose of this study was to
investigate the possible role of CSF MBP as a useful and early
marker for HIV
encephalopathy. The CSF of 40 consecutive patients with HIV
infection of various clinical stages was investigated, including 13
patients with clinical signs of HIV
encephalopathy. CSF MBP was elevated in 2 patients (5.0 and 5.3
ng/ml), both of whom had moderate to severe HIV
encephalopathy. The course of the disease was rapid in both
patients. In the remaining 38 patients, CSF MBP levels were
marginally elevated (n = 12) or normal (n = 26). Our results suggest
that CSF MBP is not a sensitive marker for the diagnosis and
evaluation of HIV
encephalopathy, but may be an indicator of prognosis for the course
of the disease. There were only few findings of elevated CSF MBP
levels in patients with HIV
encephalopathy in the current study, and this may be because the
disorder progressed slowly in most patients. It is possible that CSF
MBP levels in HIV
encephalopathy may only be elevated with acute clinical
deterioration but are normal in slowly progressive forms of
demyelination, as seen in multiple sclerosis
Porwit A, Parravicini C, Petren AL, Barkhem T, Costanzi G,
Josephs S, Biberfeld P (1989) Cell association of HIV
in AIDS-related
encephalopathy and dementia. APMIS 97:79-90
Abstract: The
presence of HIV gag and env
proteins (HIV Ag) and virus
replicating cells was studied by immunohistochemistry and in situ
hybridization, respectively, in brain specimens from five HIV
infected patients. HIV
antigens were detected in 3 of 5 brains in micronodular areas
characterized by increased cellularity and the presence of
multinuclear giant cells. By double immunostaining, HIV
Ag positive cells were shown to express markers common to
macrophages and Microglia
i.e. Leu M5+, My4+, HLA-Dr+, RCA-1+, and to a lesser extent CD4+
(Leu3+). Another macrophage specific marker, KiM6, was found only on
HIV+ cells in HIV
infected specimens and not in uninfected, control brains.
Medium-sized, virus replicating cells were found exclusively in
micronodular areas, but in much smaller quantities than HIV
Ag+ cells. Our observations provide further evidence to support the
hypothesis that macrophages play an important role in CNS infection
by HIV and additionally
support the concept that reactive Microglial
originate from activated macrophages infiltrating the brain. Both
direct effects of viral components and cell mediated reactions can
be implicated from our findings as mechanisms involved in the
pathogenesis of the CNS lesions
Stavrou D, Mehraein P, Mellert W, Bise K, Schmidtke K,
Rothemunds E, Funke I, Stocker U, Babaryka I, Zietz C, . (1989)
Evaluation of intracerebral lesions in patients with acquired
immunodeficiency syndrome. Neuropathological findings and
experimental data. Neuropathol.Appl.Neurobiol. 15:207-222
Abstract:
In this paper we present the results of post-mortem examinations of
the central nervous system in 61 male patients who died with
Acquired Immunodeficiency Syndrome (AIDS);
it includes 23 patients with reported neurological abnormalities at
the time of presentation. The analysis revealed central nervous
system (CNS) neoplasms (lymphoma, Kaposi's sarcoma) and a variety of
inflammatory lesions (bacterial, fungal, protozoal and viral) in 32
cases. A total of 11 patients without opportunistic infections
showed significant brain abnormalities characterized by Microglial
nodules and/or multinucleated giant cells, changes which are
probably related to infection by human immunodeficiency virus (HIV).
In addition, we describes results from a series of experiments
designed to define the target cell population of HIV
in the brain. The expression of CD4 complex--putative receptor for
HIV--was investigated using
short-term cultured brain cells taken from embryonic brain anlage
and from different regions of fetal brain; glioma cells were also
used. Cells derived from normal embryonic and fetal brain, as well
as glioma cells, were examined with respect to their susceptibility
to HIV. CD4 antigen
expression could be demonstrated only on glioma cells of the
permanent glioma line 85HG-59 comprised of cells with properties
characteristic of astrocytes. Nevertheless, normal embryonic and
fetal brain cells as well as glioma cells could be infected by HIV
as documented by immunocytochemical methods and southern blot
analysis. HIV infected
brain cells showed reduced growth rate and altered growth pattern.
