Monday, March 16, 2009

Waking up dormant HIV

March 16th, 2009

HAART (highly active anti-retroviral therapy) has emerged as an extremely effective HIV treatment that keeps virus levels almost undetectable; however, HAART can never truly eradicate the virus as some HIV always remains dormant in cells. But, a chemical called suberoylanilide hydroxamic acid (SAHA), recently approved as a leukemia drug, has now been shown to 'turn on' latent HIV, making it an attractive candidate to weed out the hidden virus that HAART misses.

Matija Peterlin at UCSF and colleagues had previously identified another chemical called HMBA that could activate latent , but the risk of several toxic side effects made HMBA clinically non-viable. However, the chemically similar SAHA had received FDA approval, making it a potentially safer alternate.

So, the researchers examined whether SAHA had any effect on HIV latency. They found that SAHA could indeed stimulate to begin replicating, which exposes the infected cell to HAART drugs. SAHA could activate HIV in both laboratory as well as from blood samples taken from HIV patients on antiretroviral therapy. Importantly, this successful activation was achieved using clinical doses of SAHA, suggesting toxicity will not be a problem.

More information: This study appeared in the March 13 issue of , "Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells" by Xavier Contreras, Marc Schwenker, Chin-Shih Chen, Joseph M. McCune, Steven G. Deeks, Jeffrey Martin, and B. Matija Peterlin

Article link:

Source: American Society for Biochemistry and Molecular Biology

Suberoylanilide Hydroxamic Acid Reactivates HIV from Latently Infected Cells*

Originally published In Press as doi:10.1074/jbc.M807898200 on January 9, 2009 J. Biol. Chem., Vol. 284, Issue 11, 6782-6789, March 13, 2009

Xavier Contreras{ddagger}1, Marc Schweneker§2, Ching-Shih Chen, Joseph M. McCune§3, Steven G. Deeks||, Jeffrey Martin**, and B. Matija Peterlin{ddagger}4

From the {ddagger}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

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.

Received for publication, October 15, 2008 , and in revised form, January 9, 2009.

* 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.

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: