Abstract | 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.
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Authors | Geneviève Doyon, Jennifer Zerbato, John W Mellors, Nicolas Sluis-Cremer |
Journal | AIDS (London, England)
(AIDS)
Vol. 27
Issue 2
Pg. F7-F11
(Jan 14 2013)
ISSN: 1473-5571 [Electronic] England |
PMID | 22739395
(Publication Type: Journal Article)
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Chemical References |
- Enzyme Inhibitors
- Proto-Oncogene Proteins c-akt
- PTEN Phosphohydrolase
- PTEN protein, human
- Disulfiram
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Topics |
- CD4-Positive T-Lymphocytes
(virology)
- Cell Line
- Disulfiram
(pharmacology)
- Enzyme Inhibitors
(pharmacology)
- Female
- HIV Infections
(drug therapy)
- HIV-1
(physiology)
- Humans
- Male
- PTEN Phosphohydrolase
(metabolism)
- Phosphorylation
- Proto-Oncogene Proteins c-akt
(metabolism)
- Signal Transduction
(drug effects)
- Virus Activation
(drug effects)
- Virus Latency
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