,
,
* Center for Neurovirology and Neurodegenerative Disorders, the Departments of
Pathology and Microbiology,
Medicine,
The Eppley Institute for Cancer and Allied Diseases, and
|| College of Pharmacy, University of Nebraska Medical Center, Omaha
Correspondence: Yuri Persidsky, M.D., Ph.D., Center for Neurovirology and Neurodegenerative Disorders, 985215 Nebraska Medical Center, Omaha, NE 68198-5215. E-mail: ypersids{at}unmc.edu
 TOP ABSTRACT INTRODUCTIONREFERENCES |
|---|
to its receptor on neurons
exemplifies such mechanism. In toto, these works
underscore the diverse roles of chemokines in HIV-1 neuropathogenesis
and lay the foundation for future therapeutic
interventions.
Key Words: chemokine • chemokine receptor • endothelial cell • microglia • astrocyte • tight junction
|
TOPABSTRACTINTRODUCTIONREFERENCES |
|---|
The hallmark of HIVE is productive viral replication in brain macrophages and microglia associated with giant cell formation and macrophage infiltration from blood to brain. Other features of HIVE include widespread microglial activation and accompanying reactive astrogliosis, which are found in the areas of pronounced dendritic alterations [8 , 9 ]. Synaptic loss appears to be the best correlate of mental deterioration [10 ]. Three-dimensional stereological measures showed a significant correlation between reduced synaptic density and poor neuropsychological performance. These data underscore the significance of microglial activation in HIV-1-associated neurodegeneration. Macrophage brain infiltration is associated with neurological decline [11 ]. Morphometric studies suggested that there is a significant decrease in the size of all cortical areas, in the cerebral white matter, and in the basal ganglia/thalamus (subcortical gray matter) [12 ]. Activation of microglia and diffuse microgliosis were shown to correlate with ventricular expansion and neuropathological changes [13 ].
It is important to note that MP activation also causes the production
of pro-inflammatory factors, which can lead to neural injury.
Microglial activation [detected as expression of class II major
histocompatibility complex (MHC) antigen HLA-DR] and, to a lesser
extent, HIV-1 infection and reactive astrogliosis results in prominent
chemokine secretion [11
]. Once infected with HIV, MP
populations are predisposed to immune activation. Accumulating data
suggests that HIV-1 proteins Tat and gp120 interact with brain MP,
perhaps via viral cellular receptors, to induce a cascade of
intracellular events altering the threshold required for activation
[14
15
16
17
18
19
]. HIV-1 proteins, productive viral replication,
or other stimuli may "prime" the MP for activation by
pro-inflammatory cytokines, chemokines, or T cell-expressed factors,
for example CD40 ligand (CD40L) [14
15
16
17
18
19
20
21
22
23
, and R. Cotter et
al., unpublished observations]. The combination of viral replication
and immune activation ultimately results in neurotoxin production by MP
[J. Zheng et al., unpublished results; 17
19
20
24
].
MP neurotoxins include arachidonic acid and its metabolites
[25
], platelet-activating factor (PAF)
[26
], pro-inflammatory cytokines [tumor necrosis factor
(TNF-) or interleukin-1ß (IL-1ß)], quinolinic acid
[27
], NTox [28
], and nitric oxide (NO)
[29
]. Viral proteins such as gp120 [30
],
gp41 [29
], and Tat [31
] secreted by
infected brain macrophages can directly affect neuronal viability
and/or function. Most recently, studies from our laboratories, and
those of others, indicated that progeny virions or HIV-1 gp120 may bind
to chemokine receptors (for example, CXCR4) expressed on neurons, and
alter intracellular signaling, perhaps leading to apoptosis
[32
33
34
]. These findings, taken together, underscore the
significance of MP activation in HIV-1-associated neurodegeneration.
