(Journal of Leukocyte Biology. 2003;74:691-701.)
© 2003
by Society for Leukocyte Biology
Mononuclear phagocyte immunity and the neuropathogenesis of HIV-1 infection
Yuri Persidsky*,
,1 and
Howard E. Gendelman*,,
* Center for Neurovirology and Neurodegenerative Disorders, Departments of
Pathology and Microbiology and
Medicine, University of Nebraska Medical Center, Omaha
1Correspondence: Center for Neurovirology and Neurodegenerative Disorders, 985215 Nebraska Medical Center, Omaha, NE 68198-5215. E-mail: ypersids{at}unmc.edu
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ABSTRACT
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Human immunodeficiency virus type 1 (HIV-1)-associated dementia is a neuroinflammatory brain disorder that is fueled by viral infection and immune activation of brain mononuclear phagocytes (MP; macrophages and microglia). MP serve as a reservoir for persistent viral infection, a vehicle for viral dissemination throughout the brain, and a major source of neurotoxic products that when produced in abundance, affect neuronal function. Such neurotoxic substances secreted by MP lead to clinical neurological impairment (cognitive, behavior, and motor abnormalities), which occurs usually years after the initial viral infection. How HIV-1 evades the immune function characteristic for MP as a first line of defense, including phagocytosis and intracellular killing, is not well understood despite more than two decades of study. In this report, we review the complex role(s) played by MP in the neuropathogenesis of HIV-1 infection. The clinical manifestations, pathology and pathogenesis, and treatment options are discussed in relationship to innate and adaptive immunity. Particular emphasis is given to the diversity of MP functions and how it may affect the disease process and manifestations. New insights into disease mechanisms are provided by advances in enhanced magnetic resonance imaging and proteomics to identify cell movement and genetic profiles of disease. New therapeutic strategies are discussed based on current knowledge of HIV-1-associated dementia pathogenesis.
Key Words: blood-brain barrier • animal model • HIV-1 encephalitis • neuronal damage
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INTRODUCTION
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Cognitive impairment remains a common complication of late-stage human immunodeficiency virus type 1 (HIV-1) infection. Prior to introduction of highly active antiretroviral therapy (HAART), up to half of virus-infected individuals demonstrated neuropathological findings at autopsy, and a quarter had clinical manifestations of disease including cognitive, behavioral, and motor abnormalities, ranging from mild motor/cognitive deficits to overt dementia [HIV-1-associated dementia (HAD); refs. 1
, 2
]. Despite the diminished incidence of HAD (now at 11%) [3
], the greater life expectancy of infected individuals suggests that the prevalence increases. This could occur as a result of viral mutation, decreased penetrance of antiretroviral drugs into the brain, and HAART failure [4
5
6
]. Recent studies indicate that cognitive deficits, minor cognitive/motor disorder, and depression may be early manifestations of HAD [7
].
In the pre-HAART era, HAD paralleled significant immunosuppression and CD4+ T lymphocyte loss. The natural history of HAD has changed. Indeed, a significant increase in the median CD4 cell count at HAD diagnosis and a relative increase in cognitive impairment as an acquired immunodeficiency syndrome (AIDS)-defining illness as compared with opportunistic infections have occurred in the post-HAART era [8
]. Despite the continued importance of neurological disease in the field of HIV/AIDS, host-viral interactions leading to cognitive dysfunction are not completely understood. Nonetheless, several components of the immunopathology of HAD have been unraveled in the past 20 years since HIV was discovered as the cause of AIDS.
HAD is associated pathologically with HIV-1 encephalitis (HIVE). The hallmark of brain histopathology is productive viral replication in cells of mononuclear phagocyte (MP; perivascular and parenchymal macrophages and microglia) lineage [9
]. There is limited evidence for infection in neurons or macroglia (astrocytes and oligodendrocytes) [10
, 11
]. HIVE is further characterized by multinucleated giant cell formation, presence of microglial nodules, and macrophage infiltration into the brain [12
]. A significant astrogliosis, myelin pallor, and atrophy of neocortex (neuronal loss, dendritic arbor damage, and spatial neuron alterations) occur as a consequence of MP viral infection [13
14
15
]. A new variant of HIVE has emerged in the era of HAART: severe leukoencephalopathy with significant perivascular infiltration of macrophages and lymphocytes (assumed a result of an exaggerated response from a newly reconstituted immune system) [16
]. The best histopathologic correlate of HAD is the number of activated MP in the central nervous system (CNS) [17
]. Although most patients with HIVE have HAD, not all HAD patients have HIVE [17
]. Even minimal increases in the numbers [12
] and perhaps even more importantly, the level of MP immune activation may cause neurological dysfunction [18
].
