This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In contrast to HIV infection in humans, natural SIV infections of African nonhuman primates are typically non-pathogenic 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. Recently, 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 critical for the maintenance of mucosal barrier integrity and 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 Aim of this project is to identify mechanism(s) responsible for the regulation of mucosal Th17 cells in pathogenic and nonpathogenic infections. We will test the following 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 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]. 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.
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