The mechanism of HIV-1-associated brain injury probably involves cell-cell interactions (glial, neuronal, and/or endothelial) with a number of neurotoxins. The regulation of MP effector cell responses may play both a positive and a negative role in disease pathogenesis. Although increases in cytokine and chemokine production can regulate virus replication in macrophages [17 ; R. Cotter et al., unpublished results], they also mediate chronic cellular inflammatory cascades involved with the recruitment of additional macrophages to the site of injury, leading to an amplification in neural injury [11 ; J. Zheng et al., unpublished results]. It is interesting that chemokine secretion, macrophage infiltration, blood-brain barrier (BBB) compromise, and neuronal damage have all been linked, one with the other, and are prominent features of HAD. It is important to note that all appear to be regulated through MP secretory responses and thus serve as a focal point for our laboratory’s research efforts and this article.
Impairments of BBB function in HAD
Alteration of BBB function is a common feature of HIV-1 CNS
infection [35
]. Significant structural and functional
abnormalities of the microvasculature have been demonstrated during
HIV-1 infection of the brain. This includes serum protein leakage and
morphological alterations in capillary endothelial cells and basement
membranes [35
36
37
]. In support of the idea that BBB
breakdown can be induced by HIV-1 infection of the brain, higher levels
of neurotoxins were found in peripheral blood than in the cerebrospinal
fluid (CSF) in a patient with HAD. These were associated with signs of
BBB compromise as observed by magnetic resonance imaging (MRI) of the
brain [5
]. Highly active anti-retroviral therapy can
result in a significant reduction of viral replication, neurotoxin
levels, and improvement of BBB function all associated with reversal of
HAD symptoms. Functional changes in the BBB have also been shown during
other lentiviral infections of the nervous system [38
].
An inverse relationship between severity of simian immunodeficiency
virus (SIV), encephalitis, and expression of the endothelial 55-kDa
isoform of BBB glucose transporter 1 was shown in cortical gray matter,
the caudate nucleus, and the cerebellum of virus-infected macaques.
Under normal conditions, the BBB efficiently restricts movement of ions, proteins, and other polar organic molecules to the brain. Structurally, the BBB is composed of specialized non-fenestrated microvascular endothelial cells (BMVEC) connected by tight junctions (TJ) and devoid of transcellular pores [39 ]. TJ and TJ proteins [outer membrane protein, zonula occludens (ZO-1) and integral membrane protein, occludin] formed by BMVEC ensure the BBB’s structural integrity. The development of tight junctions seems to depend on two primary processes: the appearance of high levels of the occludin and intracellular signaling processes that control the state of phosphorylation of junctional proteins [40 ]. Additional components of the barrier are the surrounding capillary basement membrane and astrocytes. Astrocyte end-feet are in close apposition to the abluminal surface of the brain endothelium and assist in the barrier function by coordinating the functional activities of BMVEC [41 42 43 ]. Structural impermeability of BBB is further enhanced by a number of special transport systems expressed on BMVEC. One of them is P-glycoprotein (P-gp), a transmembrane glycoprotein located on the apical/luminal membrane of BMVEC that transports endothelium-penetrating lipophilic molecules back into the blood [46 ]. We hypothesize that altered P-gp expression in HIVE may further disrupt BBB integrity with resulting increased toxicity to blood-borne molecules into brain [45 ].
HAD pathogenesis is influenced by BBB dysfunction documented by
MRI and single-proton emission computed tomography as perfusion defects
and white matter changes [46
, 47
].
