It has recently been reported that the rate at which T-cells in HIV-1 infected individuals are replaced may reach 1 billion per day. The mechanisms by which T-cells are killed are therefore of paramount importance, since a slight advantage in the ratio of living to dying T-cells might significantly alter the course of the disease. Cell death may be caused directly by the virus infecting the cell or indirectly by the results of virus infecting other cells. A major form of cell death in T-cells is Fas- mediated apoptosis, and evidence suggests that apoptosis in AIDS patients is at least in part Fas-mediated. We have developed a model of HIV-induced cell death in which expression of the viral envelope protein, gp160 in cultured lymphocytes, greatly enhances Fas-mediated apoptosis. This enhancement is apparently calmodulin dependent, since it correlates with calmodulin expression and can be interdicted by calmodulin inhibitors. Our goal is to identify the mechanisms by which gp160 enhances Fas-mediated apoptosis. To that end our specific aims are: Determination of the Ca2+ calmodulin signal transduction pathways utilized in gp160 enhanced Fas-mediated apoptosis. Determination of the points in Fas signaling pathways which are necessary for gp160 enhancement of Fas-mediated apoptosis; and identification of the molecular determinants of gp160 that are responsible for enhanced Fas- mediated apoptosis.
