Fas-mediated apoptosis of CD4(+) and CD8(+) T cells from human immunodeficiency virus-infected persons: Differential in vitro preventive effect of cytokines and protease antagonists

Human immunodeficiency syndrome (HIV) infection leads to a progressive loss of T-cell-mediated immunity associated with T-cell apoptosis. We report here that CD4(+) and CD8(+) T cells from HIV-1-infected persons are sensitive to Fas (CD95/APO-1)-mediated death induced either by an agonistic anti-Fas antibody or by the physiologic soluble Fas ligand, although showing no sensitivity to tumor necrosis factor alpha-induced death. CD4(+) and CD8(+) T-cell apoptosis induced by Fas ligation was enhanced by inhibitors of protein synthesis and was prevented either by a soluble Fas receptor decoy or an antagonistic anti-Fas antibody. Fas-mediated apoptosis could also be prevented in a CD4(+) or CD8(+) T-cell-type manner (1) by several protease antagonists, suggesting the involvement of the interleukin-1 beta (IL-1 beta)-converting enzyme (ICE)-related cysteine protease in CD4(+) T-cell death and of both a CPP32-related cysteine protease and a calpain protease in CD8(+) T-cell death; and (2) by three cytokines, IL-2, IL-12, and IL-10, that exerted their effects through a mechanism that required de novo protein synthesis. Finally, T-cell receptor (TCR)-induced apoptosis of CD4(+) T cells from HIV-infected persons involved a Fas-mediated death process, whereas TCR stimulation of CD8(+) T cells led to a different Fas-independent death process. These findings suggest that Fas-mediated T-cell death is involved in acquired immunodeficiency syndrome (AIDS) pathogenesis and that modulation of Fas-mediated signaling may represent a target for new therapeutic strategies aimed at the prevention of CD4(+) T-cell death in AIDS. (C) 1996 by The American Society of Hematology.