It has been hypothesized that virus enters the CNS mainly through infected monocytes and macrophages destined to become brain-resident cells or perivascular macrophages [19
]. As the CNS has been considered an immune-privileged area, it has been suggested that HIV-1 enters early after primary infection (at a peak of primary viremia). The importance of MP in the neuropathogenesis of HIV disease is underscored by emergence of specific monocyte subsets in the peripheral blood of patients with HAD. These cells can, but do not always, express CD14/CD16 and CD14/CD69 surface markers and demonstrate enhanced ability to migrate and secrete neurotoxins [20
21
22
23
]. The appearance of such monocyte subsets in blood coincides with decreased antiviral peripheral-immune responses and precedes development of HAD. Immune activation is associated with enhanced monocyte migration through the blood-brain barrier (BBB) and the secretion of a variety of immune and viral factors known to affect neuronal function [25
, 26
]. Once inside the brain, immune-competent macrophages can move within the ventricular system, the white matter tracks, and across the corpus callosum, enabling diffuse neuronal destruction [27
]. The significance of antiviral innate- and adaptive-immune responses in HAD pathogenesis is shown by enhanced monocyte trafficking into the brain during advanced HIV infection when such activities are diminished [28
].
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INNATE IMMUNITY AND MECHANISMS OF NEURONAL INJURY
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It is now widely accepted that in the absence of viral infection of neurons or macroglia, indirect mechanisms play a major role in HAD neuronal dysfunction and death. Multiple studies performed during the last decade demonstrated that virus-infected microglia and macrophages secrete or induce other neural cells to produce neurotoxic factors that lead to neuronal injury or death during HIVE. These neurotoxins include arachidonic acid (AA) and its metabolites [29
], platelet activating factor (PAF) [30
], proinflammatory cytokines [tumor necrosis factor 
(TNF-) or interleukin-1ß (IL-1ß)], quinolinic acid (QA) [31
], NTox [32
], glutamate [33
], and nitric oxide (NO) [34
]. A significant reduction in toxin levels in cerebrospinal fluid (CSF) reversed neurocognitive impairment when antiretroviral therapy was administered to a patient with HAD [28
]. Viral proteins such as gp120 [35
], gp41 [34
], and Tat [36
], secreted by infected brain macrophages, can cause neuronal injury and/or dysfunction.
In the past few years, significant progress was made in clarifying the biological importance of chemokines in the CNS. Most recently, studies from others and our group demonstrated that virions released from macrophages bind to chemokine (chemotactic cytokines) receptors expressed on neurons [37
, 38
]. Initially viewed as immune modulators, chemokines appear to play much broader biological roles in CNS, including development, neuronal excitability, and synaptic transmission, neuroinflammation, and neurodegeneration [39
]. A number of - and ß-chemokine receptors are expressed on neurons, astrocytes, and microglia [39
40
41
42
43
]. Two of them, CXCR2 and CXCR4, were found in neuronal cells [37
, 42
]. CXCR4 plays a crucial role in receptor-mediated neuronal apoptosis and cell homeostasis [37
, 38
, 44
]. As HIV-1 gp120 can bind to chemokine receptors initiating signal transduction [45
, 46
], the neuronal chemokine receptor expression and distribution on different types of neurons are significant for understanding CNS homeostasis and HAD pathogenesis. Expression of CXCR4 was found on neurons positive for choline acetyltransferase (in the caudate putamen and substantia innominata) and tyrosine hydroxylase (in the substantia nigra pars compacta) [47
]. Stimulation of neuronal chemokine receptors, through virions, viral proteins, or the CXCR4 natural ligand stromal-derived factor-1 (SDF-1; up-regulated in HIVE, ref. [48
]), may alter intracellular signaling events and cause neuronal dysfunction and apoptosis [37
, 38
]. Constitutive expression of CXCR4 on neurons suggests that HIV-1 gp120 or SDF-1 could directly interfere with cholinergic and dopaminergic neurotransmission.
There is an apparent discrepancy between the neurotoxic potential of CXCR4 using viruses and HIV-1 isolates that exist in the brain of patients with HAD. Previous studies have demonstrated that brain-derived viruses are macrophage-tropic and principally use CCR5 for virus entry [43
, 49
]. A recent study indicated the presence of HIV-1 variants with increased CCR5 affinity and reduced dependence on CCR5 and CD4 in the brains of some HIV-1-infected patients with CNS disease and suggested that R5 variants with increased CCR5 affinity may represent a pathogenic viral phenotype contributing to HIV-1 neurodegeneration manifestations [50
]. This apparent paradox could be associated with the predominance of indirect mechanisms of neurotoxicity (secretory substances of virus-infected and activated MP) in HIV-1 neuropathogenesis.
