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Molecular Medicine

, Volume 17, Issue 5–6, pp 466–472 | Cite as

Histone Deacetylase Inhibitors for Purging HIV-1 from the Latent Reservoir

  • Shay Matalon
  • Thomas A Rasmussen
  • Charles A Dinarello
Review Article

Abstract

A reservoir of latently infected memory CD4+T cells is believed to be the source of HIV-1 reemergence after discontinuation of antiretroviral therapy. HIV-1 eradication may depend on depletion of this reservoir. Integrated HIV-1 is inaccessible for expression, in part because of histone deacetylases (HDACs). One approach is to exploit the ability of HDAC inhibitors to induce HIV-1 expression from an integrated virus. With effective antiretroviral therapy, newly expressed HIV-1 is incapable of reinfecting naive cells. With HIV-1 expression, one assumes the infected cell dies and there is a progressive reduction in the size of the reservoir. The concept was tested using the HDAC inhibitor valproic acid. However, valproic acid is weak in inducing HIV-1 from latency in vitro. As such, clinical trials revealed a small or no effect on reducing the number of latently infected T cells in the peripheral blood. However, the new HDAC inhibitors vorinostat, belinostat and givinostat are more effective at targeting specific HDACs for HIV-1 expression than valproic acid. Here, we review studies on HDAC inhibitor-induced expression of latent HIV-1, with an emphasis on new and specific HDAC inhibitors. With increased potency for HIV-1 expression as well as safety and ease of oral administration, new HDAC inhibitors offer a unique opportunity to deplete the latent reservoir. An additional benefit is the antiinflammatory properties of HDAC inhibitors, including downregulation of HIV-1 coreceptor expression.

Notes

Acknowledgments

The authors thank Gregory Pott, Carrie Sailer, Leland Shapiro and Marcel F. Nold for their contributions. This work was supported by National Institutes of Health Grant AI-15614 (to CAD) and Ital-farmaco, SpA, Cinisello Balsamo, Italy.