Increased BBB permeability was shown by increased levels of quinolinic
acid, metalloproteinases, and NO in the CSF of HIV-1-infected patients
[7
, 48
49
50
]. How BBB dysfunction occurs is
not well understood. TJ or P-gp, if disrupted, could affect BBB
function and influence HAD progression. To evaluate the regulation of
P-gp and TJ proteins during HIVE, we performed a series of
cross-validating experiments. First, we examined expression of P-gp,
ZO-1, occludin, markers of MP activation/infection (CD68, HLA-DR, HIV-1
p24), and astrogliosis (GFAP) by immunohistochemistry in different
brain regions (seven with HIVE, four HIV-1 seropositive without
HIVE/HAD, and three seronegative controls) as previously described
[11
]. Analyses of HIVE brain tissue showed a focal
decrease of ZO-1/occludin antigen expression associated with MP brain
infiltration. Although both TJ proteins showed continuous membrane
immunoreactivity on BMVEC in control HIV-1-seronegative cases, both
medium-size and small microvessels featured fragmented or weak
immunoreactivity for ZO-1 occludin in brain tissue with HIVE
(Fig. 1A
B
C
D
E
F
and G
H
I
J
). Such diminished TJ
expression was strongly associated with macrophage perivascular
infiltration. Microvessels in the areas without significant macrophage
accumulation usually had weak but continuous ZO-1 or occludin
endothelial immunostaining. Consistent with intensity of HIVE, white
matter and deep gray matter showed the most prominent decrease in TJ
antigen expression. Cortical gray matter was affected only in the two
most severe HIVE cases that demonstrated focal monocyte perivascular
infiltrate in cortical neuropil. Microglial activation (but not MP
numbers) was associated with lowered P-gp immunostaining in HIVE (Fig. 1E and 1F)
. Only P-gp expression was decreased in HIV-1-infected
patients without HIVE when compared with controls. Its decrease
appeared to correlate with focal microglia activation (as detected by
increased HLA-DR expression). Dalastra et al. [51
]
recently demonstrated significant TJ disruption (fragmentation or
absence of immunoreactivity for occludin and ZO-1) within vessels from
subcortical white matter, basal ganglia, and, to a lesser extent,
cortical gray matter in HIVE patients. Second, we examined expression
of P-gp, ZO-1, occludin, and CD14 (a marker for MP) by
reverse-transcriptase polymerase chain reaction (RT-PCR) in brain
regions (adjacent to those investigated immunohistochemically for TJ
protein and P-gp expression). Levels of mRNAs were examined after
reverse transcription with antisense primers and PCR amplification of
the initially amplified cDNA. RNA for the cellular gene actin served as
an internal standard for these studies. TJ and P-gp mRNAs were
significantly down-regulated in HIVE and strongly associated with MP
CD14 expression. P-gp was lower both in HIV-1-seropositive patients
without neurological impairment and HIVE patients when compared with
controls. Overall, immunolabeling for TJ and P-gp correlated with their
mRNA expression in the same brain regions. Third, we studied expression
of ZO-1, occludin, and P-gp in our SCID mouse model of HIVE
[52
]. HIV-1ADA-infected MDM were
stereotactically inoculated into basal ganglia of SCID mice. Animals
were killed 1 week later. Immunohistochemical analysis of brain tissue
showed focal decrease in TJ and P-gp expression in microvessels
surrounded by virus-infected MP. Areas around human cells featured
microglia activation and reactive astrocytosis. Expression of TJ
proteins and P-gp was unchanged in brains of sham-operated animals.
Fourth, we examined functional activity of P-gp in primary cultures of
human BMVEC through the use of rhodamine 123 uptake assay as previously
described [53
]. When pro-inflammatory cytokines
[TNF-, IL-1ß, interferon-
(IFN-)] or supernatants from
HIV-1-infected, activated MP were placed onto BMVEC P-gp was
down-regulated (seen functionally as an increase in rhodamine 123
accumulation). Supernatants from HIV-1-infected and immune-stimulated
MDM elicited the most prominent rhodamine accumulation. Overall, these
findings demonstrate both structural and functional impairments of BBB
during HIV-1 infection.
  View larger version (266K): [in a new window] |
Figure 1. Expression of TJ proteins and P-gp in BBB in HIVE. Microglial cells are
activated (shown by HLA-DR expression) in HIVE brain tissue (B)
compared with controls (A). Perivascular macrophages and parenchymal
microglia expressed HIV-1 p24 (D) but not in controls (C). Expression
of P-gp was significantly diminished on BMVEC in HIVE (F) compared with
controls (E). Down-regulation of ZO-1 was found on BMVEC in HIVE (H)
compared with controls (G). Similarly, occludin showed a continuous
immunoreactive pattern in control brain (I) but was weakly reactive in
HIVE (J). Frozen sections were immunostained using antibodies to HLA-DR
(A, B), HIV-1 p24 (C, D), P-gp (E, F), ZO-1 (H, G), and occludin (I,
J). Frozen tissue sections were counterstained with Mayer’s
hematoxylin. Original magnification: panels A and B, x100; panels C–J
x200.