Laboratory methods assaying neuronal function were developed to model neuronal injury during HAD and to establish the connections among virus infection, MP activation, chemokine production, and neuronal demise. 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. Supernatants derived from HIV-1-infected MP were applied to the CA1 area of rat hippocampal brain slices (the site of mammalian learning and memory), and neuronal long-term potentiation (LTP; a neural response linked closely to learning and memory) was assayed. LTP was induced by high-frequency stimulation. The lowest levels of LTP were detected in brain slices treated with supernatants acquired from virus-infected and activated MP as compared with uninfected or/and nonstimulated cells [51
]. Establishment of such systems allowed testing effects of inflammatory stimuli relevant to the neuropathogenesis of HAD. IL-8 could represent one of the potential perpetrators in HAD-associated neuronal demise, as elevated levels of IL-8 were detected in brain [52
] and CSF of AIDS patients with HAD [53
]. The effects of IL-8 on LTP were studied in the CA1 region of rat hippocampal slices [52
]. IL-8 inhibited LTP, and this inhibition was mediated through CXCR2 activation, suggesting a direct effect of IL-8 on synaptic transmission. The up-regulation of IL-8 in HIVE, its inhibition of LTP, and the expression of CXCR2 in the hippocampus point to its role in the cognitive dysfunction associated with HAD.
In vitro studies demonstrated that neurotoxic factors secreted by MP can induce toxicity directly or indirectly through downstream effects at the N-methyl-D-aspartate (NMDA)-type glutamate receptor leading to apoptosis [54
, 55
]. Some apoptotic effects of HIV proteins may be mediated by chemokine receptors [38
]. Clearly, the mechanism of HIV-1-associated brain injury is complex, probably involving multiple neurotoxic factors and pathways.
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ASTROCYTE ACTIVATION IN HAD
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How a finite number of infected macrophages/microglia, localized in particular areas of the brain, can lead to widespread neuronal injury is also unclear. One possibility is that interactions between immune-competent MP and astrocytes lead to an amplification of toxic-immune responses [56
]. Reactive gliosis is a prominent feature of HIVE [18
]. Histopathological studies performed with human autopsy tissue from several groups, including our own, show that in HAD, reactive astrogliosis, as identified by glial fibrillary acidic protein (GFAP) staining, coincides with increased trafficking of activated macrophages and concomitant microglial activation [18
, 58
]. Neuropathological observations also document that intense astrogliosis and microglial activation are observed in areas of axonal and dendritic damage in HAD [14
]. Astrocytes are likely effector candidates simply by virtue of being the most abundant cell type in the CNS.
There has been consistent evidence that astrocytes become infected with HIV-1, although at the low frequency as compared with brain MP. HIV-1 antigens and/or nucleic acid have been identified in astrocytes at low levels in brain autopsy tissue from adult and pediatric AIDS cases [58
, 59
]. In cell cultures, HIV-1 infection of astrocytes results in an initial, productive but noncytopathic infection that diminishes to a viral persistence or latent state [60]
. The major barrier to HIV-1 infection of primary astrocytes appears to be at virus entry and that astrocytes have no intrinsic intracellular restriction to efficient HIV-1 replication [61
].
These cells can play a dual role: amplifying the effects of inflammation and mediating cellular damage as well as protecting the CNS. Cytokine/chemokine communications between MP and astrocytes and viral proteins produced by MP are involved in the balance of protective and destructive actions by these cells. HIV-1 transactivator protein Tat significantly increases astrocytic expression and release of monocyte chemoattractant protein-1, ß-chemokine [62
]. Using tissue cocultures, animal model, artificial BBB, and postmortem human tissue, we demonstrated that interactions between activated MP and astrocytes result in a significant up-regulation of ß-chemokines, promoting MP infiltration in HIVE [18
]. Furthermore, production of -chemokines by astrocytes has been documented as a result of proinflammatory substances secreted by activated lymphocytes in the setting of HIVE [64
]. Proinflammatory cytokines [TNF-, IL-ß, and interferon-
(IFN-)] and QA, present in abundance during HAD, are potent inducers of - and ß-chemokines by astrocytes [65
]. Conversely, primary human astrocytes suppress HIV-1 replication in monocyte-derived macrophages (MDM) by soluble factors [65
] and down-regulated secretion of proinflammatory factors by HIV-1-infected MDM [29
].
