Microbes and Infection 4 (2002) 301–308

www.elsevier.com/locate/micinf

Review

HIV-1 and the brain: connections between HIV-1-associated dementia,

neuropathology and neuroimmunology
Diane M. Lawrence *, Eugene O. Major
Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health,
Building 36, Room 5W21, 36 Convent Drive, MSC 4164, Bethesda, MD 20892-4164, USA

Abstract

AIDS patients frequently exhibit neurological disorders due to the neurotoxic events that result from HIV-1 and/or opportunistic
infections in the brain. This review examines recent clinical findings related to HIV-1-associated dementia, and outlines current areas of
basic research that may clarify how HIV-1-associated encephalopathy produces clinical symptoms of brain dysfunction. © 2002 Éditions
scientifiques et médicales Elsevier SAS. All rights reserved.

Keywords: AIDS dementia complex; HIV-1 encephalopathy; Viral encephalitis

1. Clinical consequences of HIV-1 infection in
the brain
Following infection with HIV-1, several years may pass
before the virus causes enough damage to produce the
clinical symptoms of immunosuppression known as AIDS.
A wide range of neurological problems may be associated
with AIDS, including cognitive impairments, motor distur-
bances, behavioral changes, headache, and peripheral neu-
ropathy. These neurological symptoms can be the initial
manifestation of AIDS in many patients, and current obser-
vations suggest that more than half of all current AIDS
patients will experience some form of neurological abnor-
mality [1]. Many factors may contribute to these symptoms,
particularly opportunistic brain infections such as crypto-
coccus, Toxoplasma gondii, JC virus (JCV), cytomegalovi-
rus, Epstein-Barr virus, varicella zoster virus, and human
herpesvirus type 6, which are associated with the immuno-
suppression resulting from HIV-1 infection [2]. In the
absence of opportunistic infections, HIV-1-associated de-
mentia may occur; this disorder is defined by severe
impairment of specific cognitive functions, such as memory
recall and speed of information processing, and extensive
* Corresponding author. Tel.: +1-301-594-3225; fax: +1-301-594-5799.
E-mail address: lawrencd@ninds.nih.gov (D.M. Lawrence).
© 2002 Éditions scientifiques et médicales Elsevier SAS. All rights reserved.
PII: S 1 2 8 6 - 4 5 7 9 ( 0 2 ) 0 1 5 4 2 - 3
neuronal atrophy [3–5]. HIV-1-associated dementia is esti-
mated to develop in at least 20% of advanced AIDS cases
[4]. Clinical neurological examination, brain imaging using
magnetic resonance imaging or X-ray-computed tomogra-
phy, and laboratory testing for the presence of HIV-1 and
other infections in the blood and cerebral spinal fluid (CSF)
are used in combination for diagnosis [3]. Fig. 1 shows an
example of extensive damage to subcortical brain areas in a
case of advanced HIV-1 dementia.
Evidence of neuropathology has been observed in a
majority of adult AIDS patients, with a higher incidence
observed in pediatric cases [6]. The hallmarks of HIV-1-
associated neuropathology include: infiltration of macroph-
ages; the formation of microglial nodules and multinucle-
ated giant cells, suggestive of virus-induced fusion of
microglia and/or macrophages, in central white matter and
deep gray matter; widespread reactive astrogliosis, indica-
tive of astrocyte activation and damage; the loss of specific
neuron subpopulations, particularly those involved in cog-
nition (hippocampus) and motor function (basal ganglia);
the loss of synaptic connections; and myelin pallor, or the
loss of myelin surrounding neuronal axons, indicating
damage to oligodendrocytes; and the presence of HIV-1
DNA in the CSF [7–9]. Collectively these inflammatory and
degenerative neuropathological events are termed HIV-1-
associated encephalitis, the biological correlate of the clini-
cal symptoms described above. Although severe HIV-1-
associated dementia is typically observed during the late
stages of infection, it is becoming increasingly evident that
302 D.M. Lawrence, E.O. Major / Microbes and Infection 4 (2002) 301–308
Fig. 1. Magnetic resonance image showing a horizontal section from the
brain of an HIV-1 dementia patient. White areas represent subcortical
damage (lesions), associated with cognitive deficits.
