Animal models represent essential tools for dissecting the molecular mechanisms of CD4+ T-lymphocyte depletion, a process central to immunopathogenesis in HIV-1-infected humans. The goal of this application is to increase our understanding of primate immunodeficiency virus replication and pathogenicity, using chimeric viruses containing genetic segments of HIV-1 (tat, rev, vpu and env) in an SIV/mac background. Infection of macaques with certain of these simian-human immunodeficiency viruses (SHIVs) resembles HIV-1 infection of humans in the course of acute viral replication as well as in the elicitation of cellular and humoral immune responses. Moreover, some SHIVs cause rapid and specific CD4+ T-lymphocyte depletion in monkeys, with subsequent development of AIDS-like illnesses and death. Molecularly cloned SHIVs that replicate efficiently in rhesus macaques but differ in CD4-depleting ability have been identified and studied. Our results indicate that the exterior domains of the HIV-1 envelopes glycoproteins determine the efficiency with which CD4+ T-lymphocytes are depleted in the animals, independently of effects on virus replication in vivo. Two phenotypes have been identified for the more pathogenic env segments: increased ability to mediate membrane fusion and resistance to neutralizing antibodies.
The specific aims of this proposal are: 1. To identify the HIV env sequences associated with increased fusogenicity and with neutralization resistance, and to determine which of these phenotypes is more critical for CD4+ T-lymphocyte-depleting ability in SHIV-infected macaques. 2. To determine whether the HIV-1 envelope glycoprotein fusogenic capacity per se contributes to rapid CD4+ T-lymphocyte-depleting ability, independently of effects on SHIV replication in vivo. 3. To determine whether syncytium formation contributes to rapid CD4+ T-lymphocyte depletion in SHIV-infected macaques. 4. To evaluate the in vivo role of the HIV-1 specific Vpu protein in acute SHIV replication and CD4+ T-lymphocyte depletion.
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