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Journal of Virology, October 2007, p. 10914-10923, Vol. 81, No. 20
0022-538X/07/$08.00+0     doi:10.1128/JVI.01208-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

c-Myc and Sp1 Contribute to Proviral Latency by Recruiting Histone Deacetylase 1 to the Human Immunodeficiency Virus Type 1 Promoter{triangledown}

Guochun Jiang,1 Amy Espeseth,2 Daria J. Hazuda,2 and David M. Margolis1*

Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7435,1 Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 194862

Received 30 May 2007/ Accepted 23 July 2007

Histone deacetylase (HDAC) inhibitors such as valproic acid (VPA) induce the expression of quiescent proviral human immunodeficiency virus type 1 (HIV-1) and may deplete proviral infection in vivo. To uncover novel molecular mechanisms that maintain HIV latency, we sought cellular mRNAs whose expression was diminished in resting CD4+ T cells of HIV-1-infected patients exposed to VPA. c-Myc was prominent among genes markedly downregulated upon exposure to VPA. c-Myc expression repressed HIV-1 expression in chronically infected cell lines. Chromatin immunoprecipitation (ChIP) assays revealed that c-Myc and HDAC1 are coordinately resident at the HIV-1 long terminal repeat (LTR) promoter and absent from the promoter after VPA treatment in concert with histone acetylation, RNA polymerase II recruitment, and LTR expression. Sequential ChIP assays demonstrated that c-Myc, Sp1, and HDAC1 coexist in the same DNA-protein complex at the HIV promoter. Short hairpin RNA inhibition of c-Myc reduces both c-Myc and HDAC1 occupancy, blocks c-Myc repression of Tat activation, and increases LTR expression. These results expand the understanding of mechanisms that recruit HDAC and maintain the latency of HIV-1, suggesting novel therapeutic approaches against latent proviral HIV infection.

* Corresponding author. Mailing address: University of North Carolina at Chapel Hill, 3302 Michael Hooker Research Ctr., CB#7435, Chapel Hill, NC 27599-7435. Phone: (919) 966-6388. Fax: (919) 966-0584. E-mail: dmargo{at}med.unc.edu

{triangledown} Published ahead of print on 1 August 2007.

Journal of Virology, October 2007, p. 10914-10923, Vol. 81, No. 20
0022-538X/07/$08.00+0     doi:10.1128/JVI.01208-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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