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To investigate the role of the Fas–Fas ligand (FasL) interaction in HIV-1-induced apoptosis of primary CD4+ T lymphocytes.Activated CD4+ T lymphocytes are the main target of HIV, and T-cell activation leads to the expression of Fas–FasL and enhances HIV-mediated apoptosis. Phytohemagglutinin-activated primary CD4+ T cells were infected with HIV; the process of cell death was examined, and whether the dying and dead cells were the productively infected cells. The modulation of Fas and FasL expression and its role in HIV-induced cell death was also investigated.The number of viable and dead cells was determined by trypan blue exclusion. Apoptosis was quantified using an enzyme-linked immunosorbent assay measuring the release of cytoplasmic histone-associated DNA fragments. The percentage of HIV-infected cells was determined by FACS analysis, and viral production was assessed by a p24 core antigen assay. The following three markers, HIV-gp-120, annexin-V and 7-AAD, were used to monitor the apoptotic process in HIV-negative and positive cells. Fas and FasL expression was analyzed at the RNA level by reverse transcription polymerase chain reaction and at the protein level by flow cytometry. The contribution of Fas–FasL interactions to apoptosis was examined by blocking experiments using the antagonist ZB4 anti-Fas antibody.HIV-induced apoptosis in activated purified CD4+ T lymphocytes required infectious virus and was dose-dependent. Apoptosis in HIV-infected cultures was mostly confined to productively infected cells. The expression of Fas and FasL was not significantly modulated by infection and blocking Fas-FasL interactions did not reduce the extent of apoptosis.HIV-induced apoptosis of activated CD4+ T cells in vitro is confined to productively infected cells and is not mediated by a Fas–FasL interaction.