Grant: Operating Grant - PA: HIV/AIDS Bridge Funding - Biomedical/Clinical Stream

Impaired cytotoxic T-cell (CTL) activity and altered thymic function likely contribute to progression of HIV disease but the reasons for this remain to be established. Interleukin (IL)-7 signaling is essential for both CTL and thymic function and recent findings in our laboratory implicate a role for the regulation of the IL-7 receptor alpha (CD127) in the immunopathogenesis of HIV infection. We have shown that a soluble form of CD127 (sCD127) is released by CD8+ T-cells and demonstrated that sCD127 can inhibit IL-7 activity in vitro. In addition, we have detected sCD127 in human plasma and found that it is increased in HIV infection. The proposed work will investigate the mechanism(s) by which sCD127 is released by CD8+ T-cells and thymocytes and its role in HIV infection in vitro. We will also examine the whether SIV infection of rhesus macaque monkeys (a model of HIV infection), antiretroviral therapy of infected animals and/or IL-7 therapy influence the expression of sCD127. Lastly, we evaluate the functional role of sCD127 in vivo using a mouse model of Listeria monocytogenes infection, experiments that will logically lead to further in vivo experiments that model HIV infection. Regulation and/or function of sCD127 may be important in explaining HIV-associated immune dysfunction and, if so, determining the mechanism(s) involved will lead to a better understanding of HIV immunopathogenesis and may lead to the development of novel immune-based therapies.