Antipeptide sera raised against the gp120/gp41 sequences of human immunodeficiency virus type 1 (HIV-1) were used to determine their capacity to enhance infection. Antisera to the five variable regions (V1 to V5) of gp120 and conserved parts of gp120 and gp41 facilitated infection of primary human macrophages with the homologous virus HIV-1 SF2mc. In contrast, heterologous virus infection with HTLV-IIIB was mediated only by antisera to the conserved regions, predominantly C4 and C5. Heterologous virus infection occurred more rapidly and was consistent between different cell donors. The neutralizing monoclonal antibody (MAb) SC258 (murine IgG2a) but not MAb 684-238 (mIgG1) against conformational epitopes of the V2 region also induced antibody-dependent infection enhancement (ADE). Therefore, preincubation with certain antibodies can cause altered tropism of the lymphocytotropic viruses mentioned above. Viral infection was completely abolished by preincubation with the F(ab)2 fragment of MAb 3G8 against the Fc gamma receptor III (CD16). A MAb (7.3F11) against the gp120-binding site of CD4 had no effect on viral infectivity. Possible mechanisms and their implications for disease progression are discussed.