moderate neuropsychological, neurophysiological and neu-
roanatomical abnormalities in the context of HIV-1- asso-
ciated encephalitis can be observed well before the end
stages of AIDS [10]. These observations suggest that HIV-1
encephalopathy is a gradual process that, in many patients,
may begin early in the course of infection. Recent guide-
lines for the diagnosis of mild cognitive impairment [11] are
expected to provide a more thorough measure of the clinical
consequences of HIV-1 infection in the brain.
The advent of antiretroviral therapy has brought great
hope for prolonging the lives of HIV-1-infected patients,
and for reducing the immunosuppression responsible for the
susceptibility to opportunistic infections that are often the
direct cause of death in AIDS patients. In particular, highly
active antiretroviral therapy (HAART), a combination of at
least three anti-HIV-1 drugs including protease inhibitors
and reverse transcriptase inhibitors, has been most success-
ful in restoring lymphocyte function and suppressing viral
replication to nearly undetectable levels within weeks of
treatment initiation. In two of the most recent studies, the
incidence of HIV-1-associated dementia was reduced by
nearly 50% in patients receiving HAART therapy compared
to earlier cohorts of patients taking only one or two
anti-HIV-1 drugs [12,13]. However, despite this improve-
ment, the occurrence of HIV-1-related encephalitis and
neuropathology in postmortem tissue has not changed [14],
suggesting that systemic therapeutic approaches are not
likely to eradicate the neurological consequences of HIV-1
infection. Because some of the antiviral drugs used in
HAART have limited access to the brain, it is likely that
HAART reduces the occurrence of severe neurological
outcomes by indirect means: the peripheral replication of
HIV-1 is blocked, so there is less of the virus available to
enter the brain, and there are fewer opportunistic infections
due to less advanced immunosuppression. Whereas some
believe that this approach to treatment is sufficient to
eliminate HIV-1-associated encephalopathy in the future,
there is evidence that HIV-1 can enter the brain soon after
infection [15,16], perhaps before treatment is begun. Fur-
thermore, up to 85% of the AIDS patients worldwide do not
have access to HAART, and among those patients who
begin and maintain the complex HAART regimen, systemic
HIV-1 infection is resistant to therapy in 20–50% of patients
[16]. Thus, while blocking viral entry into the central
nervous system is essential for the prevention of HIV-1-
associated neurological disorders, the current treatment
approach is not likely to be completely successful.
In order to develop better treatment options for HIV-1-
associated encephalopathy, it is critical to understand that
this disease is not a simple case of virus-induced cell
damage, but rather a chain of events that leads to neuronal
dysfunction. In other words, eliminating virus may not stop
the process of HIV-1-induced cell damage in the brain.
Understanding the specific mechanisms linking HIV-1 in-
fection and neuronal damage has been far from simple.
Damage to critical populations of neurons in the brain is
generally considered the most direct cause of cognitive and
motor disorders, yet HIV-1 does not productively infect
neurons. In addition, the level of viral gene product expres-
sion in the brain does not always correlate with neurological
symptoms [17], and the distribution of virus in the brain is
highly variable [18]. To better understand the basis of
HIV-1-associated neurological disorders, it is necessary to
examine how HIV-1 enters the brain, what cell types are
infected, and what biological events occur in response to
brain infection.
2. Cell types involved in HIV-1 infection
In order for HIV-1 to enter a cell efficiently, it must first
bind to a CD4 receptor, commonly found on T lymphocytes,
blood monocytes, and monocyte derivatives (macrophages).
