Although cytotoxic CD8+ T cells (CTL) play an important protective role during HIV infection, a number of studies have suggested that these cells may suffer from functional defects that impair their efficiency in controlling HIV virus. Studies from our laboratory have revealed that HIV-specific CD8+ T cells exhibit increased susceptibility to CD95/Fas-induced apoptosis and that HIV-infected macrophages can kill HIV- specific CD8+ T cells by a CD95/Fas-dependent mechanism. In addition, HIV-specific CD8+ T cells lack terminal differentiation and CD95/Fas apoptosis may be involved in this skewing of differentiation. The ability of HIV-specific CD8+ T cells therefore to kill infected cells and their differentiation may be compromised due to CD95/Fas-mediated apoptosis of these cells. Recently, we have found a decrease in the anti-apoptotic molecules Bcl-2 and Bcl-xL in HIV-specific CD8+ T cells, and this may account at least partially for their increased apoptosis sensitivity. Interleukin 15 (IL-15) we found can inhibit CD95/Fas- mediated apoptosis of HIV-specific CD8+ T cells and can restore the levels of Bcl-2 and Bcl-xL in these cells. Based on our findings we hypothesize that an imbalance of pro- and anti-apoptotic factors combined with increased mitochondria! mass and a pro-apoptotic CD95/Fas signaling pathway result in the apoptosis sensitivity of HIV-specific CD8+ T cells. We hypothesize that IL-15 inhibits CD95/Fas-mediated apoptosis of HIV-specific CD8+ T cells by acting at a very early step of CD95/Fas death receptor signaling. In the current proposal we will investigate the molecular mechanism(s) involved in the increased apoptosis sensitivity of HIV-specific CD8+ T cells and how IL-15 inhibits this apoptosis. Understanding the mechanism behind this defect of HIV-specific CD8+ T cells may allow for the restoration of survival or function of HIV- specific CD8+ T cells which in turn would have a profound effect in controlling or clearing HIV. Finally, such an understanding will be critical for the development of vaccines that provide long lasting CTL immunity. Lay language description: These studies will investigate why immune cells that can kill HIV infected cells are sensitive to dying and ways to increase the survival and function of these cells. These killer cells play a critical role in controlling HIV infection therefore increasing their survival would benefit patients with HIV infection. These studies may lead to new treatments for HIV infection a serious public health problem.