Certain retroviral envelope proteins and peptides have been shown to be highly immunosuppressive. Recently, we have demonstrated that a synthetic 17 amino acid peptide (CKS-17*) homologous to a highly conserved region in the transmembrane portion of the envelope of several human or animal retroviruses suppresses the production of human interferon-gamma (IFN gamma) by human peripheral blood leukocytes (PBL). In the present investigation, we studied the role of exogenous IL-1 or IL-2, and IL-1 plus IL-2 on the suppressive action of CKS-17* in the production of IFN gamma. The results showed that preculture of PBL with CKS-17* reduced the production of IFN gamma in a dose-dependent manner. The addition of IL-1 or IL-2 reduced, in part, this suppression of IFN gamma production. Full abrogation of the inhibition attributable to CKS-17, however, occurred only when PBL precultured with CKS-17* were recultured with staphylococcus enterotoxin A (SEA) together with exogenous IL-1 plus IL-2. These results show that the inhibition of IFN-gamma production by CKS-17* is reversible. The findings indicate that cytokines can modulate certain of the immunosuppressive actions attributable to retroviruses or their components and suggest that some cytokines influence immunosuppressive consequences of retroviral infection.