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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 Savarino, Antonello Mai, Sandro Norelli, Sary El Daker, Sergio Valente, Dante Rotili, Lucia Altucci, Anna Teresa Palamara and Enrico Garaci
Retrovirology 2009, 6:52doi:10.1186/1742-4690-6-52
Published: 2 June 2009
Abstract (provisional)
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.
"The concept to activate provirus transcription to target latency is not new, and several clinical trials have been conducted in the past years along this line, ranging from the administration of IL-2 to the utilization of valproic acid [34-36]. The results of these trials have been largely disappointing so far. Valproic acid, a relatively weak HDACI, was tested in a small clinical trial in combination with antiretroviral therapy intensified with the fusion inhibitor enfuvirtide [35, 36], but some more recent studies have failed to show a decay of resting CD4+ T cell infection in individuals under valproic acid treatment for clinical reasons while also receiving standard ART [37]. Our study provides a potentially more powerful approach for the "shock" phase of experimental HIV-1 eradicating strategies and a potential tool for the "kill" phase. Notwithstanding the aforementioned need for amelioration, it is interesting to point out that both MS-275 and BSO have passed class I clinical trials for safety in humans and are therefore ready for testing in animal models. Such testing would be important at a time when no proof-of-concept exists for the "shock and kill" theory. In this regard, even a partial response (e.g. a reduction in latently infected cells) would be a valuable indicator of the validity of this approach. The possible efficacy of the "shock and kill" approach is still a matter of debate. For example, a recent study of Jeeninga et al. suggests that there are different cellular reservoirs for HIV-1 latency and that each reservoir may require a specific activation strategy [38]. Viral factors, along with cellular factors, may contribute to HIV-1 quiescence, and these factors may not be controlled by strategies using HDACIs."
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