Astrocytes directly participate in synaptic integration by releasing glutamate (transmitter) via an exocytosis-like process. This occurs after activation of the receptor CXCR4 by SDF-1 [66
]. Autocrine/paracrine TNF--dependent signaling leading to prostaglandin formation not only controls glutamate release and astrocyte communication. Derangement of astrocyte processes is seen when activated microglia enhance release of cytokines in response to CXCR4 stimulation. Altered glial communication has direct neuropathological consequences, as agents interfering with CXCR4-dependent astrocyte-microglia signaling prevent neuronal apoptosis induced by HIV-1 gp120. In addition to other functions, astrocytes are a significant component of the BBB, ensuring maintenance of unique phenotypic properties of brain microvascular endothelial cells [67
], which are altered in HIVE [68
, 69
].
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ADAPTIVE IMMUNITY AND CONTROL OF HIV-1 INFECTION IN THE NERVOUS SYSTEM
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Although HIV-1 enters the brain early following viral infection [19
], productive viral replication and brain macrophage invasion occur years later and only in some infected people [6
]. One explanation is that virus reseeds the brain or endogenous control mechanisms that inhibit HIV-1 breakdown. Such an apparently effective control of viral replication in the brain, measured over years, is thought to be mediated by acquired T cell immunity [70
71
72
]. Indeed, cytotoxic T lymphocytes and natural killer cells provide the principal, regulatory elements that control persistent viral production. Both are operative in the periphery as well as the CNS [73
74
75
76
77
].
A strong association between HAD and profound immunodeficiency has given rise to the notion that a lack of effective T cell-immune responses is associated with ongoing viral production in the brain. Nonetheless, it is likely even more complex, as not all patients with profound immunodeficiency develop HAD and not all HAD patients have significant lymphocyte depletion. These observations led us to investigate whether functional deficits exist in recruitment and/or trafficking of lymphocytes into the brain associated with impaired chemotactic responses. If present, defective chemotactic activities could lead to persistent viral replication in the CNS during later stages of HIV-1 infection. Brain tissue affected by HIVE features activation and productive infection of MP and limited lymphocyte infiltration. As -chemokines [including IFN--inducible protein of 10 kDa (IP-10)] attract T lymphocytes (expressing CXCR3 receptor) into the brain, we hypothesized that -chemokine deficits could alter T cell responses in HIVE. Our experiments demonstrated that CXCR3-mediated lymphocyte-chemotactic responses remained operative duringHIV-1 infection [63
]. In human brain tissue with HIVE, a positive correlation was found between HIV-1 pol and IP-10/CD14 (MP marker)/CXCR3 (lymphocyte marker) and between CD14 and CXCR3 mRNA expression, reflecting an association between virus replication in MP and MP-mediated attraction of T cells [63
].
We found increased numbers of CD8+ lymphocytes within the neuropil (next to virus-infected MP) in HIVE brains as compared with brain tissue from seropositive patients without evidence of encephalitis (Y. Persidsky, unpublished observation). In this setting, the inflammatory cytokines and cytotoxic molecules (such as granzyme B or perforin) released by these cells upon activation could contribute to the neurological sequelae of infection. Infiltrating CD8+ T cells may serve as a source of activation stimuli (such as IFN- or CD40 ligand). Consistent with these observations, a recent study demonstrated up-regulation of the IFN--inducible enzyme, indoleamine 2,3-dioxygenase (IDO) in brain MP of monkeys infected with simian immunodeficiency virus (SIV), an animal model for HIV-1 infection [78
]. Animals with SIV encephalitis (SIVE) have the highest levels of IDO mRNA, which correlate with IFN- and viral load. IDO is a key enzyme for the kynurenine pathway leading to QA production. QA is significantly increased in brain tissue of patients with HAD and associated with HAD progression [79
].
Why do CD8+ cells lose their protective role in the late stages of infection? One plausible explanation is that circulating HIV-specific CD8+ cells could be partially anergic and may be unable to eliminate HIV-1-infected cells in vivo in the setting of functionally impaired helper CD4+T lymphocytes during late stages of infection [80
, 81
]. Direct effects of reduced CD8+ cell immunity in the pathogenesis of HAD were demonstrated in the SIV model using CD8-depleting monoclonal antibody [76
]. Half of the animals treated with the anti-CD8 antibody exhibited a persistent depletion of the CD8+ phenotype for longer than 28 days. Of the monkeys showing this persistent CD8 depletion, greater than 80% developed AIDS with SIVE [82
]. What role impaired-immune responses play in HIV-1 neurodegeneration and HAD pathogenesis is currently under investigation in our laboratories [83
].