Subsequent binding to one of a family of α- or β-chemokine
co-receptors, such as CXCR4 and CCR5, respectively, is
crucial for viral entry. The cell types known to be suscep-
tible to HIV-1 infection include CD4+ dendritic cells,
lymphocytes and macrophages [19]. Dendritic cells are
found in skin and mucosa, but can migrate into other areas;
 D.M. Lawrence, E.O. Major / Microbes and Infection 4 (2002) 301–308
lymphocytes and macrophages are present in various tis-
sues, including the brain [19]. Over the long course of
infection, HIV-1 undergoes dramatic changes, particularly
in the nucleotide sequence encoding envelope glycoproteins
(gp120 and gp41, cleavage products of gp160). The differ-
ences in the resulting envelope proteins determine which
co-receptors the virus uses to enter cells, and thus, which
cells become infected. Initially, during a systemic infection,
there is a predominance of the less virulent ‘R5’ virus,
which enters cells using the CCR5 co-receptor (usually
expressed by macrophages, monocytes and dendritic cells).
During the later stages of disease, the more virulent ‘X4’
strains appear, using the CXCR4 co-receptor (expressed by
T lymphocytes, for example) [20].
In the brain, the vast majority of infected cells that
actively produce HIV-1 particles are monocyte-derived
macrophages and brain-resident microglia [7,19]. HIV-1 is
thought to enter the brain by the infiltration of infected
monocytes, which then differentiate into macrophages. Viral
replication within these cells is the source of viral particles
that can infect other cells, such as microglia, the brain-
resident macrophages. Several studies have shown substan-
tial differences in nucleotide sequence and biological char-
acteristics of HIV-1 derived from brain and blood of the
same patients [21], indicating that the brain may harbor and
allow virus modification for several years. The numbers of
infected macrophages in the brains of patients with HIV-1-
associated dementia, as well as the total amounts of virus
production within the brain tissues, are highly variable.
However, these numbers are generally too low to explain
the extent of pathology observed, suggesting that the
cellular responses to HIV-1 infection of brain macrophages
and microglia are the primary factors contributing to the
process of HIV-1 encephalitis, rather than viral replication
and virus-mediated cell lysis [7–9].
In addition to macrophages and microglia, astrocytes and
capillary endothelial cells have been found to contain HIV-1
protein and/or DNA in the brains of HIV-1 patients [20,22].
Studies of cultured human astrocytes have shown that
HIV-1 infection is initially productive yet noncytopathic,
and ultimately is converted to a latent stage with little
expression of viral protein [22]. Although the proportion of
HIV-1-infected astrocytes is very low, approximately 70%
of the cells in the brain are astrocytes, so this cell population
may be a significant factor in HIV-1-mediated neuropatho-
genesis. Interestingly, astrocytes can be infected in the
absence of the classical CD4 receptor [23], and it is unclear
whether the CCR5, CXCR4, or other chemokine receptors
are involved in HIV-1 entry in these cells. Astrocyte
function, critical for the survival of neurons, may be
impaired in the context of HIV-1 infection; in addition,
infected astrocytes can produce cellular factors that may
adversely affect neuronal survival [22]. Under certain con-
ditions, latent HIV-1 infection of astrocytes can be reacti-
vated, e.g. by an inflammatory response or contact with
susceptible cells [24]. This activation could produce a wave
303
of increased virus levels in the CNS, which would result in
both direct and indirect effects on brain function.
Other resident brain cells may be infected by HIV-1, but
at an extremely low level. While most studies have found a
lack of infection of neurons, there are some reports of HIV-1
DNA and protein expression in neurons [25,26]. The pos-
sibility of neuronal infection certainly would be an impor-
tant factor in neuropathology, and infected neurons, like
astrocytes, may provide a reservoir of virus with the
capacity for reactivation. Oligodendrocytes, cells that create
the insulating myelin sheath critical for neuronal function,
are believed to be minimally involved in HIV-1 dementia.