|
-subfamily (one
amino acid separates the first two cysteine residues, CXC), ß-
(cysteine residues are adjacent, CC), - (only two cysteine residues
are present, C), and 
- (three amino acids separate the first two
cysteine residues, CX3C) [54
]. Members of a
subfamily show considerable homology in amino acid sequence and
overlapping cell-specific chemoattractive properties. Because ß
chemokines [macrophage inflammatory proteins-1 and -1ß (MIP-1
and MIP-1ß), macrophage chemotactic protein-1 (MCP-1), MCP-2, MCP-3,
and regulated upon activation normal T cell expressed and secreted
(RANTES)] specifically promote monocyte migration, they received
special attention in studies of HIV-1 neuropathogenesis. Indeed,
ß-chemokines were detected in both HIVE brain tissue
[55
, 56
] and CSF of HIV-1-infected patients
with neurocognitive impairment [21
]. Microglia, resident
brain MP, and astrocytes produce ß-chemokines in vitro
after stimulation with viral proteins, inflammatory cytokines,
lipopolysaccharide (LPS) or CD40L [18
21
,
23
, 57
, 58
]. Weiss and
colleagues [54
] using an in vitro BBB system
(umbilical vein endothelial cells and fetal astrocytes seeded on
opposite sides of a porous membrane) showed that MCP-1 was the primary
chemoattractant for monocytes and that astrocytes stimulated by
pro-inflammatory cytokines were the major source of this chemokine.
Although the works described above provide circumstantial evidence of
ß-chemokine involvement in HIV-1 neuropathogenesis, the exact
composition of chemokines secreted, their cellular sources, and the
role of MP infection and immune activation remain unclear. To address
these questions, we developed an integrated approach utilizing an
in vitro model for the BBB (human BMVEC and astrocytes
seeded on the opposite sides of porous membrane), a SCID mouse model of
HIVE, and the use of brain autopsy tissue to confirm the observations
made in cell culture and animals [52
, 59
,
60
]. First, to mimic BBB compromise during HIVE we placed
MDM or microglia with or without HIV-1 infection in the bottom of our
transwell BBB inserts ("brain" side). Migration of peripheral blood
monocytes (isolated at the time of the experiment and placed in the
upper chamber of inserts) were evaluated. Microglia-containing BBB
models showed the most prominent monocyte migration (2.5–3 times more
than the MDM-seeded inserts). Second, we explored the idea that
production of ß-chemokines or cytokines (TNF-) was distinct
between MDM and microglial cells. This proved correct because microglia
secreted 5–20 times more of both TNF- and chemokines [shown by
enzyme-linked immunosorbent assay (ELISA)] than the same numbers of
MDM. Immune stimulation further enhanced their secretion in both cell
types. It is interesting that there was no difference in chemokine and
TNF- production between HIV-1-infected and uninfected cells. Because
these data did not correlate with the results observed in the BBB
model, we hypothesized that cells other than microglia or macrophages
could be a source of chemokines. Astrocytes are likely candidates. A
strocytes were part of our BBB constructs and are known to produce
chemokines. Furthermore, signs of astrocyte reactions were detected
previously in our BBB models during MDM migration [61
].
To study the interactions between virus-infected MP and astrocytes,
supernatants derived from HIV-1-infected or uninfected activated
microglia or MDM were applied to primary human astrocytes. Under these
experimental conditions, astrocytes produced significant amounts of
ß-chemokines (in particular MCP-1). Culture fluids collected from
immune-activated virus-infected microglia elicited the greatest
chemokine production. Collectively, these results indicated that the
interplay between activated microglia and astrocytes may be of critical
importance for HIV-1 neuropathogenesis. Third, to determine the
possible pro-inflammatory and transendothelial migratory effects of
resident brain macrophages in SCID mice with HIVE we inoculated equal
numbers of infected or uninfected MDM and microglia into the basal
ganglia of the mice. In our previous works we showed that salient
features of HIVE are reproduced in such animals, including
neuropathological changes, neurotoxin production, and behavioral
abnormalities [52
, 61
, 62
].