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BBB AND HAD
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Although no global, quantitative correlations have been established between axonal damage and neuronal apoptosis in HAD, there exists an obvious topographic correlation, which supports the view that axonal damage occurs secondary to local microglial activation or to systemic blood-derived factors (BBB compromise) [84
]. Significant structural and functional abnormalities in the microvasculature during HIV-1 CNS infection have been identified, including serum protein leak and alterations in capillary endothelial cells and basement membranes [86
, 87
]. Increased BBB permeability has been shown by increased levels of serum albumin, QA, metalloproteinases, and NO metabolites in the CSF of HIV-1-infected patients [87
88
89
]. In addition, the increased levels of neurotoxins found in the peripheral blood of patients with HAD are accompanied by signs of BBB compromise, as detected by neuroimaging techniques [28
]. Furthermore, antiretroviral therapy, which leads to a significant reduction in viral replication and toxin levels, results in improvement of BBB function, as determined by neuroimaging studies in vivo.
Although Dallasta and colleagues [68
] recently demonstrated significant disruption of tight junctions (TJ; providing structural integrity of BBB) in HIVE patients, we showed that expression of TJ and P-glycoprotein (which protects from toxins in peripheral blood) is diminished in parallel to the severity of HIVE [69
]. These findings prove the existence of structural and functional impairments in the BBB during HIV-1 infection, which may contribute to the development of HAD. Similar changes in occludin and ZO-1 expression were found in SIVE [90
], a relevant animal model for disease [91
]. Mankowski et al. [92
] found an inverse relationship between the severity of SIVE and expression of the endothelial glucose transporter 1 at the BBB in brains of infected macaques. Taken together, these data point to a functional-structural inter-relationship between two diverse systems within brain microvascular endothelial cells. Despite the longstanding notion that the BBB is impaired in HAD, how BBB dysfunction occurs is not well understood.
Mechanisms underlying TJ regulation associated with leukocyte migration are relevant for studies of structural integrity of the BBB during HIVE. An accumulating body of evidence suggests that small, dimeric G-proteins, such as Rho, can play a role in TJ disassembly in brain endothelial cells through activation of signaling pathways that regulate cytoskeletal organization [93
]. Given our in vivo observations (TJ down-regulation in HIVE) and current understanding of the role of Rho in cytoskeletal alterations in endothelial cells, we propose that Rho’s activation in brain endothelial cells is associated with monocyte brain egress and TJ compromise during HAD. To investigate the role of Rho in monocyte migration across brain endothelium, we used a functional BBB consisting of brain microvascular endothelial cells and astrocytes seeded on opposing sides of a porous membrane [25
]. Inhibition of the Rho pathway in brain endothelial cells resulted in TJ up-regulation and diminution of monocyte-transendothelial migration [94
]. Results of our experiments demonstrate that Rho signaling in brain endothelium plays a crucial role in the structural integrity of the BBB.
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ANIMAL MODELS FOR HIV-1 CNS INFECTION
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The importance of animal models for studies of pathogenesis cannot be overemphasized. To study neuropathogenesis of HAD, our laboratories developed an animal model system that reflects the biologic, immune, and pathophysiologic effects of HIV-1 replication in brain MP [95
96
97
98
99
100
]. Severe combined immunodeficient (SCID) mice, stereotactically inoculated in the basal ganglia/cortex with HIV-1-infected MDM (Fig. 1
,) demonstrate neurodegeneration and associated cognitive impairment related to macrophage/microglia activation [101
]. SCID mice were examined in the MWM (a system that relies on a rodent’s ability to apply spatial cues to complete a task) at 4, 8, and 15 days after injection with HIV-1-infected MDM, uninfected MDM, vehicle (sham), and unmanipulated controls. By day 8, mice in the HIV-1–MDM and MDM groups developed cognitive impairment, as evidenced by failure to acquire spatial information (Fig. 1A 1B
1C)
. Then, synaptic potentiation within the CA1 subregion of the murine hippocampal formation was measured (Fig. 1D)
; alterations in neuronal physiology and apoptosis were assessed; and expression of a neuronal synaptic marker (synaptophysin, SP) and neuronal axonal marker (NF) were evaluated. Impaired, synaptic potentiation in the hippocampal CA1 subregion was demonstrated at 8 and 15 days (Fig. 1E)
. By day 15, post-tetanic LTP was significantly decreased in mice injected with HIV-1 MDM (P<0.001) as compared with the two other groups: 212 + 7% (sham), 160 + 16% (MDM), and 116 + 4% (HIV-1 MDM). NF (Fig. 1 I
and 1K
) and SP antigens were decreased significantly in the CA1/2 hippocampal subregions of HIVE mice with limited evidence of neuronal apoptosis. These findings support the idea that HIV-1-infected and immune-competent brain macrophages can cause neuronal damage at distant, anatomic sites. It is important that the findings demonstrate the value of the model in exploring the physiological basis and therapeutic potential for HAD.
