|NeuroAids Vol. 2, Issue 11 (December 1999)|
The SIV Model of HIV-associated Dementia
Dianne M. Rausch1
Q: What is the value of the SIV Model of HIV-associated dementia?
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
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?
Q: Is there a reservoir of HIV-infected cells in the CNS and what
is its physiological significance?
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