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Journal of Virology, May 2005, p. 5952-5962, Vol. 79, No. 10
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.10.5952-5962.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Mitogen-Activated Protein Kinases Regulate LSF Occupancy at the Human Immunodeficiency Virus Type 1 Promoter

Loyda Ylisastigui,1 Rupinderjeet Kaur,1 Holly Johnson,1 Janet Volker,2 Guocheng He,1 Ulla Hansen,2 and David Margolis1,3*

University of Texas Southwestern Medical Center at Dallas, Department of Medicine, Division of Infectious Diseases, Dallas, Texas 75390,1 Department of Biology, Boston University, Boston, Massachusetts,2 North Texas Veterans Health Care Systems, Dallas, Texas 752163

Received 30 November 2004/ Accepted 3 January 2005

Human immunodeficiency virus type 1 (HIV-1) establishes a persistent, nonproductive state within a small population of memory CD4+ cells. The transcription factor LSF binds to sequences within the HIV-1 long terminal repeat (LTR) initiation region and recruits a second factor, YY1, to the LTR. These factors then cooperatively recruit histone deacetylase 1 to the LTR, resulting in inhibition of transcription. This appears to be one mechanism contributing to HIV persistence within resting CD4+ T cells. We sought to further detail LSF binding to the HIV-1 LTR and factors that regulate LSF occupancy. We find that LSF binds the LTR as a tetramer and that binding is regulated by phosphorylation mediated by mitogen-activated protein kinases (MAPKs). In vitro, phosphorylation of LSF by Erk decreases binding to the LTR, while binding is increased by p38 phosphorylation. LSF occupancy at LTR chromatin is increased by the p38 agonist anisomycin and decreased by specific p38 inhibition. p38 inhibition also results in increased acetylation of histone H4 at the LTR nucleosome adjacent to the LSF binding site. p38 inhibition also blocked the ability of YY1 to inhibit activation of the integrated HIV promoter. Finally, HIV was recovered from the resting CD4+ T cells of aviremic, HIV-infected donors upon treatment of these cells with specific inhibitor of p38. These data suggest that the MAPK pathway regulates LSF binding to the LTR and thereby one aspect of the regulation of HIV expression. This mechanism could be exploited as a novel therapeutic target to disrupt latent HIV infection.

* Corresponding author. Mailing address: University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Y9-206a, Dallas, TX 75390-9113. Phone: (214) 648 3593. Fax: (214) 348 0231. E-mail: david.margolis{at}utsouthwestern.edu.

Journal of Virology, May 2005, p. 5952-5962, Vol. 79, No. 10
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.10.5952-5962.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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