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Figure 1. SCID mouse model for HIVE: reproduction of cognitive abnormalities, neuronal dysfunction, and neuropathologic features of HIVE. Learning in the Morris Water Maze (MWM; A–C). Swim paths of untrained (A) and trained (B) mice are shown in hidden platform sessions in MWM. Spatial cognition was analyzed at 8 days after injection of HIV-1-infected MDM (MO) or sham inoculation with unmanipulated animals as controls (each group contained 12 mice). HIV-1–MDM mice demonstrated an inability to learn. Synaptic potentiation recorded in the CA1 hippocampal subregion at 6–8 days after HIV-1–MDM or sham inoculation (D and E). Hippocampi from mice injected with media alone (sham) and HIV-1-infected human MDM were analyzed. A stimulating electrode applied current to the Shaffer collateral pathway, and a recording electrode measured field potential in the CA1 region (D). Each point represents the initial slope of the falling phase of the evoked excitatory post-synaptic potentials (EPSPs) recorded from the CA1 dendrite field before and after high-frequency stimulation (HFS; 100 Hz, 0.5 s). Significant differences in synaptic potentiation were observed following HFS at days 6–8 (E). Morphological features of HIVE in SCID mouse brain tissue (F–I). Multi- and single-nucleated, vimentin-positive human MDM are present in basal ganglia (F). Most of these cells express HIV-1 p24 antigen (G). A pronounced and widely spread astrogliosis is detected by GFAP immunostaining in areas containing HIV-1-infected cells (H). Decrease in neurofilament (NF) staining in the CA2 region of hippocampus ipsilateral to the injection was found mice inoculated with HIV-1-infected MDM (I) and to a lesser extent, with uninfected MDM (J) as compared with sham-inoculated (K) animals. Original magnification, panels F and G, x200; I and K, x1000.
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These electrophysiologic observations have been confirmed in a recent study in the SCID–HIVE mouse model [102
]. Impaired synaptic function was detected through measuring synaptic responses induced by stimuli with different intensities. Paired-pulse facilitation (PPF) showed deficits in HIVE mice at days 3, 7, and 15. At day 3, PPF ratios were 1.13 ± 0.02 and 1.24 ± 0.04 in HIVE and sham. The induction and maintenance of LTP were also impaired in HIVE mice. The average magnitude of LTP was 131.23 ± 15.26% of basal in HIVE as compared with sham animals of 232.63 ± 24.18%. MDM-injected mice showed an intermediate response. Levels of the neuronal dendritic marker, microtubule-associated protein-2 (MAP-2), were assessed in the same animals. Reduced MAP-2 was observed in the HIVE animals at days 3 and 7. At day 15, the MDM group expressed MAP-2 at similar levels to that observed in sham animals, whereas the HIVE group showed reduced levels of MAP-2 immunoreactivity. This correlated, in part, with reduced numbers of viable human MDM. A range of neuronal synaptic transmission and plasticity changes in HIVE mice may reflect mechanisms of cognitive dysfunction in human HAD.
Although HIVE is likely a macrophage-mediated disease, there is no clear understanding of the relationship between the virus and clinical manifestations of HAD. The levels of virus in brain do not always correlate with the degree of neurological impairment [103
], and it was suggested that qualitative differences between viral strains might be important in development of dementia [104
]. Past reports of viral genome sequence analysis support the notion that CNS-specific or neurotropic forms of the virus exist [105
, 106
]. Yet, recent studies question this idea, demonstrating that viral sequences within specific CNS regions match, phylogenetically, with sequences found in the bone marrow [107
], which thereby supports the hypothesis that the virus could be carried into the CNS in hematogenously derived cells. Smit and colleagues [108
] demonstrated that viruses isolated from HAD patients were macrophage-tropic with consistent CCR5 use. They suggested that the appearance of primary macrophage-adapted isolates during HAD could be important in the development and progression of CNS–HIV-1 infection. It is possible that neurotropic variants exist, which may be governing the neurological manifestation of HIV disease.