However, the loss of these cells may be a significant factor
in AIDS-related neurological disorders, particularly because
they are targets of HIV-1-induced cellular toxins and oppor-
tunistic infections, including JCV. Analysis of brain tissue
from an AIDS patient with progressive multifocal leukoen-
cephalopathy showed the presence of proteins from both
HIV-1 and JCV [27]. Although the oligodendrocytes in
these brains did not appear to be infected with HIV, the
HIV-1 Tat protein and JCV genome were detected in these
cells. Tat can upregulate the transcription of JCV genes,
which speeds the lytic infection of the target oligodendro-
cytes, leading to demyelination and dysfunction of neurons.
Oligodendrocytes are also susceptible to damage by viral
envelope proteins and cellular factors produced by infected
macrophages in the brain [28]. Thus, as cells critical for
neuronal function, oligodendrocytes must be considered as
factors in HIV-1-related neurological disease, particularly in
the context of opportunistic pathogens, such as infection
with JCV.
3. Viral and cellular sources of neuronal damage
Because the low number of infected cells in the brain
cannot explain the extent of damage observed in HIV-1
encephalopathy, it is widely accepted that viral proteins
shed by infected cells, as well as a variety of toxic products
secreted by activated cells (infected or uninfected), are the
major factors involved in the underlying neuropathology.
One well-studied viral protein with putative neurotoxic
effects is the HIV-1 envelope glycoprotein, gp160. This
protein can be cleaved into two products that remain
noncovalently associated: gp120 and gp41. The cleaved
gp120 is soluble and can be shed from infected cells, and at
low concentrations, gp120 can damage neurons cultured
from various regions of the brain [29,30]. For several years
it was believed that this damage was a direct effect of gp120
on the neurons, but recent evidence indicates that gp120-
mediated neurotoxicity depends on the presence of other
cells, either macrophages, microglia, or astrocytes, suggest-
ing an indirect mechanism involving toxic intermediates
[30]. When macrophages or microglia are stimulated with
gp120, these cells produce inflammatory cytokines and
arachidonic acid metabolites; the neurotoxic effects of these
304 D.M. Lawrence, E.O. Major / Microbes and Infection 4 (2002) 301–308
products are discussed below. Astrocytes exposed to gp120
exhibit both cytoskeletal and functional changes, including
induction of nitric oxide synthase [9]; these changes most
likely impair the ability of these cells to protect neurons
from damage.
The gp41 molecule remains inserted in the membrane of
infected cells, yet it has also been implicated in HIV-1
dementia [31]. A recent report found that gp41 is directly
toxic to neurons, and that this toxicity was prevented when
inducible nitric oxide synthase was not functional, suggest-
ing that gp41-mediated induction of nitric oxide may be
responsible for neuropathology in the HIV-1-infected brain
[31]. The HIV-1 transactivator protein, Tat, which is ac-
tively secreted by infected cells, has the capacity to induce
neuronal death both directly and indirectly [9,32]. The
mechanism of Tat-induced neurotoxicity involves prolonged
increases in intracellular calcium, which stimulates the
production of toxic reactive oxygen intermediates and
caspase activation of the apoptosis pathway [9]. Tat may
also induce neuronal death indirectly, by stimulating mac-
rophages to secrete matrix metalloproteinases, which induce
neuronal apoptosis and are found in the brain of HIV-1
dementia patients [32].