This study emphasizes the diversity of HIV
conditioned CNS impairments, suggesting that genomic variability of
HIV may result in varying
cell type preference of the virus. The experimental data indicate
that CD4 expression in brain cells is probably not 'conditio sine
qua non' for HIV
susceptibility. The alterations of HIV-infected
brain cells demonstrated provide further evidence for a direct
involvement of HIV in the
pathogenesis of AIDS-related
neurological syndromes
Vinters HV, Kwok MK, Ho HW, Anders KH, Tomiyasu U, Wolfson
WL, Robert F (1989) Cytomegalovirus in the nervous system of
patients with the acquired immune deficiency syndrome. Brain 112 (
Pt 1):245-268
Abstract: Clinicopathological features of infection
of the nervous system by cytomegalovirus (CMV) in 31 patients with
the acquired immune deficiency syndrome (AIDS)
are reviewed. Neuropathology was variable, ranging from rare
isolated CMV inclusions in brain without associated inflammation or
necrosis, to severe necrotizing ependymitis and meningoencephalitis.
In 1 patient, CMV had produced a necrotizing meningoradiculitis
which presented clinically as ascending paralysis. In the brains and
spinal cords of 6 patients, evidence of human immunodeficiency virus
(HIV) infection of neural
parenchyma was seen in close proximity to CMV infection. Both
viruses individually or together were associated with low grade
(Microglial
nodule) encephalitis. In retrospect, the diagnosis of CMV had been a
difficult one to make clinically in neurologically impaired patients
with AIDS. The results
suggest that CMV may also localize in the nervous system without
significant clinical sequelae. Imaging studies and analysis of
cerebrospinal fluid revealed abnormalities in many patients, but
none of them (short of culture of CMV itself in two cases) appeared
to be specific to this neurological complication of the
immunodeficiency
Walker DG, Itagaki S, Berry K, McGeer PL (1989) Examination
of brains of AIDS cases for
human immunodeficiency virus and human cytomegalovirus nucleic
acids. J.Neurol.Neurosurg.Psychiatry 52:583-590
Abstract: The
role of direct virus infection as a determining factor in acquired
immunodeficiency syndrome (AIDS)
dementia was investigated using in situ hybridisation for human
immunodeficiency virus (HIV)
and human cytomegalovirus (HCMV). Four of the five AIDS
dementia patients in this series demonstrated HIV
infected cells distributed in widely different parts of the brain,
but only one case showed HCMV infected cells. The greater abundance
of HIV was in subcortical
white matter in nodular areas consisting of monocyte/macrophage
infiltrates. The cells were occasionally arranged as a
multinucleated syncitium. In two cases, a few large cells with the
appearance of neurons were positive for HIV
hybridisation. By appropriate treatment with ribonuclease, it was
shown that hybridisation was primarily to HIV
RNA. HCMV infected cells were observed in small numbers in only one
of the positive cases, suggesting that HCMV is not a determining
factor in AIDS dementia.
HCMV positive cells were located in the grey matter, with an
appearance suggestive of neurons. Cells expressing the MHC-class II
antigen HLA-DR, a marker of reactive Microglia
and macrophages, were observed to be extensive in affected brain
sections in the one case examined. These cells were present in
greater number than HIV
infected cells. In this case, extensive numbers of HIV
infected cells were noticed along the peripheral margin of the
substantia innominata. This could indicate infection in this case of
a critical brain region from the cerebrospinal fluid
Gray F, Fenelon G, Gherardi R, Favolini M, Goulon M, Guillard
A, Poirier J (1988) [Neuropathologic study of 15 cases of
multinucleated giant cell encephalitis in acquired immunodeficiency
syndrome (AIDS)].
Ann.Pathol. 8:281-289
Abstract: The central nervous system (CNS)
of 40 patients who died of acquired immune deficiency syndrome
(AIDS) between August 1982
and August 1987 was examined. In 15 cases, multinucleated giant
cells (MGC) characteristic of Human Immunodeficiency Virus (HIV)
infection were observed. In 3 cases ultrastructural examination
disclosed HIV-like viral
particles in the cytoplasm of some MGC. All cases with MGC showed,
in addition, predominant white matter lesion: diffuse myelin pallor,
multiple small, usually subcortical, necrotic foci, vacuolar
myelopathy, proliferation of rod-shade Microglia
and Microglial
nodules, reactive astrocytosis, mineralization of the vessel walls.