SCID mice, which received infected microglia, showed the most prominent
neuropathological changes (including astrogliosis and mouse microglia
reaction) and elicited the greatest accumulation of mouse macrophages
in the inoculated areas when compared with animals inoculated with
equal numbers of
MDM. Fourth, expression of chemokines was compared to the intensity of HIVE
in human brain tissues. We found that the severity of HIVE (level of
macrophage brain infiltration, formation of microglial nodules, and
astrogliosis) correlated with microglia activation (MHC class II HLA-DR
expression) and, to a lesser extent, HIV-1 infection and chemokine
expression (detected by immunohistochemical tests). Both activated
microglial cells and reactive astrocytes were the major sources of
chemokines in HIVE. It is important that neuropathological evidence of
HIVE severity correlated with neurocognitive impairment. Diffuse
microglia activation may explain how relatively small numbers of
HIV-1-infected perivascular MP could cause widespread neurological
dysfunction. In support of this notion, microglia activation was shown
to be the best predictor of neuronal injury and behavioral
abnormalities in SIV-infected macaques [63
].
Chemokines and their receptors in HIV-1-associated neuronal injury
Much of the work described above outlines the role of chemokines
in monocyte trafficking into the brain. However, because chemokine
receptors are expressed on a wide range of neural cells we hypothesized
that such factors might also play roles in neural injury. This was
tested in a number of experimental systems in our laboratories. It is
interesting to note there are several ways that chemokines and their
receptors may perturb neural function and these are delineated below.
Chemokines exert their effects by activating members of a
seven-transmembrane G-protein-coupled receptor (GPCR) family. These
receptors are divided into four categories as described above
[64
, 65
]. -chemokine receptor, CXCR4,
and ß-chemokine receptor, CCR5, are believed to be the important
viral co-receptors for HIV-1 infection. Macrophage-tropic (M-tropic)
HIV-1 strains use the chemokine receptors CCR5 or CCR3 as co-receptors
for viral infection [66
67
68
69
70
71
], whereas CD4+ T
lymphocyte-tropic (T-tropic) HIV-1 strains use CXCR4
[72
]. It is important that HIV-1 virion-associated gp120
can also instigate signal transduction through binding to chemokine
receptors of MP or CD4+ T lymphocytes
[73
74
75
].
Recently, a variety of chemokine receptors have been found to be shared by leukocytes and neuronal cells. Because viral proteins and chemokines are present in the HIV-1-infected brain tissue, chemokine receptor-chemokine interactions may affect spread of infection and its associated neurodegenerative events [32 , 34 , 69 70 71 , 76 77 78 79 80 81 82 83 ]. One of these receptors is CXCR4 [72 ]. A number of studies have linked CXCR4 to the immune and neuronal compromise that occurs during late-stage HIV-1 infection [32 , 36 , 77 , 79 , 81 82 83 ]. Several reports document CXCR4 expression by a number of neuroectodermal cell types, including neurons, microglia, and astrocytes [69 70 71 , 76 77 78 79 80 81 82 ]. Furthermore, CXCR4 also plays a substantial role in neuronal function and apoptosis [32 , 34 , 84 , 85 ].
We previously demonstrated that the HIV-1 envelope glycoprotein, gp120,
or ligand for CXCR4, SDF-1, can elicit neuronal apoptosis
[32
33
34
]. This response can be inhibited by antibody to
CXCR4 (12G5). It is important that progeny virions may also bind to
chemokine receptors (for example, CXCR4) expressed on neurons and lead
to apoptosis [84
, 86
] (Fig. 2
). Thus, HIV-1 virions or chemokines produced by immune-activated
glial cells may bind to neuronal receptors and alter cellular function.
The interaction of these ligands with receptors on neurons may lead to
the neuronal loss, alterations in dendritic arborization, and decreased
synaptic density observed in tissue specimens of affected individuals
[16
, 32
33
34
, 84
,
87
, 88
]. However, the exact mechanism for
the interaction among chemokines, virion, and neuronal chemokine
receptors is still unknown. Alternatively, some chemokines may have a
neuroprotective function in the brain [16
,
89
, 90
]. Certainly, the overabundant
expression of chemokines in both normal and diseased brain raises an
important question regarding the exact role of these chemokines and
their receptors for neuronal function.
