The SIV Model of HIV-associated Dementia

Dianne M. Rausch<sup>1

1</sup>Center for Mental Health Research on AIDS, National Institute of Mental Health
6100 Executive Blvd., Room 6212, MSC 9623, Bethesda, Maryland 20892-9623; USA
E-mail: [email protected]

Keywords: animal model, neuropathogenesis, HIV-associated dementia, SIV.

Q: What is the value of the SIV Model of HIV-associated dementia?
HIV-associated dementia (HAD) refers to a spectrum of progressive cognitive and motor abnormalities of the central nervous system (CNS) resulting from HIV infection (1). HAD eventually develops in about 15-30 percent of infected patients (2). While the advent of highly active antiretroviral therapy (HAART) has dramatically decreased the death rate from AIDS, its impact on HAD is less clear. Most of the medications in this combination therapy have poor penetration into the CNS (3). While it appears that, at least in some cases, treatment with HAART results in improvements in HAD and significant decreases in plasma viral load (4)(5), some evidence suggests that HAART is less effective for HAD than for other AIDS-defining diseases (6). The neuropathogenesis of HAD is not well understood, in part because it cannot be readily studied in humans. Yet insights about pathogenic mechanisms are crucial to improved drug targeting and prevention strategies.

The simian immunodeficiency virus (SIV) model of HAD is widely considered the preeminent animal model in which to study the neuropathogenesis of HAD. Rhesus monkeys infected with SIV become immunosuppressed and display neuropathological (7)(8) and behavioral (9) features resembling those in HIV-infected humans. SIV is genetically, antigenically and morphologically close to HIV (10). The principal targets of SIV infection, like those of HIV, are monocytes and lymphocytes (11). There is evidence of HIV infection of astrocytes (12). SIV and HIV also infect brain capillary endothelial cells in vitro (13)(14), and there is evidence of SIV infection of these cells in vivo (15), although the latter finding is more controversial. The major advantage of the SIV model is that it permits sacrifice of animals, and thus access to CNS tissue, at any point during disease progression (9). In contrast, human HIV-infected CNS tissue is only available post-mortem. Another advantage of the model is the elimination of treatment-related effects. The major difference between SIV- and HIV-infection is that the former is more rapid in its progression (16), yet this very feature makes the model advantageous for research. Although the principal drawback of using rhesus monkeys for research is their expense, the SIV model has the potential to answer some key questions about HAD neuropathogenesis presented below.

Q: What are the mechanisms of HIV trafficking into the central nervous system?
It is generally agreed that microglia/macrophages (MG/MP) are the sites of productive infection within the CNS, but the mechanisms of viral entry into the CNS are still debated (17)(18). One of the foremost mechanisms of entry is thought to be through trafficking of HIV-infected lymphocytes or monocytes, the so-called Trojan Horse hypothesis, although several other mechanisms are possible (19).

Studies with the SIV model have shown that neuroinvasion across the blood brain barrier (BBB) is dependent on host factors and viral strain (20). Neuroinvasive strains yield a higher number of perivascular macrophages (derived from monocytes) in the CNS (21). The infiltrating cells in encephalitic vs. non-encephalitic brains of SIV-infected macaques display increased expression of several chemokines and corresponding chemokine receptors (22). Since chemokines serve as potent chemoattractants, this suggests that normal monocyte trafficking into the CNS is enhanced in HAD through upregulation of chemokines and their receptors. The roles of specific cell types and the mechanisms through which upregulation occur have been the subject of theoretical models (22), as well as in vitro studies. With an artificial BBB using co-cultures of endothelial cells and astrocytes, the astrocyte-derived chemokine, monocyte-chemoattractant protein-1 (MCP-1), appears to play a vital role in causing enhanced migration of leukocytes across the BBB (23). This process, which appears to be under the influence of the viral protein tat (24), may also include upregulated expression of adhesion molecules on endothelial cells (25). A major advantage of the SIV model is the ability to determine the in vivo relevance of in vitro findings about mechanisms of viral entry.

Q: What are the functional consequences of HIV infection in the central nervous system?
According to the prevailing model of HAD pathogenesis, neuronal dysfunction and death are the result of indirect mechanisms of neurotoxicity, namely excessive local concentrations of soluble neurotoxic factors released by infected MG/MP or astrocytes, or viral components (18)(26). The indirect model of HAD is the only way to account for neurotoxicity and death in the absence of productive HIV infection of neurons. Findings from the SIV model have substantiated the indirect model of HAD and have established early neurochemical markers of toxicity that correlate with the onset of behavioral impairment. These markers include quinolinic acid in macrophages, glial fibrillary acidic protein in astrocytes, and somatostatin in neurons (27). The SIV model also has uncovered an early electrophysiological marker—a delay in sensory evoked potentials—that precedes the onset of behavioral impairments (28). Identification of neurochemical or electrophysiological markers has tremendous utility for monitoring the efficacy of new strategies for treatment of HAD. These strategies are emerging from in vitro studies showing that prevention of neurotoxic damage can be achieved by blocking chemokine or NMDA receptors on neurons. Interaction with these receptors is the first step by which soluble factors from HIV-infected cells mediate abnormalities in neuronal signaling and apoptosis (29)(30).

Q: Is there a reservoir of HIV-infected cells in the CNS and what is its physiological significance?
Peripheral tissues contain viral reservoirs of latently infected, resting T-cells that are resistant to HAART (31). If activated, these reservoirs present serious consequences for controlling HIV. In the CNS, the existence of a reservoir of HIV-infected MG/MP is difficult to verify but widely assumed because HIV penetrates into the CNS soon after infection yet symptoms may not become manifest until years later (18). A CNS reservoir is considered even more refractory to treatment than are peripheral reservoirs because of poor treatment penetration across the BBB. A CNS reservoir may eventually account for an increase in HAD incidence among individuals now living longer (3). Moreover, evidence from the SIV model also suggests that a CNS reservoir may be responsible for reemergence of systemic infection via trafficking of infected cells from the CNS into the peripheral circulation (20). The possibility of a CNS reservoir contributing to peripheral disease has been overlooked, and thus represents a critical area of inquiry. Much needs to be learned about viral clearance (14) and the trafficking of distinct immune cells types into and out of the CNS with normal physiology and HIV infection (32). The SIV model is beneficial for studying the roles of a CNS reservoir and the types of cells infected through the ability to control viral type and time of inoculation and to evaluate the impact via bodily fluid sampling, peripheral tissue biopsy, behavioral assessment, and CNS tissue pathology.

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