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Journal of Virology, March 2004, p. 2819-2830, Vol. 78, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.6.2819-2830.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Retinoid-Dependent Restriction of Human Immunodeficiency Virus Type 1 Replication in Monocytes/Macrophages

Timothy M. Hanley,1 Heather L. B. Kiefer,1,{dagger} Aletta C. Schnitzler,2 Jennifer E. Marcello,1,{ddagger} and Gregory A. Viglianti1*

Departments of Microbiology,1 Pathology, Boston University School of Medicine, Boston, Massachusetts 021182

Received 7 April 2003/ Accepted 25 November 2003

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.

* Corresponding author. Mailing address: Department of Microbiology, Boston University School of Medicine, 715 Albany St., Boston, MA 02118. Phone: (617) 638-7790. Fax: (617) 638-4286. E-mail: gviglian{at}bu.edu.

{dagger} Present address: Intelligent Medical Devices, Cambridge, MA 02141.

{ddagger} Present address: V.I. Technologies, Watertown, MA 02472.

Journal of Virology, March 2004, p. 2819-2830, Vol. 78, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.6.2819-2830.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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