HIV infection of CD4+ T cells in culture results in the production of virus and induction of cell killing by apoptosis. Such a cytopathic effect is observed during infection with syncytium-inducing or non-syncytium-inducing HIV isolates. Apoptosis is triggered by the interaction of the cell membrane-expressed HIV envelope glycoprotein heterodimer gp120-gp41 complex (external and transmembrane glycoprotein complex) with the CD4 receptor. Here we demonstrate an experimental model for the induction of apoptosis independent of HIV infection, using transiently transfected HeLa cells with the HIV1 env gene as effector cells and the CD4+ MOLT4-T4 T cells as target cells. Results obtained confirm that the induction of apoptosis requires the membrane expression of the two HIV env gene products, gp120 and gp41. Single amino acid point mutations of the envelope products that affect binding to the CD4 receptor or the fusion process abrogate the capacity of the gp120-gp41 complex to induce apoptosis. Interestingly, a point mutation in the V3 loop which inhibits fusion without affecting CD4 binding also results in the abrogation of apoptosis. These observations indicate that the induction of apoptosis is an intrinsic property of the cell membrane-expressed gp120-gp41 complex, and thus should be considered as one of the functions of HIV env gene products.