In addition to viral proteins, other sources of neuronal
damage in the infected brain include the cellular products of
HIV-1-infected cells. Macrophages and microglia that are
activated by infection secrete several products that can
cause neuronal damage directly (typically by altering the
intracellular calcium homeostasis), indirectly by stimulating
uninfected macrophages and microglia (amplifying the
response), and/or indirectly by damaging or overstimulating
other cell types in the CNS, such as astrocytes and oligo-
dendrocytes. Activated macrophages and microglia,
whether infected or not, can produce nitric oxide, superox-
ide anions, platelet activating factor, arachidonic acid me-
tabolites, matrix metalloproteinases, and glutamate receptor
agonists [7,9]. These factors are implicated not only in
HIV-1-associated encephalopathy, but also in other neuro-
degenerative diseases, such as Alzheimer’s disease and
Parkinson’s disease. Nitric oxide has potent antiviral effects
and acts as a neurotransmitter at moderate levels, but at high
concentrations it can stimulate a biochemical cascade that is
toxic to neurons [9]. Nitric oxide combined with superoxide
anions can produce direct neurotoxicity, possibly due to
excess calcium influx into the neuron. Arachidonic acid, a
precursor of prostaglandins, leukotrienes, and thrombox-
anes, is involved in many biological functions including
inflammation; in the brain, these products may also cause
neuronal damage by NMDA receptor overstimulation.
Glutamate-mediated neurotoxicity, or overstimulation of
glutamate receptors including the NMDA subtype, is a
common basis for toxicity in many neurodegenerative
diseases. In the case of HIV-1 dementia, high levels of
quinolinic acid, a glutamate receptor agonist produced by
activated and/or HIV-1-infected macrophages, are found in
the CSF and are associated with increased brain atrophy
[33]. While glutamate stimulation is necessary for neuronal
function and development, excessive levels can affect the
homeostasis of the neuronal environment, particularly by
altering the intracellular calcium concentration and thus
reducing the neuron’s capacity to produce action potentials
and release neurotransmitters [22]. Normally astrocytes
have ‘buffering’ functions to help maintain optimal extra-
cellular levels of calcium and glutamate. These functions
include calcium uptake, glutamate uptake and catabolism,
and production of kynurienic acid, which blocks glutamate
receptors. However, astrocytes are also susceptible to the
toxic products of activated and/or HIV-1-infected macroph-
ages, and their function may be altered by latent HIV-1
infection and/or reactivation. Thus, astrocytic dysfunction
may play a major role in HIV-1 dementia by the loss of
neuroprotective functions [34,35].
4. The brain immune response in HIV-1 encephalitis
One of the areas most intensely studied to elucidate the
mechanisms of HIV-1 encephalitis is that of inflammatory
cytokine production in the CNS. Whereas profound defi-
ciency of cellular immunity is the hallmark of AIDS, it is
clear that inflammatory responses from activated monocytes
and lymphocytes occur during HIV-1 infection. Antibody
synthesis occurs systemically and in the brain early after
HIV-1 infection, during the asymptomatic phase. Increased
levels of pro-inflammatory cytokines such as IL-1, IFN-γ,
and especially TNF-α, anti-inflammatory cytokines includ-
ing TGF-β and IL-6, and soluble cytokine receptors are
found in the CSF of AIDS patients [36,37]. Importantly, the
levels of cytokine production in the CNS correlate with the
severity of neurologic symptoms [36,37]. It is suspected that
activated macrophages are the source of these pro-
inflammatory cytokines in the CNS, but astrocytes, neurons,
and endothelial cells, particularly when stimulated by acti-
vated macrophages or HIV-1-Tat protein, have the capacity
for cytokine production as well [9,36,37].
It is unclear exactly how these cytokines contribute to
brain pathology, but it has been shown that TNF-α and
IL-1β enhance HIV-1 replication through increased produc-
tion and viral DNA binding of the NFjΒ transcription factor
in macrophages [37]. These same cytokines can activate
HIV-1 replication in latently infected astrocytes [38]. Cy-
tokines are also known to stimulate macrophages and
microglia to produce the cellular toxins described above
[9,36]. TNF-α can affect astrocytes by stimulating the
production of other cytokines and chemokines [36], and can
inhibit the ability of astrocytes to buffer extracellular
glutamate [39]. Cytokines such as TNF-α and IL-1 in the
brain can adversely affect oligodendrocyte function and
pituitary hormone secretion, as well as induce fever, nausea
and loss of appetite, explaining some of the more general
symptoms associated with HIV-1-associated dementia [36].
