We examined the sera of volunteers vaccinated with recombinant gp160 of human immunodeficiency virus type 1 (HIV-1) and control volunteers for the presence of anti-(anti-gp160 idiotype) antibodies which antigenically mimic gp160 and, therefore, bind to CD4 on human cells. Anti-CD4 antibodies were detected in the sera of 3 of 5 rgp160 recipients and 1 of 5 controls by indirect immunofluorescence using CD4-transfected HeLa cells or enzyme-linked immunosorbent assay (ELISA) using recombinant soluble CD4 as the solid phase. The control volunteer who was positive subsequently developed antibodies to HIV-1 by Western blot analysis. The anti-CD4 antibodies detected in the sera of the rgp160 vaccinees and the control volunteer appeared to be anti-idiotypic in nature, reacting with a paratope expressed on goat anti-gp160 antibodies but not on antibodies from normal goat serum. Binding to either transfected CD4+ HeLa cells or blotted anti-gp160 serum could be inhibited by preincubating the anti-CD4 serum with soluble CD4, or preincubating the cells or blotted anti-gp160 serum with recombinant gp160. Anti-CD4 antibodies were initially detectable only after the antibody response to gp160 began to decrease in the vaccinees, and the HIV-1-infected volunteer mounted a detectable anti-HIV-1 antibody response only after a decline in the anti-CD4 antibodies in his serum. These data strongly suggest that anti-CD4 antibodies which are anti-idiotypic to a paratope expressed on anti-gp160 antibodies are generated in response to both vaccination with rgp160 and infection with HIV-1.(ABSTRACT TRUNCATED AT 250 WORDS)