NATURAL HOST RESISTANCE TO SIVAGM INDUCED DISEASE

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Simian immunodeficiency viruses in African green monkeys (SIVagm) constitute an important resource for studing host resistance to naturally- occuring viruses. While the cytopathic phenoty[e of the virus, cell and tissue tropism, viral load, host immune responses and host genetic factors are all thought to be associated with progression to AIDS, very little is s ll known concerning natural resistance to disease for lentiviral infections of african nonhuman primates. The SIV agm model will be used to define viral and host determinants of natural resistance to disease and to directl assess viral heterogenceity and the expected rated of variation of boh the natural and unnatural host to be better understand viral evolution. In this propodal, the specific aims are as follows: 1. To compare the viral load present in both naturally infected African green monkeys and experimentally infected pigtailed macaques. Viral load is an important marker for disease progression in humans and is postulated to reflect the level of cell killing, turnover, and immune depletion. Preliminary evidenc suggests that the viral load in naturally infected african monkeys is high without clinical disease suggesting fundamental differences in viral pathogenesis. We will define temportal variation in virral load as a function of CD4 munber and disease state. 2. To define and compare viral heterogeneity and viral evolution in the natural and unnatural host species We will use heteroduplex mobility assays (HMA) to first address the range of complexity within plasma virus. We will then select individual samples for direct sequencing to study viral variation in plasma, PBMC and tissue compartments. The study of accumulation rates of non-synonymous to synonymous substitutions may provide important clues in the understanding of co-evolution of virus and host and the lack of pathogenicity. 3. To examine the cytopathic nature of SIVagm in the natural and unnatural hosts. Deifferences in pathogenesis in the natural host may coincide with differences in the ability of SIVagm to induce cytopathology in susceptible cells. Beta-chemokine receptors are thought to function as co-receptors fo viral entry and in part may define cell and tissue tropism. The study of c receptor usage among SIVagm viruses may aid in understanding differential pathogenicity of HIV and SIVagm. 4. To further investigate a pathogenic animal model for SIVagm infection. We will further refine and define the SIVagm pathogenic model in pigtailed macaques. Emphasis will directed toward the study of tissue-specific variants of SIVagm and their role in th disease process.