A recombinant fusion peptide, Env-Gag, derived from the human immunodeficiency virus type 1 (HIV-1) genome corresponding to a defined portion of the envelope (Env) and internal core (Gag) proteins was examined for immunoregulatory effects on the cytotoxic activity of natural killer (NK) cell-enriched, large granular lymphocytes (LGL) from healthy donors. Percoll-separated, NK cell-enriched LGL precultured for 24 h with Env-Gag at 10-and 50-ng/ml concentrations, which significantly stimulated lymphocyte proliferation, caused significant suppression of NK cell activity. Denatured Env-Gag did not cause any effect on the NK cell activity of LGL. Two other control peptides, one derived from the Escherichia coli vector used to clone the HIV Env-Gag fusion peptide and the other derived from a non-HIV-1 viral antigen (rubeola virus), did not produce any observable effect on the NK cell activity of LGL, demonstrating the specificity of the effect produced by Env-Gag. Subsequent treatment of LGL with alpha interferon (IFN-␣) or interleukin 2 (IL-2) alone partially reversed the Env-Gag-induced suppression of NK cell activity. However, LGL treated with both IFN-␣ and IL-2 completely reversed the suppression of NK cell cytotoxicity by Env-Gag. The combined effect of IFN-␣ and IL-2 in enhancing NK cell activity may provide a novel therapeutic approach to the restoration of depressed NK cell activity observed in HIV-infected patients.Natural killer (NK) cells are considered to be a first line of defense against virus infections and tumors and may be responsible for controlling occult metastases (for a review, see reference 42). NK cells also play a significant regulatory role in various immune reactions (9, 22). Defective NK cell activity is an early manifestation of human immunodeficiency virus type 1 (HIV-1) infection (1,4,40), and severe dysfunction of NK cells occurs in the later stages of the disease (10) despite their normal numbers in peripheral blood as identified by several monoclonal antibodies (36,40). This finding suggests that either the virus or soluble factors derived from HIV-1 may be responsible for this inhibition of NK cell activity in HIV-1-infected patients. We previously demonstrated that the recombinant HIV-1 peptide Env-Gag, a fusion product of the env, gp41, and gag p24 genes, can induce de novo polyclonal immunoglobulin synthesis and can suppress pokeweed mitogenstimulated immunoglobulin production by normal lymphocytes in vitro (26). We also reported differential effects of HIV-1 gp120 on interferon (IFN) production by mononuclear cells (25). Further, we have shown that certain HIV-1 peptides can inhibit the NK cell activity of normal lymphocytes and that NK cells from HIV-1-infected subjects are selectively sensitive to the inhibitory effects of Env-Gag (24). Our previous studies also showed that lymphocytes from intravenous drug abusers demonstrate lower NK cell and antibody-dependent cellular cytotoxic activities and that the suppressed NK cell activity can be partially reversed by in vitro treatm...
