Abstract: This proposal and progress report are intended to continue the work started in R37 AI066998. In the next funding cycle, we plan to expand this work in three broad areas that are outlined below. Area #1. To define the molecular mechanisms responsible for the differences in the pattern of infected cells between SIV-infected SMs and SIV-infected macaques and/or HIV-infected humans. Area #2. To characterize the relationship between the specific pattern of infected cells observed in SIV- infected SMs and their ability to avoid the chronic Immune activation of pathogenic HIV/SIV infections. Area #3. To determine how the SM-specific pattern of infected cells results in different features of the virus reservoir under anti-retroviral therapy (ART). We believe that these studies will advance significantly our understanding of how naturally SIV-infected SMs are resistant to AIDS despite high viremia. We envision that answering this question will provide clues to AIDS pathogenesis in humans that will have ultimately an impact on the prevention and treatment of HIV infection. RELEVANCE (See instructions): Sooty mangabeys do not progress to AIDS despite being naturally infected with SIV, a virus closely related to HIV. The proposed studies are aimed at understanding why the sooty mangabeys are able to remain healthy when infected with SIV. We believe that these studies will improve our comprehension of AIDS pathogenesis in humans and that this knowledge will ultimately translate in better prevention and therapies fnr thfi infection