These changes, typical of HIV
encephalitis, were isolated in 3 cases. In the other cases, they
were associated with other AIDS-related
CNS lesions, i.e., cerebral toxoplasmosis (9 cases), cytomegalovirus
infection (5 cases), progressive multifocal leukoencephalitis (1
case), cryptococcosis (1 case) and cerebral lymphoma (1 case). The
involvement of MGC with these lesions was remarkable
Gray F, Gherardi R, Keohane C, Favolini M, Sobel A, Poirier J
(1988) Pathology of the central nervous system in 40 cases of
acquired immune deficiency syndrome (AIDS).
Neuropathol.Appl.Neurobiol. 14:365-380
Abstract: The central
nervous system was examined in 40 AIDS
patients who died between August 1982 and 1987. The cases included
two children born to intravenous drug abusers and 38 male adults.
The brains of eight patients who had no clinical or radiological
evidence of central nervous system involvement showed non-specific
changes which included Microglial
nodules, perivascular mononuclear cuffs, mineralization of blood
vessels and granular ependymitis. In 32 brains from patients with
neurological symptoms, toxoplasmosis was the most frequent finding
(19 cases) manifested by multifocal, necrotic lesions or a diffuse
pseudo-encephalitic process. Other opportunistic infections included
cytomegalovirus (eight cases), progressive multifocal
leucoencephalopathy (two cases), cryptococcosis (one case),
aspergillosis (one case), multiple bacterial microabscesses (one
case) and Mycobacterium avium intracellulare (one case). Two
patients had cerebral lymphoma. Subacute encephalitis with white
matter lesions and multinucleated giant cells characteristic of HIV
infection was present in 15 cases. Various combinations of all these
infections were encountered in the same brain, sometimes in the same
area and, occasionally, in the same cell
Michaels J, Price RW, Rosenblum MK (1988) Microglia
in the giant cell encephalitis of acquired immune deficiency
syndrome: proliferation, infection and fusion. Acta
Neuropathol.(Berl) 76:373-379
Abstract: The autopsied brains of
three homosexual men with acquired immune deficiency syndrome
(AIDS), progressive
encephalopathy and widespread multinucleated giant cell encephalitis
were investigated by lectin and immunohistochemical methods to
ascertain the cellular distribution of a human immunodeficiency
virus (HIV) core protein,
p25. Abundant viral antigen was present in all brains, limited to
perivascular macrophages, Microglial
and multinucleated cells, some bearing elongated cytoplasmic
processes. The multinucleated cells were consistently labelled by
the lectin Ricinus communis agglutinin-1, a marker for Microglia,
which demonstrated process-bearing variants of these cells. The
prominent staining of Microglia
for viral antigen and the morphological suggestion that they fuse
with other Microglia
and/or macrophages to form the multinucleated cells characteristic
of HIV encephalitis
indicate that Microglia
are probably direct targets of HIV
infection and serve to propagate and amplify this retroviral
encephalitis
Parravicini CL, Klatzmann D, Jaffray P, Costanzi G, Gluckman
JC (1988) Monoclonal antibodies to the human immunodeficiency virus
p18 protein cross-react with normal human tissues. AIDS
2:171-177
Abstract: The immunohistochemical reactivity of four
monoclonal antibodies (MAbs): CVK, 49-5, 49-6 and 63-FH2, raised
against the p18 protein of HIV-1
was assessed in tissues obtained from HIV-infected
and uninfected individuals. As already reported, all the MAbs
specifically labelled follicular dendritic cells (FDC) in lymph
nodes from HIV-infected
patients with lymphadenopathy, and cells of Microglial
nodules in the brain from patients with AIDS-related
encephalopathy. However, cross-reactivity with normal uninfected
tissues was also observed: epithelial cells of the skin, the thymus
and tonsils with CVK, and astrocytes in the brain of 49-6 and
63-FH2. Such cross-reactivities suggest that 'molecular mimicry'
could exist between p18 of HIV
and normal constituents of human cells. This phenomenon could be
