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. This project focuses on understanding the reasons why natural hosts for Simian Immunodeficiency Virus infection, such the African monkey species sooty mangabeys (SMs), in striking contrast to what happens in HIV-infected individuals, are not susceptible to AIDS despite being infected with a virus that replicates continuously and at very high levels. We previously showed that CCR5 expression is significantly lower in CD4+ T cells of SMs when compared to humans and macaques. In the work conducted in the past year, which is now submitted for publication, we found that, after in vitro stimulation, SM CD4+ T cells fail to up-regulate CCR5 expression, and that this phenomenon is more evident in CD4+ central-memory T cells (TCM). The same disconnection between activation and CCR5 up-regulation was observed in vivo in SMs during acute SIV infection and in the phase of CD4+ T cell proliferation that follows antibody-mediated depletion of these cells. Remarkably, this low CCR5 expression on CD4+ TCM is associated with an approximately 20-fold reduced susceptibility to SIV infection in vivo. These data suggest that reduced CCR5 expression on SM CD4+ TCM protects these cells from SIV infection, thus favoring the preservation of CD4+ T cell homeostasis and an AIDS-free status in SIV-infected SMs. We are hopeful this data will pave the way to new therapies for HIV infection.