IFN-γ can stimulate macrophage production of quinolinic
 D.M. Lawrence, E.O. Major / Microbes and Infection 4 (2002) 301–308
acid, which as described above can overstimulate and
destroy neurons via glutamate receptor activation [7]. Thus,
in addition to promoting the survival of the virus, cytokines
in the HIV-1-infected brain serve as messengers between
various cell types to amplify the production of molecules
that are toxic to neurons.
Another aspect of the immune response currently con-
sidered to be very important in the process of HIV-1
encephalitis is chemokine production in the brain. Chemok-
ines, a family of small cytokines typically produced by
damaged or infected cells, work in a gradient fashion to
activate and attract particular subsets of cells from the
immune system to the site of damage. Cells expressing
receptors that recognize a specific chemokine respond to
low concentrations, and move in the direction of increasing
concentrations of the chemokine until the source is reached.
Chemokines can also increase adhesion molecules on vari-
ous cell types, including the responding cells and the
endothelial cells of the blood–brain barrier, which helps the
responding cells enter the damaged tissue more easily from
the blood. In some cases, an infected cell upregulates the
production of a particular chemokine in order to attract cells
that can bring a protective immune response into the tissue.
However, if the magnitude of this response is too great,
damage to resident cells, such as neurons, can occur.
Several studies have shown a specific upregulation of
monocyte chemoattractant protein-1 (MCP-1) in the CSF of
HIV-1 dementia patients [40,41] and in cultured astrocytes
and microglia exposed to the HIV-1 regulatory protein Tat
[41,42]. TNF-α is a known inducer of MCP-1, and may play
a role in the upregulation observed in HIV-1 dementia [40].
Production of other chemokines, such as macrophage in-
hibitory protein (MIP)-1α, MIP–1β, or RANTES, has also
been detected in the CSF of HIV-1 dementia patients [40].
In HIV-1 encephalopathy, it is likely that these chemokines
contribute to pathogenesis by bringing into the brain in-
creased numbers of infected and/or activated monocytes,
another source of both viral and cellular toxins that affect
neuronal function and survival [41]. In addition, resident
brain cells, including neurons, express chemokine receptors
and it is possible that chemokines act directly on neurons to
induce death [19].
Not all immune responses in the brain have damaging
effects, however. In addition to the toxic effects of TNF-α
described earlier, the same molecule may have neuroprotec-
tive effects under certain conditions [9]. TGF-β, produced in
response to IL-1, is a classically ‘anti-inflammatory’ cytok-
ine that can stabilize calcium homeostasis and stimulate
anti-apoptotic pathways in neurons. Both TGF-β and IL-1,
with seemingly opposing actions, are upregulated in HIV-
1-infected brains [36]. TGF-β-mediated prevention of
HIV-1 gp120-induced neuronal death was demonstrated in
mixed neuron–glia cultures [43]. The chemokines MIP-1α
and RANTES, which can recruit inflammatory cells into the
brain, also prevent gp120-induced neuronal death, most
likely due to competition with HIV-1 binding to chemokine
305
receptors on glial cells [20]. Fractalkine, a chemokine that is
highly expressed in the central nervous system, is upregu-
lated in the context of HIV-1 encephalitis, and protects
neurons from the toxic effects of HIV-1-Tat protein and
platelet activating factor [44]. Thus, some cytokines and
chemokines may provide neuroprotection by competing
with viral particles or viral envelope proteins for binding to
target cells, as well as by preventing cytokine-mediated or
cellular toxin-mediated effects in the HIV-1-infected brain.