relevant for the diagnostic use of anti-p18 MAbs on pathological
specimens, and it could be of importance in the pathophysiology of
HIV infection
Henin D, Duyckaerts C, Chaunu MP, Vazeux R, Brousse N,
Rozenbaum W, Hauw JJ (1987) [Neuropathological study of 31 cases of
acquired immunodeficiency syndrome]. Rev.Neurol.(Paris)
143:631-642
Abstract: Post-mortem study of every patient who died
from AIDS in
Pitie-Salpetrire Hospital from June 1984 to November 1985 was
performed without regard to the presence of neurological signs and
symptoms. Autopsy were performed in 31/48 cases. Patients had been
hospitalized in the Departments of Parasitology-Infectious Disease
(24 cases) Internal Medicine (4 cases) and Neurology (3 cases). In
every case, formalin-fixed material from the brain and the spinal
cord were embedded in paraffin (20 samples), stained with
hematoxylin-eosin, PAS, Alcian blue, Giemsa, Grocott and Ziehl
techniques and Bodian's silver impregnation along with Luxol fast
blue, and, in celloidin (8 samples), stained with hematoxylin-eosin
and Loyez' impregnation. There were 30 men (27 caucasian, 1
egyptian, 1 haitian, 1 senegalese) and one woman (congolese). Twenty
eight (28) patients were homosexuals. AIDS
was transfusion-associated in two cases. Neurologic complications
revealed the disease in 2 cases. Eighteen (18) patients had
neurological signs or symptoms before death. Age range at death was
22-58 (mean 38). Brain weight in AIDS
(from 1150 gms to 1750 gms-mean 1428 gms) was not statistically
different from the mean weight of 100 male patients in the same age
range autopsied in the same laboratory during the identical period
(mean 1427 gms, standard deviation: 23). Microscopic abnormalities
were present in every brain examined. These included non-Hodgkin
lymphoma (3 cases), opportunistic infections (21 cases: 13
toxoplasmosis, 4 cytomegalovirus encephalitis, 3 cryptococcal
meningitis, 1 infection by mycobacterium avium-intracellulare), and
subacute encephalitis (17 cases, 9 isolated, 8 associated with other
disorders). The characteristic changes consisted of lympho-monocytic
focal infiltrates (so-called Microglial
nodules) and mild lympho-monocytic perivascular cuffs in 10 cases.
Typical giant cells were seen only in one case. Mild demyelinating
changes were also seen in only one case. No spinal cord spongiosis,
nor Progressive Multifocal Leukoencephalopathy was found. HIV
localization was performed on frozen sections utilizing in situ
hybridization techniques (2 cases) and immunohistologic techniques
(5 cases). HIV, RNA and
proteins, was detected in 2 cases with subacute encephalitis.
Infected cells were labeled with macrophage markers, and rarely with
T4 lymphocyte markers. Infected astrocytes (identified by anti-GFAP
serum) or neurons (identified by anti-NSE serum) were never
observed. No giant cells were seen in these two cases
Perry VH, Gordon S (1987) Modulation of CD4 antigen on
macrophages and Microglia
in rat brain. J.Exp.Med. 166:1138-1143
Abstract: Mononuclear
phagocytes which express the HIV
entry receptor CD4 have been implicated as possible sites of virus
replication in brain, but there is still considerable uncertainty as
to which cells in the CNS express CD4 Ag. Although it is not
susceptible to HIV
infection the rat provides a model to define expression of the CD4
Ag on MO in brain. We report that the CD4 epitopes W3/25 and OX35
are found only on monocytes, MO, Microglia,
and occasional lymphocytes and not on neurons, other glia, or
endothelium. CD4 Ag levels are modulated during Microglial
differentiation, after reactivation after local inflammation, and
within the intact blood brain barrier. MO and Microglia
also express other potential plasma membrane binding and entry sites
for HIV viz Fc and
complement receptors that are regulated independently of CD4
Uldry PA, Steck AJ, Regli F, Deruaz JP, Chave JP, Glauser MP
(1987) [Neurologic complications accompanying acquired
immunodeficiency syndrome (AIDS):
study of a group of 8 cases]. Schweiz.Med.Wochenschr.
