APOPTOTIC CELL-DEATH UPON CONTACT OF CD4(-LYMPHOCYTES WITH HIV GLYCOPROTEIN-EXPRESSING CELLS IS MEDIATED BY CASPASES BUT BYPASSES CD95 (FAS() T)APO-1) AND TNF RECEPTOR-1/

Loss of CD4(+) T helper lymphocytes is central to the development of i mmunodeficiency after infection with HIV. In this study, we demonstrat e that contact of primary uninfected CD4(+) T lymphocytes with HIV-inf ected or HIV envelope glycoprotein-expressing cells results in apoptot ic cell death of both uninfected and infected cells. Apoptosis was blo cked by inhibitors of caspases/IL-1 beta-converting enzyme-like protea ses. This finding provides conclusive evidence that cytotoxicity upon contact of HIV-infected and uninfected primary cells is an active proc ess and represents another example for the role of caspases in the ind uction of apoptosis. Prevention of apoptosis by inhibition of caspases did not block the formation of syncytia, indicating that apoptosis oc curs either in a subpopulation of cells or of syncytia. Cell death was not mediated by the CD95 (Fas/Apo-1) or TNF receptor 1 molecules, whi ch indicates a different pathway of apoptosis induction. The data indi cate that initiation of apoptosis significantly shortens the life span of uninfected CD4(+) T cells upon contact with HIV-infected cells and may represent a factor that contributes to the destruction of CD4(+) T lymphocytes in vitro. Elucidation of the mechanism that initiates ap optosis in this situation will add to our understanding of both HIV pa thogenesis and apoptotic signaling.