PROGRAMMED CELL-DEATH IN AIDS-RELATED HIV AND SIV INFECTIONS

One of the difficulties in understanding the complex pathology of huma n immunodeficiency virus (HIV) infection is to explain the progressive depletion of the CD4 helper T cell population and consequently the de struction of the immune system. Although cytopathic effects of HIV are observed in vitro, they cannot in vivo account for CD4 T cell depleti on because relatively few cells are productively infected. Thus immuno logical mechanisms must be envisaged. We have found that peripheral bl ood lymphocytes (PBLs) from asymptomatic HIV-infected individuals are primed for a suicide process known as apoptosis or programmed cell dea th (PCD). DNA fragmentation characteristic of apoptosis was enhanced b y stimulation of lymphocytes with ionomycin, a known inducer of apopto sis in suitably primed cells. Identification of the T cell subpopulati ons programmed for apoptosis indicated that both CD4+ and CD8+ cells d ied when cultured without stimulation or when polyclonally stimulated with ionomycin. Activation-induced cell death was also observed after stimulation with self-MHC class II-dependent superantigens, namely bac terial toxins from Staphylococcus (SEB), Streptococcus (ETA), and Myoc oplasma (MAM) and under these conditions the CD4+ T cells were prefere ntially affected. To explore whether new macromolecular synthesis were required for apoptosis, various known inhibitors of apoptosis such as cycloheximide, cyclosporin A, Zn2+, or EGTA were tested. Activation-i nduced apoptosis was found sensitive to these inhibitors, indicating a n active mechanism, but apoptosis observed in nonstimulated cultures w as not, suggesting that these cells already contained the complete mac hinery for death. Prevention of apoptosis could be obtained in the pre sence of a mixture of cytokines and the minimal signal necessary for t his prevention was IL-1alpha and IL-2. Finally, a correlation between PCD and AIDS pathogenesis was suggested by the comparison of lymphocyt es from lentivirus-infected primates suceptible (SIV-infected macaques ) and resistant (HIV-infected chimpanzees) to AIDS. Altogether our res ults suggest that, during HIV or SIV infection, PCD may contribute in vivo to the deletion of reactive T cells after antigenic stimulation.