 View larger version (67K): [in a new window] |
Figure 2. Immunocytochemical analysis of CXCR4 antigen expression in human fetal
neurons and signal transduction and neuronal apoptosis is induced by
SDF-1 and gp120. Human neurons were double immunostained with 12G5
for CXCR4 (green, B, C) and antibody for neurofilament (NF 150 kDa,
red, B, C). Neuronal networks showed branched dendrites by NF staining
(B, C). Neuronal cell bodies and process were double immunostained with
12G5 and NF antibody (B, C). MAP-2 (green, A) and GFAP staining (red,
A) showed more than 70% cells identified as neurons and less than 30%
were astrocytes. All original magnifications are x200 for A and B.
Panel C is a high-power view of B illustrating cell membrane (CXCR4)
and dendritic (NF) morphology (x600). In panel D, SDF-1 (50 nM) and
recombinant gp120SF-2 (1 nM) with or without 12G5
(administered at 5 µg/mL) were placed on human neurons for 4 days and
apoptosis detected by ELISA (D) shows results using anti-histone and
anti-DNA antibodies. In panel E, PI hydrolysis induced by SDF-1 or
gp120 were determined in replicate cultures. These experiments are
representative of three replicate assays. Data are expressed as
means ± SD. *P < 0.01
with or without SDF-1 or gp120. P <
0.01 with or without 12G5.
|
-chemokine receptors such as CXCR2
[77
] or CXCR5 [91
] are expressed by
neurons. Preliminary data from our laboratory and those of others
suggest that CXCR5 are mainly expressed on neuronal dendrites, whereas
CXCR2 and CXCR4 are expressed both on neuronal cell bodies and
processes [90
]. Production of IL-8, ligand for CXCR2, is
increased in astrocytes or astrocytoma cell lines under
pro-inflammatory conditions [90
]. IL-8 is also produced,
at lower levels, by astrocytes under normal conditions
[92
, 93
]. It is important to note that our
recent preliminary data suggests that IL-8 is also produced by
HIV-1-infected lymphocytes. Similarly, HIV-1 infection and immune
activation induced the production of high levels of IL-8 by MDM
[90
]. Similar results were obtained in the primary
cultures of human fetal microglia. Importantly, IL-8 production appears
to be up-regulated in human brain tissues affected by HIVE, adding
in vivo relevance to the laboratory results [Y. Persidsky
et al., unpublished observations]. In summary, HIV-1 infection and
secondary immune activation induce the production of chemokines from MP
and/or astrocytes. Some of the chemokines (such as SDF-1) or viral
proteins (such as gp120) can affect neuronal apoptosis. Alternatively,
some of the chemokines may be neuroprotective [89
,
90
]. How and under what circumstances chemokines exert
protective or toxic results are central questions currently being
investigated in our laboratories and others.
Chemokine receptor signaling may link inflammation to neuronal
apoptosis
Our data and others show that chemokine receptor (such as
CXCR4)-ligand binding stimulates at least three distinct intracellular
signaling cascades in neuronal cells under normal physiological
conditions. First, binding of SDF-1 to CXCR4 causes transient
increases in cytosolic inositol triphosphate (IP3) and
[Ca2+] levels in cultured neurons and astrocytes. Second,
SDF-1 binding to CXCR4 inhibits adenylate cyclase activity, leading
to decreased cytosolic cAMP levels. Third, CXCR4 stimulation induces
MAP kinase phosphorylation [J. Zheng et al., unpublished
observations]. The IP3 adenylate cyclase and MAP kinase
pathways are likely to have an important role in the normal neuronal
homeostasis. Because SDF-1 can also induce neuronal apoptosis
through binding of CXCR4 receptors expressed on neurons, these same
pathways may provide potential mechanisms through which virion or
gp120-chemokine receptor interactions trigger neuronal apoptosis. How
these physiological signal transduction pathways are linked to
apoptosis signaling certainly awaits elucidation.
