Suberoylanilide Hydroxamic Acid Reactivates HIV from Latently Infected Cells

doi:10.1074/jbc.M807898200

Suberoylanilide Hydroxamic Acid Reactivates HIV from Latently Infected Cells*

^‡Department of Medicine, University of California, San Francisco, California 94143, ^§Division of Experimental Medicine, ^∥HIV/AIDS Division, and ^**Department of Epidemiology and Biostatistics, San Francisco General Hospital, University of California, San Francisco, California 94143, and ^¶Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210

4 To whom correspondence should be addressed: University of California, San Francisco, 533 Parnassus Ave., Rm. U432, Box 0703, San Francisco, CA 94143. Fax: 415-502-1901; E-mail: matija.peterlin{at}ucsf.edu.

Abstract

Human immunodeficiency virus (HIV) persists in a latent form in infected individuals treated effectively with highly active antiretroviral therapy (HAART). In part, these latent proviruses account for the rebound in viral replication observed after treatment interruption. A major therapeutic challenge is to purge this reservoir. In this study, we demonstrate that suberoylanilide hydroxamic acid (SAHA) reactivates HIV from latency in chronically infected cell lines and primary cells. Indeed, P-TEFb, a critical transcription cofactor for HIV, is released and then recruited to the viral promoter upon stimulation with SAHA. The phosphatidylinositol 3-kinase/Akt pathway is involved in the initiation of these events. Using flow cytometry-based single cell analysis of protein phosphorylation, we demonstrate that SAHA activates this pathway in several subpopulations of T cells, including memory T cells that are the major viral reservoir in peripheral blood. Importantly, SAHA activates HIV replication in peripheral blood mononuclear cells from individuals treated effectively with HAART. Thus SAHA, which is a Food and Drug Administration-approved drug, might be considered to accelerate the decay of the latent reservoir in HAART-treated infected humans.

Footnotes

↵5 The abbreviations used are: HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus; SAHA, suberoylanilide hydroxamic acid; PI3K, phosphatidylinositol 3-kinase; PBMC, peripheral blood mononuclear cell; PMA, phorbol 12-myristate 13-acetate; LTR, long terminal repeat; ChIP, chromatin immunoprecipitation; ELISA, enzyme-linked immunosorbent assay; HMBA, hexamethylene bisacetamide; RNAPII, RNA polymerase II; SC, small complex; LC, large complex; IL, interleukin; MAPK, mitogen-activated protein kinase.
↵* This work was supported, in whole or in part, by National Institutes of Health Grants AI49104 and AI058708 (to B. M. P.) and R01 AI40312 and AI47062 (to J. M. M.). This work was also supported by the University of California, San Francisco, Center for AIDS Research Grants P30 AI027763, P30 MH59037, and CC99-SF-001 and the University of California, San Francisco, Clinical and Translational Research Institute Grant UL1 RR024131, a component of the National Institutes of Health Roadmap for Medical Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement”in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵1 Supported by a grant from the California Foundation for AIDS Research.
↵2 Supported by the University-wide AIDS Research Program Grant F05-GI-219.
↵3 Recipient of National Institutes of Health Grant DPI OD00329 (Director's Pioneer Award Program, part of the National Institutes of Health Roadmap for Medical Research) and the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research.
- Received October 15, 2008.
- Revision received January 9, 2009.
The American Society for Biochemistry and Molecular Biology, Inc.