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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AI084556-03
Application #
8307934
Study Section
Special Emphasis Panel (ZRG1-AARR-H (22))
Program Officer
Sanders, Brigitte E
Project Start
2010-08-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$57,734
Indirect Cost
Name
Seattle Biomedical Research Institute
Department
Type
DUNS #
070967955
City
Seattle
State
WA
Country
United States
Zip Code
98109
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