RETINOID-INDUCED REPRESSION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 CORE PROMOTER ACTIVITY INHIBITS VIRUS-REPLICATION

The rates of mother-to-child transmission of human immunodeficiency vi rus type 1 (HIV-1), progression to AIDS following HIV-1 infection, and AIDS-associated mortality are all inversely correlated with serum vit amin A levels (R. D. Semba, W. T. Caiaffa, N. M. H. Graham, S. Cohn, a nd D. Vlahov, J. Infect. Dis. 171:1196-1202, 1995; R. D. Semba, N. M. H. Graham, W. T. Caiaffa, J. B. Margolik, L. Clement, and D. Vlahov, A rch. Intern. Med. 153:2149-2154, 1993; R. D. Semba, P. G. Miotti, J. D . Chiphangwi, A. J. Saah, J. K. Canner, G. A. Dallabetta, and D. R. Ho over, Lancet 343:1593-1596, 1994). Here we show that physiological con centrations of vitamin A, as retinol or as its metabolite, all-trans r etinoic acid, repressed HIV-1(Ba-L) replication in monocyte-derived ma crophages (MDMs), Repression required retinoid treatment of peripheral monocytes during their in vitro differentiation into MDMs, Retinoids had no repressive effect if they were added after virus infection. Ret inol, as well as all-trans retinoic acid and 9-cis retinoic acid, also repressed HIV-1 long terminal repeat (LTR)-directed expression up to 200-fold in transfected THP-1 monocytes, Analysis of HIV-1 LTR deletio n mutants demonstrated that retinoids were able to repress activation of HIV-1 expression by both NF KB and Tat, A cis-acting sequence requi red for retinoid-mediated repression of HIV-1 transcription was locali zed between nucleotides -51 and +12 of the HIV-1 LTR within the core p romoter. Protein DNA cross-linking experiments identified four protein s specific to retinoid-treated cells that bound to the core promoter, We conclude that retinoids render macrophages resistant to virus repli cation by modulating the interaction of cellular transcription factors with the viral core promoter.