Title |
"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
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Published in |
Retrovirology, June 2009
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DOI | 10.1186/1742-4690-6-52 |
Pubmed ID | |
Authors |
Andrea Savarino, Antonello Mai, Sandro Norelli, Sary El Daker, Sergio Valente, Dante Rotili, Lucia Altucci, Anna Teresa Palamara, Enrico Garaci |
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. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 2 | 3% |
Australia | 1 | 1% |
Denmark | 1 | 1% |
United Kingdom | 1 | 1% |
Japan | 1 | 1% |
China | 1 | 1% |
Unknown | 70 | 91% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 17 | 22% |
Researcher | 13 | 17% |
Student > Master | 8 | 10% |
Professor > Associate Professor | 6 | 8% |
Student > Bachelor | 6 | 8% |
Other | 13 | 17% |
Unknown | 14 | 18% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 22 | 29% |
Medicine and Dentistry | 14 | 18% |
Biochemistry, Genetics and Molecular Biology | 9 | 12% |
Chemistry | 6 | 8% |
Immunology and Microbiology | 4 | 5% |
Other | 9 | 12% |
Unknown | 13 | 17% |