DETERMINANTS OF NATURAL HOST RESISTANCE TO SIV AGM

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Despite significant progress in identifying important mechanisms underlying HIV-1 pathogenesis, the role of host and viral factors contributing to progression to disease are still poorly understood. There is growing evidence supporting the hypothesis that differences in HIV/SIV co receptor usage, and the host response to early infection are critical determinants of HIV-1 transmission and AIDS pathogenesis. The natural host species for SIV displays an unusual feature; lack of SIV-induced AIDS. A major focus on this proposal is to develop a differential model for pathogenesis. SIVagm infection in African green monkeys (Agms) does not result in clinical disease however, infection of pigtailed macaques (Ptm) results in classical T cell depletion and AIDS. Like HIV-1, most SIVagm and SIVsm strains utilize CD4 and CCR5 for viral entry, thus targeting these cells for infection and killing. In this application, we propose to: 1. Determine if host-specific differences in receptor/coreceptor expression at anatomically relevant sites of viral replication are a factor in the differential pathogenesis of SIVagm. 2. Determine if SIVagm strains with broader cell tropism (R5X4) will alter pathogenesis in Agm and Ptm. 3. Determine if host-specific differences in cellular immune responses at anatomic sites for viral replication are a factor in SIVagm pathogenesis. In summary, this proposal seeks to understand the role of coreceptor expression, viral replication and cellular immunity in the pathogenesis of SIV.