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"Shock and kill" effects of class I-selective histone deacetylase inhibitors in combination with the glutathione synthesis inhibitor buthionine sulfoximine in cell line models for HIV-1 quiescence

Andrea Savarino1*, Antonello Mai2, Sandro Norelli1, Sary El Daker1, Sergio Valente2, Dante Rotili2, Lucia Altucci3, Anna Teresa Palamara46 and Enrico Garaci5

Author Affiliations

1 Dept of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy

2 Pasteur Institute, Cenci-Bolognetti Foundation, Dept of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro, 5, 00185, Rome, Italy

3 Dept of General Pathology, 2nd University of Naples, Vico L. De Crecchio 7, 80138 Naples, Italy

4 Pasteur Institute, Cenci-Bolognetti Foundation, Dept of Public Health Sciences, Sapienza University of Rome, P.le A. Moro, 5, 00185, Rome, Italy

5 Dept of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy

6 IRCCS San Raffaele Pisana, via della Pisana 235, 00163 Rome, Italy

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Retrovirology 2009, 6:52  doi:10.1186/1742-4690-6-52

Published: 2 June 2009

Abstract

Latently infected, resting memory CD4+ T cells and macrophages represent a major obstacle to the eradication of HIV-1. For this purpose, "shock and kill" strategies have been proposed (activation of HIV-1 followed by stimuli leading to cell death). Histone deacetylase inhibitors (HDACIs) induce HIV-1 activation from quiescence, yet class/isoform-selective HDACIs are needed to specifically target HIV-1 latency. We tested 32 small molecule HDACIs for their ability to induce HIV-1 activation in the ACH-2 and U1 cell line models. In general, potent activators of HIV-1 replication were found among non-class selective and class I-selective HDACIs. However, class I selectivity did not reduce the toxicity of most of the molecules for uninfected cells, which is a major concern for possible HDACI-based therapies. To overcome this problem, complementary strategies using lower HDACI concentrations have been explored. We added to class I HDACIs the glutathione-synthesis inhibitor buthionine sulfoximine (BSO), in an attempt to create an intracellular environment that would facilitate HIV-1 activation. The basis for this strategy was that HIV-1 replication decreases the intracellular levels of reduced glutathione, creating a pro-oxidant environment which in turn stimulates HIV-1 transcription. We found that BSO increased the ability of class I HDACIs to activate HIV-1. This interaction allowed the use of both types of drugs at concentrations that were non-toxic for uninfected cells, whereas the infected cell cultures succumbed more readily to the drug combination. These effects were associated with BSO-induced recruitment of HDACI-insensitive cells into the responding cell population, as shown in Jurkat cell models for HIV-1 quiescence. The results of the present study may contribute to the future design of class I HDACIs for treating HIV-1. Moreover, the combined effects of class I-selective HDACIs and the glutathione synthesis inhibitor BSO suggest the existence of an Achilles' heel that could be manipulated in order to facilitate the "kill" phase of experimental HIV-1 eradication strategies.