5. Conclusions
Subsequent to systemic viral infection in humans, HIV-1
clearly can invade the brain, where it has the capacity to
induce inflammatory responses, neuropathology, and pro-
gressive symptoms of neurological disorders. There is
substantial evidence that neurons susceptible to damage in
HIV-1 associated encephalopathy are rarely infected, and
the numbers of infected macrophages and microglia as well
as the amount of virus they produce are too low to explain
the widespread areas of brain pathology. It is thus apparent
that the cellular responses to infection, and the effects of
these responses on different cell populations in the brain, are
the links between HIV-1 infection, HIV-1 encephalopathy,
and the HIV-1-associated dementia complex. Fig. 2 depicts
what is currently understood about the complex and indirect
mechanisms of HIV-1-induced neuronal damage. Virus
enters the brain via infected monocyte infiltration; the
monocytes differentiate into macrophages, and virus can
replicate and spread to other macrophages, microglia, and
astrocytes. Viral proteins shed from infected cells may
directly affect neuronal function, or they can stimulate other
cells in the CNS to produce cytokines or toxic products.
These cellular products can cause damage to specific
neuronal populations, or can further stimulate different cell
types in the CNS, providing amplification of this toxic
inflammatory response. Some cells may respond by produc-
ing defensive molecules, providing a possibility of antiviral
or anti-inflammatory effects. Normally functioning astro-
cytes and oligodendrocytes act to promote neuronal func-
tion and survival, but if these cells are damaged by the
inflammatory response, their neuroprotective functions are
lost.
Taken together, it is clear that a critical balance exists in
the HIV-1-infected brain. Virus replication and viral prod-
ucts, antiviral and neuroprotective responses, and damaging
inflammatory responses all compete over the course of
many years, and whichever of these three dominates deter-
mines the outcome of infection. As discussed, actual viral
replication seems relatively minor in the brain environment,
yet it is indeed this replication and the production of
extracellular viral products that stimulates the cascade of
events that leads to both neuroprotection and neurotoxicity.
In addition, as the rapidly changing virus becomes more
virulent over time, HIV-1 replication in the brain may
306 D.M. Lawrence, E.O. Major / Microbes and Infection 4 (2002) 301–308

Fig. 2. Schematic of the processes and cell types that interact during HIV infection of the brain. Leukocytes in the bloodstream include monocytes (MO),
T lymphocytes (T), and B lymphocytes (B). HIV-1 infection is represented by a dotted pattern. Virus is transported into the brain via infected monocytes,
which differentiate into macrophages (MAC). HIV-1 can replicate and spread to other macrophages, microglia (MG), and astrocytes (A). 1. Viral products
shed from infected cells can be toxic to neurons (N), either directly or indirectly through stimulation of uninfected macrophages, microglia, or astrocytes.
2. Cellular products from either infected or uninfected but activated macrophages and microglia can stimulate and/or damage neurons, astrocytes,
oligodendrocytes (O), or other macrophages and microglia. Chemokine production, particularly from stimulated and/or infected astrocytes, may help recruit
more infected and/or activated monocytes into the brain tissue. 3. Astrocytes and oligodendrocytes provide neuroprotective functions, such as homeostasis
of calcium and glutamate levels, myelin production, and possible stimulation of anti-inflammatory molecules.

become more of a factor in the course of disease. Research
in many areas of neurodegeneration has shown that some
immune stimulation in the brain can be beneficial, both for
their antiviral effects and direct neuroprotective effects.
However, if the immune response is prolonged, or if
infection induces a chemokine that can specifically attract
more damaging cells, the outcome is neuropathology that is
potentially fatal. In HIV-1 encephalitis, the damage done by
an excessive immune response in the brain contrasts with
the immunosuppression defining AIDS, and this contrast
highlights the complexities that must be understood in order
to develop effective treatments for both. While the current
therapeutic approach to HIV-1 infection does seem to have
a beneficial effect for HIV-1 dementia, it is clearly not a
cure. A better understanding of the mechanisms in HIV-1-
induced neuropathogenesis is critical for designing treat-
ment and prevention options that access the brain and
perhaps regulate the immune response, such that the balance
is swayed toward neuroprotection.
Acknowledgements
The authors wish to thank Peter N. Jensen for helpful
discussions during the preparation of this manuscript.
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