One possibility is that specific strains of HIV-1 are more neuroinvasive than others. To address this question, we studied the "neurotoxic" features of divergent HIV-1 isolates in SCID mouse model of HIVE. MDM were infected with different virus isolates (HIV-1BAL, HIV-1JR-FL, HIV-1SF162, HIV-189.6, HIV-1DJV, and HIV-1ADA), and equal amounts of infected or uninfected cells were inoculated into mouse brains. The severity of encephalitis in SCID mice was determined by the microglial response to the presence of HIV-1-infected MDM. There was a direct relationship between the number of MDM in the given area and microgliosis. A three- to eightfold increase in microglial reaction was detected in mouse brains injected with MDM infected with HIV-1stains effectively replicating in MDM (ADA, BAL, DJV, JR-FL, and SF162) as compared with control, uninfected MDM. Levels of mouse TNF- were significantly increased in murine brains containing MDM infected with HIV-1BAL, HIV-1DJV, and HIV-1JR-FL but not in less effectively replicating strains (HIV-1SF162 or HIV-189.6). Furthermore, microglial reaction in brain tissue that received MDM infected with the slowly replicating HIV-189.6 was substantially lower as compared with the other viral strains (P<0.02) and not different from uninfected controls (P>0.6). In toto, neuropathologic analyses indicate that neuroinflammatory changes seen in the mice with HIVE are proportional to the number of MDM in brain and the ability of the given viral isolate to replicate in MDM [109
].
The ability to quantitatively evaluate neuropathological events in the SCID–HIVE model makes it suitable for further studies of pathogenesis and testing of adjunctive therapies for HAD. Indeed, SCID–HIVE mice treated with a PAF antagonist and a matrix metalloproteinase/TNF- release inhibitor showed a marked reduction in brain inflammation, astrogliosis, and microglial activation [97
]. These findings demonstrate that reduction of brain inflammatory responses, independent of viral replication, can affect HIVE pathology in an animal model.
Cellular reservoirs and anatomical sanctuary sites such as the CNS hamper penetration of HAART across the BBB allowing HIV-1 to persist. Therefore, development of new approaches to improve HAART (including novel drug-delivery systems) is necessary to increase efficacy of current drug therapies. To date, monitoring efficacy of HAART has generally been limited to changes in neuropsychological testing, monitoring of CNS inflammation, imaging of diseased brain, and measurements of viral load in the plasma and CSF. These tests, however, cannot directly measure what is occurring within an infected brain. Therefore, the use of animal models to monitor antiretroviral efficacy in the brain is crucial to screening antiretroviral and adjuvant (anti-inflammatory and neuroprotective) regimens [110
]. To these ends, we further modified the SCID mouse model and demonstrated spread of HIV-1 infection between human MDM in mouse brain tissue behind an intact BBB. These studies permitted comparative assessment of different antiretroviral drugs by measurements of viral load and numbers of infected human macrophages [99
, 100
]. In addition, neurotoxic effects of certain drug combinations were discovered [100
]. This information is essential for the current HAART regimens. New systems improving delivery of HAART across the BBB are currently under investigation in our laboratories.
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NEW FRONTIERS FOR STUDIES OF MONOCYTES, MACROPHAGES, AND HIV-1 NEUROPATHOGENESIS
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Despite current knowledge of HIV–MP interactions, little is known about the genetic factors that allow continued virus replication, BBB penetrance, and MP mobility. Based on these unresolved questions, our recent work was designed to use proteomics and enhanced imaging technologies to uncover the phenomic protein signature for circulating monocytes from HIV-1-infected patients with or at risk for HAD as well as that following productive viral replication in MDM. The technique of surface-enhanced laser desorption/ionization (SELDI)-time-of-flight (TOF) ProteinChip® technology is critical to these ends, as it couples the sensitive, analytical capabilities of mass spectrometry (MS) with novel surface chemistry, allowing high-throughput protein analysis of crude biological samples. The SELDI-TOF assays provide the ability to assess phenomic protein fingerprints of complex proteins as they are expressed in monocytes and HIV-1-infected MDM. The subsequent identification of macrophage-specific proteins was assayed by coupling proteolytic cleavage of the heterogeneous protein lysates with direct analysis of large protein complexes using the ThermoFinnigan ProteomeX system. This method couples traditional high-performance liquid chromatography (ion exchange and reverse-phase columns) with an ultrasensitive ion-trap MS and a software capable of rapid identification of proteins. The technology uncovered preliminary phenomic fingerprints from monocytes and macrophages recovered from infected people or after inoculation by HIV-1 in laboratory assays [21
, 22
, 111
]. Our data showed that a number of proteins from circulating monocytes are differentially expressed in patients who are cognitively impaired following HIV-1 infection. The data have potential importance, as they signify a distinguishable protein profile in cognitively impaired people and imply different functions of monocyte subsets. Moreover, the results provide further support for the hypothesis that circulating monocytes may play an important role in the onset and progression of HAD. A modification of our SCID mouse model of HIVE [95
, 112
] allowed an analysis of monocyte movement throughout the brain in the setting of immune activation and peripheral immune compromise. These tests were performed to more closely mimic virus host-cell interactions as they would occur in an infected person during the progression of cognitive impairment. Using SCID mice as a testing system we next followed the distribution of monocytes/macrophages in the brain. In these studies, superparamagnetic iron oxide-labeled human monocytes were followed in mouse brain [27
] by enhanced magnetic resonance imaging (MRI) techniques. MRI and histological confirmation methods were used in parallel in our assays to track cell movement into and throughout the brain and have been applied to studies of other neurodegenerative disorders [113
]. Using this technology, it was demonstrated that MDM migrate through the ventricular system, corpus callosum, and throughout the brain. The proteomics and MRI approaches open new investigations for studying cellular biodynamics and its relationship to HIV-1 neuropathogenesis.
