Human immunodeficiency virus type 1 (HIV-1)-infected individuals, but not HIV-seronegative controls, have non-HLA-restricted T-cell receptor alpha beta+ CD8+ cytotoxic T-lymphocytes (CTL) that kill activated uninfected CD4+ lymphocytes. In vitro stimulation of peripheral blood mononuclear cells from HIV-1-infected individuals with concanavalin A (Con A) or by coculture with phytohemagglutinin-activated autologous lymphoblasts induced CTL that killed autologous and heterologous CD4+ lymphocytes, but not Con A-activated CD8+ lymphocytes or Epstein-Barr virus (EBV)-transformed B lymphocytes. EBV did not stimulate such CTL in two subjects tested, although stimulation with Con A or autologous lymphoblasts induced CTL activity against CD4+ lymphocytes in both subjects. CTL activity against autologous CD4+ lymphocytes varied over time; killing of heterologous CD4+ lymphocytes was often higher than that of autologous CD4+ lymphocytes. HIV-infected individuals with Con A-inducible CTL against autologous CD4+ lymphocytes lost more CD4+ lymphocytes within 6 months of testing than HIV-infected individuals with no such CTL (p < .01). The mean (+/- SD) decrease in CD4+ lymphocyte counts in a group of HIV-infected individuals with CTL activity against autologous CD4+ lymphocytes was 121 +/- 84, or 36%, of total CD4+ lymphocytes over 6 months. In contrast, there was no significant change in mean CD4+ lymphocyte count over 6 months in a group of HIV-infected individuals without CTL activity against autologous CD4+ lymphocytes. In some HIV-infected individuals, CTL activity against autologous CD4+ lymphocytes fell coincident with a drop in CD4+ lymphocyte number in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)