Much work has been done to explore the apoptotic mechanisms mediating
brain cell injury in HAD. Apoptosis of neurons, astrocytes, and/or MP
is a major feature of cellular injury in HIVE [52
,
94
95
96
97
]. These observations are supported by work
performed in human neuronal culture systems where MP-secretory products
induce neuronal apoptosis. Binding of neuronal CXCR4 by cellular and
viral factors [34
, 84
] can instigate
intracellular signaling. In general, apoptosis is induced by
extracellular signals such as the Fas ligand, TNF-, or others,
and/or by deprivation of neurotrophic factors. The final steps in
neuronal gene expression leading to apoptosis in brains of HAD patients
is not known.
The newly characterized caspase system provides a suitable starting point for understanding the molecular mechanisms through which chemokine receptor binding and apoptosis may be linked in neurons. Caspases are a family of proteases that stimulate apoptosis. Ten caspases have been identified [98 , 99 ] and have been grouped according to sequence homology as being either ICE- (caspases 1, 4, and 5) or ced-3 like (caspases 3, 6, 7, 9, and 10) [98 , 99 ]. Caspases are synthesized as inactive "pro-enzymes" that are processed by proteolytic cleavage to form an active enzyme. For example, caspase-3 is a key protease that becomes activated during the early stages of apoptosis [100 ]. Active caspase-3, found in cells undergoing apoptosis, consists of a heterodimer of 17- and 12-kDa subunits, which are derived from the 32-kDa proenzyme. In its active form, caspase-3 proteolytically cleaves and activates other caspases, as well as relevant targets in the cytoplasm (D4-GDI) and nucleus (PARP) [98 , 99 ]. It is interesting to note that we have demonstrated that caspase-3 is activated by HIV-1 in human neurons [34 ]. However, it is still not clear how G-protein-coupled chemokine receptors stimulate signaling pathways linked to caspase activation.
Nevertheless, although chemokine and chemokine receptors are widely expressed in affected brain, understanding the expression and function of chemokine and chemokine receptors on neurons holds great importance. The determination of chemokine, viral-associated or secreted protein and chemokine receptor interactions and influence on neuronal second messengers may help the elucidation of such important questions. It is possible that these ligand-bound chemokine receptors may directly stimulate the apoptosis-promoting signaling machinery. On the other hand, neuroprotective factors present in the healthy brain may operate through abrogation of the same events or stimulation of anti-apoptotic pathways. This research will certainly help to explain why some of the chemokines play a neurotoxic role, whereas other chemokines are neuroprotective.
Taken together, these data indicate the central role for HIV-1-infected and immune-activated MP in the neuropathogenesis of HAD. Clearly, MP orchestrates many biological and biochemical pathways in brain that regulate cell trafficking, viral infection, and compromise of the neuropil. Substantial levels of chemokines and pro-inflammatory cytokines are produced by MP as well as by astrocytes. These two cell types may communicate with each other in steady state and disease, resulting in defined physiological outcomes. The rapidly developing field of neural chemokine-ligand interactions and cell signaling has led to the delineation of how neurons may be destroyed during the progression of HAD. The outcome of such chemokine-chemokine receptor interactions for neural cells is of pivotal importance because under certain sets of circumstances the process may lead to apoptosis, whereas in others it may lead to neuroprotection.
|
TOPABSTRACTINTRODUCTIONREFERENCES |
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M.-O. Kim, H.-S. Suh, Q. Si, B. I. Terman, and S. C. Lee Anti-CD45RO Suppresses Human Immunodeficiency Virus Type 1 Replication in Microglia: Role of Hck Tyrosine Kinase and Implications for AIDS Dementia J. Virol., January 1, 2006; 80(1): 62 - 72. [Abstract] [Full Text] [PDF]
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S. L. Archibald, E. Masliah, C. Fennema-Notestine, T. D. Marcotte, R. J. Ellis, J. A. McCutchan, R. K. Heaton, I. Grant, M. Mallory, A. Miller, et al. Correlation of In Vivo Neuroimaging Abnormalities With Postmortem Human Immunodeficiency Virus Encephalitis and Dendritic Loss Arch Neurol, March 1, 2004; 61(3): 369 - 376. [Abstract] [Full Text] [PDF]
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