Inhibition of human immunodeficiency virus type 1 by alpha-melanotropin. The effect of alpha-melanotropin (alpha-MSH) on human immunodeficiency virus (HIV-1) was examined in T cell lines and peripheral blood mononuclear cells (PBMC) isolated from patients infected with HIV-1. Exposure of HIV-1 to alpha-MSH resulted in dose-dependent inhibition of viral replication as evidenced by a decrease in reverse transcriptase activity in culture supernatants of infected PBMC. The level of alpha-MSH which inhibited viral replication by 50% was 0.5-1.0 ng/ml. alpha-MSH-mediated inhibition of HIV-1 was reversible in PBMC, suggesting that the inhibitory effect of alpha-MSH was not due to cell toxicity. The inhibitory activity of alpha-MSH was neutralized by a rabbit polyclonal antibody to alpha-MSH but not by a rabbit polyclonal antibody to human growth hormone. In addition, alpha-MSH blocked the activity of an alpha-MSH peptide agonist but had no effect on other alpha-MSH family peptides. In vitro, alpha-MSH binds to intact PBMC but not to cell-free virions. Northern blot analysis of HIV-1 mRNA levels from infected PBMC and T cells demonstrated that alpha-MSH reduced the level of late viral transcripts while having no effect on the levels of early viral transcripts. These results suggest that alpha-MSH regulates the expression of HIV-1 by modulating transcription of the late gene. The data provide direct evidence of the potential anti-HIV-1 activity of alpha-MSH and may contribute to understanding the possible mechanisms of action of the hormone in vivo.