The level of CD4 T cells in HIV infected individuals have been historically used as an immunologic measure their progression to AIDS. Similarly, SIV infected Rhesus macaques also show a drop in CD4 T cells level as a predictor to advanced disease. However, SIV infected African non-human primates (natural hosts) generally do not progress to simian AIDS and maintain healthy CD4 T cells levels. Interestingly, in some SIV infected natural hosts and some HIV+ patients even a significant drop in CD4 levels has not lead to disease progression. Our laboratory has been monitoring a cohort of SIV infected sooty mangabeys (CD4-low) which have exhibited dramatic loss in CD4 T cells to levels associated with AIDS in humans or SIV+ macaques, yet still remain free of simian AIDS. A significant observation seen in these animals is that the SIV+ CD4-I0W could mount antigen specific immune responses in the absence of CD4 T cell help. Previous research from the Sodora Lab has demonstrated that all mangabeys, including the CD4-low animals, contain a higher level of CD3+/CD4-/CD8- (double negative) T cells compared to humans;and that these cells are not infected by SIV. We hypothesize that the double negative T cell population (CD3 +/CD4-/CD8-) has the ability to compensate for the CD4 T cell loss during SIV infection of sooty mangabeys. This study is designed to examine the role of double negative T cells during SIV infection in natural hosts (sooty mangabeys) and pathogenic hosts (Rhesus macaques). Aim 1 will characterize double negative T cells by flow cytometry and real time PCR to see if they resemble CD4, Cd8 or NKT cells. Aim 2 is designed to assess the double negative cells functionally by their cytokine profile upon stimulation and their capacity to functionally interact with B cells. The discovery and characterization of this double negative T cell subset with the ability to function like CD4 T cells, without becoming infected with SIV/HIV, might provide important insights to develop improved vaccine formulations or immune therapeutics. PUBLIC HEALTH RELEVANCE: HIV and SIV infections infect host CD4 T cells, leading to AIDS. The role played by other immune cells which do not become infected and may compensate for the CD4 T cell would yield significant clues about battling this disease.