Article thumbnail
Location of Repository

"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

By Andrea Savarino, Antonello Mai, Sandro Norelli, Sary El Daker, Sergio Valente, Dante Rotili, Lucia Altucci, Anna Teresa Palamara and Enrico Garaci


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

Topics: Short Report
Publisher: BioMed Central
OAI identifier:
Provided by: PubMed Central

Suggested articles


  1. (2009). A: Non-cancer uses of histone deacetylase inhibitors: effects on infectious diseases and β-hemoglobinopathies. Curr Top Med Chem
  2. (2004). Administration of HDAC inhibitors to reactivate HIV-1 expression in latent cellular reservoirs: implications for the development of therapeutic strategies. Biochem Pharmacol
  3. (2009). Altucci L: Epi-drugs to fight cancer: From chemistry to cancer treatment, the road ahead.
  4. (2008). ANRS EP39 study: Prolonged valproic acid treatment does not reduce the size of latent HIV reservoir. AIDS
  5. (2008). B: HIV-1 latency in actively dividing human T cell lines. Retrovirology
  6. (2004). Can HIV be Cured? Mechanisms of HIV persistence and strategies to combat it. Curr HIV Res
  7. (2003). Class II histone deacetylases: versatile regulators. Trends Genet
  8. (2009). Determinants of the establishment of human immunodeficiency virus type 1 latency.
  9. (2009). DM: A limited group of class I histone deacetylases act to repress human immunodeficiency virus type-1 expression.
  10. (2005). DM: Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet
  11. (2003). E: HIV reproducibly establishes a latent infection after acute infection of T cells in vitro.
  12. (2005). Exploring the connection unit in the HDAC inhibitor pharmacophore model: novel uracil-based hydroxamates. Bioorg Med Chem Lett
  13. (2000). Genetic and metabolic control of the mitochondrial transmembrane potential and reactive oxygen intermediate production in HIV disease. Antioxid Redox Signal
  14. (1998). Glutathione: an overview of biosynthesis and modulation. Chem Biol Interact Chem Biol Interact.
  15. (1997). Gougerot-Pocidalo MA: Oxidative stress in human immunodeficiency virus infection. Cell Mol Life Sci
  16. (2007). Greene WC: Regulation of HIV-1 latency by T-cell activation. Cytokine
  17. (2008). GSH and analogs in antiviral therapy. Mol Aspects Med
  18. (2007). Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res
  19. (2007). Human immunodeficiency virus integrase inhibitors efficiently suppress feline immunodeficiency virus replication in vitro and provide a rationale to redesign antiretroviral treatment for feline AIDS. Retrovirology
  20. (2007). In-Silico docking of HIV-1 integrase inhibitors reveals a novel drug type acting on an enzyme/DNA reaction intermediate. Retrovirology
  21. (1999). Iron metabolism and HIV infection: reciprocal interactions with potentially harmful consequences? Cell Biochem Funct
  22. (2003). Kuilemburg ABP: Histone deacetylases (HDACs): Characterization of the classical HDAC family.
  23. (1997). Lafavia E, Rotilio G: Intracellular GSH content and HIV replication in human macrophages.
  24. (2007). Legrand-Poels S: HIV-1 protease inhibitors do not interfere with provirus transcription and host cell apoptosis induced by combined treatment TNF-alpha + TSA. Biochem Pharmacol
  25. (2006). Okamoto T: Transcriptional repression of human immunodeficiency virus type 1 by AP-4.
  26. (2000). Oxidative stress response and signaling in hematological malignancies and HIV infection.
  27. (1994). PJ: Stereoselective pharmacokinetics of L-buthionine SR-sulfoximine in patients with cancer. Drug Metab Dispos
  28. (2002). Racz P: Effects of interleukin-2 plus highly active antiretroviral therapy on HIV-1 replication and proviral DNA (COSMIC trial). AIDS
  29. (2004). Redox modulation of chromatin remodeling: impact on histone acetylation and deacetylation, NF-kappaB and pro-inflammatory gene expression. Biochem Pharmacol
  30. (2009). RJ: The challenge of finding a cure for HIV infection. Science
  31. (2006). RW: Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov
  32. (2007). SD: A liquid chromatography/tandem mass spectrometry assay to quantitate MS-275 in human plasma.
  33. (2008). Sehested M: Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors.
  34. (2007). The therapeutic uses of chromatin-modifying agents. Expert Opin Ther Targets
  35. (1909). Über den jetzigen Stand der Chemotherapie. Dtsch Chem Ges
  36. (2005). Valproic acid and HIV-1 latency: beyond the sound bite. Retrovirology
  37. (1994). Valproic acid reduces the intracellular level of glutathione and stimulates human immunodeficiency virus. Chem Biol Interact

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.