Retinoid-dependent restriction of human immunodeficiency virus type 1 replication in monocytes/macrophages.
Vitamin A deficiency has been correlated with increased severity of human immunodeficiency virus type 1 (HIV-1)-associated disease. Moreover, vitamin A supplementation can reduce AIDS-associated morbidity and mortality. 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-trans-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.
Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Timothy M
TM
Hanley
Heather L B
HL
Kiefer
Aletta C
AC
Schnitzler
Jennifer E
JE
Marcello
Gregory A
GA
Viglianti
D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000821:virology; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000821:virology*; D009000:Monocytes / Q000821:virology*; D011691:Puromycin / Q000494:pharmacology; D012176:Retinoids / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*
D012176:Retinoids; D011691:Puromycin; D003513:Cycloheximide