117:560-569
Abstract: Eight patients with acquired immune
deficiency syndrome (AIDS)
presented complications affecting the nervous system. The complaints
were headache, seizure, confusion or hallucination. Neurologic
manifestations included meningitis, focal deficits, cranial nerve
palsy, and dementia. Cerebrospinal fluid exhibited a decrease in the
percentage of T helper lymphocytes with an inverted
helper-to-suppressor cell ratio. The neurologic manifestations of
AIDS may depend on multiple
factors, such as HIV
infection of the central nervous system, concomitant infections with
other agents or meningeal invasion by systemic lymphoma or Kaposi's
sarcoma. Many patients develop a diffuse encephalopathy which
characteristically begins with impaired concentration and mild
memory loss, and progresses to severe global cognitive impairment
and dementia. Perivascular infiltrates and scattered Microglial
nodules, consisting of aggregates of Microglia
and astrocytes, are the most common findings in these patients
Vazeux R, Brousse N, Jarry A, Henin D, Marche C, Vedrenne C,
Mikol J, Wolff M, Michon C, Rozenbaum W, . (1987) AIDS
subacute encephalitis. Identification of HIV-infected
cells. Am.J.Pathol. 126:403-410
Abstract: Human immunodeficiency
virus (HIV) RNA and
proteins were detected in the brains of several AIDS
patients with subacute encephalitis, by in situ hybridization and
immunohistology. The majority of infected cells were mononucleated
and bore processes. Using single and double immunohistologic
procedures, the authors identified these cells as macrophages. The
majority of them had the phenotype of Microglial
cells (Leu-M3-, CD4-), others were labeled with markers of
circulating macrophages (Leu-M3+, CD4+/-). The presence of HIV
RNA and proteins in CD4- cells could be explained by depressed CD4
antigen expression, as a result of infection or macrophage tissue
differentiation
Gabuzda DH, Ho DD, de la Monte SM, Hirsch MS, Rota TR, Sobel
RA (1986) Immunohistochemical identification of HTLV-III antigen in
brains of patients with AIDS.
Ann.Neurol. 20:289-295
Abstract: Human T-cell lymphotropic virus
type III (HTLV-III) has been isolated from neural tissues and
cerebrospinal fluid (CSF) of patients with neurological syndromes
associated with the acquired immune deficiency syndrome (AIDS)
and the virus may be directly involved in the pathogenesis of the
syndromes. To detect HTLV-III antigen in neural tissues from
patients with AIDS,
immunoperoxidase studies using a goat anti-HTLV-III serum were
performed on frozen tissue sections of brain, spinal cord, and nerve
from 13 patients with AIDS
or HTLV-III-related neurological syndromes. HTLV-III was cultured
from neural tissues or CSF in 11 of 13 of these patients. HTLV-III
antigen was detected in the brains of 5 patients with AIDS
and in none of the 13 non-AIDS
control subjects. Rare positively stained cells were seen,
frequently associated with capillaries and often located near
Microglial
nodules. Morphologically, the cells resembled monocyte/macrophages
and were found most frequently in the cortex of the frontal,
temporal, and parietal lobes. These results provide further evidence
that the subacute encephalitis of AIDS
is associated with central nervous system infection by HTLV-III and
that monocyte/macrophages are among the infected cell populations
Stoler MH, Eskin TA, Benn S, Angerer RC, Angerer LM (1986)
Human T-cell lymphotropic virus type III infection of the central
nervous system. A preliminary in situ analysis. JAMA
256:2360-2364
Abstract: Patients with the acquired
immunodeficiency syndrome (AIDS)
are subject to a spectrum of central nervous system (CNS) disorders.
Recent evidence implicates the human T-cell lymphotropic virus type
III (HTLV-III) in the pathogenesis of some of these illnesses,
although, the cells infected by the virus have yet to be identified.
Using in situ hybridization, we examined brain tissue from two
patients with AIDS
encephalopathy for the presence of HTLV-III RNA. In both cases,
viral RNA was detected and concentrated in, though not limited to,
the white matter. The CNS cells most frequently infected included
macrophages, pleomorphic Microglia,
and multinucleated giant cells. Less frequently, cells
morphologically consistent with astrocytes, oligodendroglia, and
rarely neurons were also infected. The findings strengthen the
association of HTLV-III with the pathogenesis of AIDS
encephalopathy. In situ hybridization can be applied to routinely
prepared biopsy tissue in the diagnosis of HTLV-III infection of the
CNS