In stark contrast to HIV infection in humans, natural SIV infections of African non-human primates are typically nonpathogenic despite similarly high virus replication. While the mechanisms underlying this strikingly different outcome are still largely unknown, a consistent feature of natural SIV infections is the lack of chronic immune activation. In HIV-infected humans, loss of mucosal immunity and microbial translocation from the intestinal lumen to the systemic circulation contribute to chronic immune activation and disease progression. In a series of recent studies, we have shown that pathogenic HIV and SIV infections of humans and rhesus macaques (RMs) are associated with preferential depletion of mucosal CD4+ Th17 cells, a T helper cell population deemed critical for the maintenance of mucosal barrier integrity and the production of anti-microbial molecules. Remarkably, this depletion of mucosal Th17 cells is not observed during natural, nonpathogenic SIV infection of sooty mangabeys (SMs), a natural host species. The overarching Aim of this project is to identify the mechanism(s) responsible for the different regulation of mucosal Th17 cells in pathogenic and nonpathogenic lentiviral infections. We will test the following non-mutually exclusive hypotheses to explain why Th17 cells are preserved in SIV-infected SMs but not in HIV-infected humans or SIV-infected RMs: (i) Th17 cells are more resistant to direct virus infection [Aim 1];(ii) Th17 cell renewal and/or differentiation are more effective in maintaining Th17 homeostasis [Aim 2];(iii) Th17 cell homing to mucosal tissues is better preserved [Aim 3]. Elucidation of the mechanisms underlying the preservation of Th17 cells in SIV-infected SMs may provide fundamental insights on how these animals have evolved to preserve mucosal immunity upon infection and thus become AIDS resistant. We believe that this information will be relevant to the design of an AIDS vaccine that will confer protection from the HIV-associated mucosal immune dysfunction. We recently showed that pathogenic HIV/SIV infections of humans and rhesus macaques are associated with preferential depletion of mucosal CD4+ Th17, a cell population deemed critical for mucosal immunity, whose severity correlates with the levels of chronic immune activation and disease progression. Remarkably, Th17 cells are preserved at a healthy frequency during nonpathogenic SIV infection of sooty mangabeys. The overarching Aim of this project is to identify the mechanism(s) responsible for the different regulation of mucosal Th17 cells in pathogenic and nonpathogenic lentiviral infections. The elucidation of these mechanisms may provide fundamental insights on the pathogenesis of the HIV/SIV-associated mucosal immune dysfunction. We believe that this information will ultimately inform the design of an AIDS vaccine that will confer protection from HIV transmission and disease progression.