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Disulfiram reactivates latent HIV-1 expression through depletion of the phosphatase and tensin homolog

Doyon, Geneviève; Zerbato, Jennifer; Mellors, John W.; Sluis-Cremer, Nicolas

doi: 10.1097/QAD.0b013e3283570620
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Objective: Disulfiram (DSF), an inhibitor of acetaldehyde dehydrogenase that is used for the treatment of alcoholism, was shown to reactivate latent HIV-1 expression in a primary cell model of virus latency and is currently being assessed in a clinical trial for its potential to deplete the latent HIV-1 reservoir in patients on combination antiretroviral therapy. The mechanism by which DSF reactivates latent HIV-1 expression, however, is not known and was the focus of this study.

Design/methods: The impact of DSF treatment on HIV-1 latency was assessed in the ACH2, J89GFP and U1 cell line models of HIV-1 latency and in resting CD4+ T cells isolated from HIV-negative donors.

Results: DSF reactivated latent HIV-1 expression in the U1 cell line, but not in the J89GFP or ACH2 cell lines. Interestingly, we found that DSF significantly reduced phosphatase and tensin homolog (PTEN) protein levels in U1 cells and in resting CD4+ T cells from HIV-negative donors. Decreased PTEN resulted in increased phosphorylation of protein kinase B (Akt) and activation of the Akt signaling pathway. Consistent with these finding, pharmacological inhibitors of Akt and nuclear factor-kappaB (NF-κB) block the latent HIV-1-reactivating activity of DSF. Furthermore, we show that HIV-1 expression in the U1 cell line could be activated by a small molecule inhibitor of PTEN or by siRNA knockdown of PTEN expression. Neither the J89GFP nor ACH2 cells express PTEN, explaining the lack of DSF effect on HIV-1 expression in both these cell lines.

Conclusion: DSF reactivates latent HIV-1 expression via the Akt signaling pathway through depletion of PTEN.

Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Correspondence to Nicolas Sluis-Cremer, S817 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA. Tel: +1 412 648 8457; fax: +1 412 648 8521; e-mail: nps2@pitt.edu

Received 5 April, 2012

Revised 29 May, 2012

Accepted 15 June, 2012

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© 2013 Lippincott Williams & Wilkins, Inc.