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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-AARR-H (22))
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Sanders, Brigitte E
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Seattle Biomedical Research Institute
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Sundaravaradan, Vasudha; Saleem, Ramsey; Micci, Luca et al. (2013) Multifunctional double-negative T cells in sooty mangabeys mediate T-helper functions irrespective of SIV infection. PLoS Pathog 9:e1003441
Sundaravaradan, Vasudha; Mir, Kiran D; Sodora, Donald L (2012) Double-negative T cells during HIV/SIV infections: potential pinch hitters in the T-cell lineup. Curr Opin HIV AIDS 7:164-71
Durudas, Andre; Chen, Hui-Ling; Gasper, Melanie A et al. (2011) Differential innate immune responses to low or high dose oral SIV challenge in Rhesus macaques. Curr HIV Res 9:276-88