HIV pathogenesis is characterized by dynamic changes in T-cell populations. While population abnormalities have been clearly documented in CD4 T-cells, less information is available on CD8 T-cells and on their part in HIV infection. CD8 T-cells play a critical role in the control of HIV replication by their cytotoxic activity and by the release of soluble inhibitors of HIV replication. During HIV infection, CD8 T-cells undergo increased apoptosis, demonstrate accelerated turnover (as reflected by telomere shortening), and decrease substantially in number late in the infection process. CD8 T-cells also represent the majority of infiltrating cells present in the lungs of HIV-infected patients with lymphocytic interstitial pneumonitis and are therefore likely to be involved in this disease process. Because of their important role in the control of HIV infection, we are investigating the effects of HIV infection on the differentiated functions and survival of CD8 T-cells. We recently observed that the HIV envelope protein, gp120, exerts indirect cytopathic effects on CD8 T-cells during infection of peripheral blood mononuclear cells (PBMCs) in vitro. HIV-mediated CD8 T-cell killing was macrophage-dependent and occurred as a result of signaling by HIV envelope protein via a chemokine receptor (CXCR4) on CD8 T-cells. Here we propose to expand on these observations and to explore the spectrum of CD8 T-cell modifications that occurs as a result of HIV infection. Our specific goals are: (1) To define the molecular mechanism of induction of CD8 T-cell apoptosis by the HIV envelope emphasizing the role of CD4 T-cells in chemokine signaling by gp120; (2) To identify the gp120 determinants that are critical for CD8 T-cell apoptosis and particularly gp120 presentation and role of other HIV chemokine coreceptors; (3) To define the role of chemokines and CD8 T-cells in HIV-induced lymphoid interstitial pneumonitis with a particular emphasis on the role of gp120 as a chemotactic factor responsible for the recruitment of CD8 T-cells to the lungs; (4) To define the full spectrum of phenotypic alterations induced by HIV envelope protein in CD8 T-cell differentiated functions (changes in mRNAs expression, chemotaxis, cytolytic activity, chemokine release). We anticipate that these experiments will further our understanding of the immune dysfunction that occurs during HIV infection with a particular emphasis on CD8 T-cells and their involvement in the pathogenesis of lymphocytic interstitial pneumonitis and the control of HIV infection.
