Several aspects of human immunodeficiency virus (HIV)-induced pathology in vitro warrant close examination to ascertain their role in the development of disease in vivo. The ability of HIV to produce cytopathology of CD4 cells has been well documented, although the extent and mechanism(s) may be varied. Further, immune suppression by HIV envelope (env) is well documented in vitro, but its importance in vivo remains unknown and the role of other HIV components in immune suppression has not been examined. We have exposed peripheral blood mononuclear cells (PBMC) from normal donors to ultraviolet-irradiated HIV (uv-HIV) at concentrations similar to those found in AIDS patient serum and determined that in some normal donors (3/7) depletion of CD8 cells as well as CD4 cells is demonstrable. Abrogation of phytohemagglutinin (PHA)-induced proliferation by uv-HIV was also examined in the same normal donors. Immune suppression, unlike CD4 cell killing, does not require intact virus and occurs at physiologically relevant concentrations of HIV. Furthermore, PBMC exposed to uv-HIV in the presence of PHA produce a heat- and protease-labile suppressor factor(s) following removal of virus, whether or not they are reexposed to PHA. Our results suggest that cell killing may be a more broad event than previously described, including the killing of at least CD8 cells either directly or indirectly. In addition, suppressor factors produced following exposure of patient lymphocytes to agents that induce proliferation may exacerbate the development of opportunistic infection.