The ability of human immunodeficiency virus type-1 (HIV-1) and recombinant HIV-1 gp120 to prevent target cell lysis by herpes simplex virus type 1 (HSV-1)-specific cytotoxic T lymphocytes (CTL) was assessed by limiting dilution analysis. Live and inactivated HIV-1 as well as recombinant-derived gp120 all substantially inhibited HSV-1-specific CTL. Soluble CD4 antigen reversed the inhibition by gp120 when simultaneously added with gp120 to the assay. In addition, the monoclonal anti-CD4 antibody a-Leu3a mimicked the effects of gp120 in these experiments. These data suggest that the observed decrease in measurable CTL activity is caused by direct or steric hindrance of the CD4-class II major histocompatibility complex interaction between the effector and target cells.