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Our group and others have shown that retinoids, the bioactive metabolites of vitamin A, repress HIV-1 replication in monocytic cell lines and primary macrophages by blocking long-terminal-repeat (LTR)-directed transcription. Based on these studies, we hypothesize that retinoids are natural repressors of HIV-1 in vivo. We show here that all-<jats:italic>trans<\/jats:italic>-retinoic acid (RA)-mediated repression of HIV-1 activation requires pretreatment for at least 12 h and is blocked by the protein synthesis inhibitors cycloheximide and puromycin. Studies of the kinetics of RA-mediated repression in U1 cells and primary monocyte-derived macrophages (MDMs) reveal that the repressive effects of RA on HIV-1 expression are long-lasting but reversible. We demonstrate that HIV-1 expression is activated when U1 cells or MDMs are cultured in retinoid-free synthetic medium and show that physiological concentrations of RA repress this activation. In addition, the synthetic pan-retinoic acid receptor antagonist BMS-204 493 activates HIV-1 replication in U1 cells in a dose-dependent manner, suggesting that RA-induced transactivation of cellular gene expression is required for HIV-1 repression. Together, these data support the hypothesis that retinoids present in tissue culture media in vitro and serum in vivo maintain HIV-1 in a transcriptionally repressed state in monocytes\/macrophages.<\/jats:p>","DOI":"10.1128\/jvi.78.6.2819-2830.2004","type":"journal-article","created":{"date-parts":[[2004,2,27]],"date-time":"2004-02-27T21:47:38Z","timestamp":1077918458000},"page":"2819-2830","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":22,"title":["Retinoid-Dependent Restriction of Human Immunodeficiency Virus Type 1 Replication in Monocytes\/Macrophages"],"prefix":"10.1128","volume":"78","author":[{"given":"Timothy M.","family":"Hanley","sequence":"first","affiliation":[{"name":"Departments of Microbiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather L. 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