MECHANISMS OF CELL LOSS IN HIV INFECTIONS

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The objectives of this proposal are to examine the mechanisms of cell-mediated killing of autologous lymphocytes among persons infected by the human immunodeficiency virus (HIV), and to determine if levels of autocytotoxicity are associated with or predict the clinical outcome of HIV infection. HIV infection results in expansion and activation of several populations of cytotoxic lymphocytes. Although some of these cytotoxic lymphocytes may kill HIV infected cells, we hypothesize that some activated cytotoxic lymphocytes participate in dysregulated destruction of uninfected autologous lymphocytes and result in progressive lymphopenia and immune deficiency. We will first characterize the activation signals, effectors, targets and cytolytic mechanisms of the alloantigen-induced, CD8 lymphocyte-mediated killing of autologous lymphocytes that we have observed among HIV-infected persons. Concurrent experiments will help us ascertain if autologous killing mechanisms can be dissociated from the mechanisms of killing of allogeneic cells by sensitized lymphocytes of healthy controls. We will next determine if lymphokine activated killer (LAK) cells also participate in the destruction of autologous lymphocytes in HIV-infected persons. If this is the case, we will characterize the activation signals, effectors, targets and mediators of this killing mechanism. Concurrent experiments will help us determine if mechanisms of autologous killing by LAK cells can be dissociated from the mechanisms of tumor killing by these cells. Our second specific aim is to determine the relationship between the levels of autocytotoxicity in HIV-infected persons to the clinical manifestations of HIV infection. Using one or more assays of autocytotoxicity selected on the basis of the above studies, we will examine the association between levels of cytotoxic activities to the stage of HIV infection in a cross- sectional study and to the outcome of HIV infection in a three year longitudinal study. The results of these studies may provide a better understanding of the pathogenesis of immunodeficiency in AIDS. They also may provide direction to strategies aimed at preventing the development of immunodeficiency after infection with HIV.