MOLECULAR AND CELLULAR ANALYSIS OF HUMAN IMMUNODEFICIENCY VIRUS-INDUCED APOPTOSIS IN LYMPHOBLASTOID T-CELL-LINE-EXPRESSING WILD-TYPE AND MUTATED CD4 RECEPTORS

We have previously shown that the presence of the CD4 cytoplasmic tail is critical for human immunodeficiency virus (HIV)-induced apoptosis (J. Corbeil, M. Tremblay, and D. D. Richman, J. Exp. Med. 183:39-48, 1 996). We have pursued our investigation of the role of the CD4 transdu ction pathway in HN-induced apoptosis. To do this, wild-type and mutan t forms of the CD4 cytoplasmic tail were stably expressed in the lymph oblastoid T cell line A2.01. Apoptosis was prevented when CD4 truncate d at residue 402 was expressed; however, cells expressing mutated rece ptors that do not associate with p56(lck) (mutated at the dicysteine m otif and truncated at residue 418) but which conserved proximal domain s of the cytoplasmic tail underwent apoptosis like nild-type CD4. The differences between wild-type and mutated receptors in the induction o f apoptosis were not related to levels of p56(lck) or NF-kappa B activ ation. Initial signaling through the CD4 receptor played a major role in the sensitization of HIV-infected T cells to undergo apoptosis. Inc ubation of HIV-infected cells with monoclonal antibody (MAb) 13B8-2, w hich binds to CD4 in a region critical for dimerization of the recepto r, prevented apoptosis without inhibiting HN replication. Moreover, th e apoptotic process was not related to Fas-Fas ligand interaction; how ever, an antagonistic anti-Fas MAb (ZB-4) enhanced apoptosis in HIV-in fected cells without inducing apoptosis in uninfected tells. These obs ervations demonstrate that CD4 signaling mediates HN-induced apoptosis by a mechanism independent of Fas-Fas ligand interaction, does not re quire p56(lck) signaling, and may involve a critical region for CD4 di merization.