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CONCLUSION
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A significant amount of data has accumulated regarding HAD pathogenesis over the last two decades. Despite the diminished incidence of HAD since the introduction of HAART, the greater life expectancy of infected individuals and epidemiologic data suggest that the prevalence is on the rise. The initial hypothesis proposing the importance of immune activation of brain MP was confirmed and further extended by discoveries of a number of neurotoxic factors secreted by MP and pathways through which these substances cause neuronal damage (Fig. 2
). Involvement of acquired immune responses, totally overlooked in initial works, appears to be important in explaining the evolution of HAD and providing additional clues to how MP become activated. New methodologies (proteomics and neuroimaging) are available to further explore unique protein profiles of monocytes from HAD patients and to study cell trafficking into the CNS in relevant animal models for HIVE. Studies of mechanisms underlying monocyte migration across the BBB will allow development of new therapeutic strategies to prevent HAD. New systems improving delivery of HAART and adjunctive therapies across the BBB are under investigation.
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Figure 2. Overview of the pathobiological events underlying the neurodegenerative processes in HAD. During the process of monocyte-macrophage differentiation, the cells acquire the ability to become productively infected by HIV-1. Peripheral activation causes the differentiating macrophages to produce a variety of immune products that lead to the up-regulation of adhesion molecules on brain microvascular endothelial cells and the expression of adhesins on the monocyte-macrophage cell surface. Adhesion of blood-derived monocytes to the endothelium is a critical step for the transendothelial migraion of the cells into the brain. After penetration of the BBB, the differentiated brain MP and microglia can be vehicles for viral dissemination throughout the brain and focal points for productive viral replication. The neurotoxic events in the brain are caused as a consequence of secretory neurotoxins produced by MP. Brain MP are primed by HIV-1 and secondarily activated by factors such as immune stimuli (proinflammatory cytokines, AA, and CD40L among others) or by T cells trafficking through the nervous system. The primed and immune-activated brain MP secrete a variety of factors (cytokines, chemokines, platelet-activating factor, QA, glutamate, and to a lesser extent, NO), which affect neural and glial function and lead to CNS inflammation. A proinflammatory cytokine response (TNF-, IL-1ß, and IL-6 among others) from blood-derived MP, microglia, and astrocytes inventiably becomes amplified (by autocrine and paracrine mechanisms) and leads ultimately to neurodegeneration. Immune neurotoxic factors may contribute to the breakdown of the BBB and affect the generation of a chemokine gradient, leading to transendothelial migration of monocytes into the brain perpetuating the inflammatory cascade. Resulting from the neurotoxic activities of activated MP, astrocytes may suppress or increase MP secretory functions and toxicity depending on their own functional status. Not pictured here are the cytolytic T lymphocytes, which serve to eliminate infected cells but in late-stage disease, are lost, allowing the virus-induced, neurodegenerative response to continue unabated. QUIN, QA; TRAIL, TNF-related apoptosis-inducing ligand; MHC II, major histocompatibility complex type II; MIP-1, macrophage-inflammatory protein-1; Rantes, regulated on activation, normal T expressed and secreted; I-CAM-1, intercellular adhesion molecule-1; VCAN, vascular cell adhesion molecule.
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ACKNOWLEDGEMENTS
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This work was supported in part by NIH grants RO1 MH 65151-01 (to Y. P.) and RO1 NS1316127-01 (to H. E. G.). We thank Ms. Robin Taylor for excellent editorial support and Drs. Anuja Ghorpade and Jenae Limoges for critical reading of the manuscript.
Received May 7, 2003;
revised July 8, 2003;
accepted July 9, 2003.
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ABSTRACT
INTRODUCTION