References

  1. 1.
    Imamichi H, et al. (2001) Human immunodeficiency virus type 1 quasi species that rebound after discontinuation of highly active antiretroviral therapy are similar to the viral quasi species present before initiation of therapy. J. Infect. Dis. 183:36–50.CrossRefPubMedGoogle Scholar
  2. 2.
    Zhang L, et al. (2000) Genetic characterization of rebounding HIV-1 after cessation of highly active antiretroviral therapy. J. Clin. Invest. 106:839–45.CrossRefPubMedGoogle Scholar
  3. 3.
    Davey RT Jr, et al. (1999) HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc. Natï. Acad. Sci. U. S. A. 96:15109–14.CrossRefGoogle Scholar
  4. 4.
    Chun TW, et al. (2000) Relationship between preexisting viral reservoirs and the re-emergence of plasma viremia after discontinuation of highly active anti-retroviral therapy. Nat. Med. 6:757–61.CrossRefPubMedGoogle Scholar
  5. 5.
    Chun TW, et al. (1997) Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature. 387:183–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Finzi D, et al. (1997) Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science. 278:1295–300.CrossRefPubMedGoogle Scholar
  7. 7.
    Chun TW, et al. (1998) Early establishment of a pool of latently infected, resting CD4(+) T cells during primary HIV-1 infection. Proc. Natl. Acad. Sci. U. S. A. 95:8869–73.CrossRefPubMedGoogle Scholar
  8. 8.
    Lori F, et al. (1999) Treatment of human immunodeficiency virus infection with hydroxyurea, didanosine, and a protease inhibitor before serocon-version is associated with normalized immune parameters and limited viral reservoir. J. Infect. Dis. 180:1827–32.CrossRefPubMedGoogle Scholar
  9. 9.
    Siliciano JD, et al. (2003) Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat. Med. 9:727–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Zhang L, et al. (1999) Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. N. Engl. J. Med. 340:1605–13.CrossRefPubMedGoogle Scholar
  11. 11.
    Ramratnam B, et al. (2000) The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged anti-retroviral therapy. Nat. Med. 6:82–5.CrossRefPubMedGoogle Scholar
  12. 12.
    Chun TW, et al. (2005) HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir. J. Clin. Invest. 115:3250–5.CrossRefPubMedGoogle Scholar
  13. 13.
    Ramratnam B, et al. (2004) Intensification of antiretroviral therapy accelerates the decay of the HIV-1 latent reservoir and decreases, but does not eliminate, ongoing virus replication. J. Acquit. Immune Defic. Syndr. 35:33–7.CrossRefGoogle Scholar
  14. 14.
    Chun TW, et al. (2007) Decay of the HIV reservoir in patients receiving antiretroviral therapy for extended periods: implications for eradication of virus. J. Infect. Dis. 195:1762–4.CrossRefPubMedGoogle Scholar
  15. 15.
    van Praag RM, et al. (2001) OKT3 and IL-2 treatment for purging of the latent HIV-1 reservoir in vivo results in selective long-lasting CD4+ T cell depletion. J. Clin. Immunol. 21:218–26.CrossRefPubMedGoogle Scholar
  16. 16.
    Prins JM, et al. (1999) Immuno-activation with anti-CD3 and recombinant human IL-2 in HIV-1-infected patients on potent antiretroviral therapy. Aids. 13:2405–10.CrossRefPubMedGoogle Scholar
  17. 17.
    Dybul M, et al. (2002) Pilot study of the effects of intermittent interleukin-2 on human immunodeficiency virus (HIV)-specific immune responses in patients treated during recently acquired HIV infection. J. Infect. Dis. 185:61–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Bowman MC, Archin NM, Margolis DM. (2009) Pharmaceutical approaches to eradication of persistent HIV infection. Expert Rev. Mol. Med. 11:e6.CrossRefPubMedGoogle Scholar
  19. 19.
    Tran TA, et al. (2008) Resting regulatory CD4 T cells: a site of HIV persistence in patients on long-term effective antiretroviral therapy. PLoS One. 3:e3305.CrossRefPubMedGoogle Scholar
  20. 20.
    Thornton AM, Shevach EM. (1998) CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 188:287–96.CrossRefPubMedGoogle Scholar
  21. 21.
    Stellbrink HJ, et al. (2002) Effects of interleukin-2 plus highly active antiretroviral therapy on HIV-1 replication and proviral DNA (COSMIC trial). Aids. 16:1479–87.CrossRefPubMedGoogle Scholar
  22. 22.
    Reddy P, et al. (2008) Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase-dependent DC functions and regulates experimental graft-versus-host disease in mice. J. Clin. Invest. 118:2562–73.PubMedCentralPubMedGoogle Scholar
  23. 23.
    Wang L, de Zoeten EF, Greene MI, Hancock WW. (2009) Immunomodulatory effects of deacetylase inhibitors: therapeutic targeting of FOXP3+ regulatory T cells. Nat. Rev. Drug. Discov. 8:969–81.CrossRefPubMedGoogle Scholar
  24. 24.
    Verdin E, Paras P Jr, Van Lint C. (1993) Chromatin disruption in the promoter of human immunodeficiency virus type 1 during transcriptional activation. EMBO J. 12:3249–3259.CrossRefPubMedGoogle Scholar
  25. 25.
    Williams SA, et al. (2006) NF-kappaB p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation. EMBO J. 25:139–49.CrossRefPubMedGoogle Scholar
  26. 26.
    Keedy KS, et al. (2009) A limited group of class I histone deacetylases acts to repress human immunodeficiency virus type 1 expression. J. Virol. 83:4749–56.CrossRefPubMedGoogle Scholar
  27. 27.
    Coull JJ, et al. (2000) The human factors YY1 and LSF repress the human immunodeficiency virus type 1 long terminal repeat via recruitment of histone deacetylase 1. J. Virol. 74:6790–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Hsia SC, Shi YB. (2002) Chromatin disruption and histone acetylation in regulation of the human immunodeficiency virus type 1 long terminal repeat by thyroid hormone receptor. Mol. Cell. Biol. 22:4043–52.CrossRefPubMedGoogle Scholar
  29. 29.
    Jiang G, Espeseth A, Hazuda DJ, Margolis DM. (2007) c-Myc and Sp1 contribute to proviral latency by recruiting histone deacetylase 1 to the human immunodeficiency virus type 1 promoter. J. Virol. 81:10914–23.CrossRefPubMedGoogle Scholar
  30. 30.
    Tyagi M, Karn J. (2007) CBF-1 promotes transcriptional silencing during the establishment of HIV-1 latency. EMBO J. 26:4985–95.CrossRefPubMedGoogle Scholar
  31. 31.
    Imai K, Okamoto T. (2006) Transcriptional repression of human immunodeficiency virus type 1 by AP-4. J. Biol. Chem. 281:12495–505.CrossRefPubMedGoogle Scholar
  32. 32.
    Lusic M, Marcello A, Cereseto A, Giacca M. (2003) Regulation of HIV-1 gene expression by histone acetylation and factor recruitment at the LTR promoter. EMBO J. 22:6550–61.CrossRefPubMedGoogle Scholar
  33. 33.
    Thierry S, et al. (2004) Cell cycle arrest in G2 induces human immunodeficiency virus type 1 transcriptional activation through histone acetylation and recruitment of CBP, NF-kappaB, and c-Jun to the long terminal repeat promoter. J. Virol. 78:12198–206.CrossRefPubMedGoogle Scholar
  34. 34.
    Lehrman G, et al. (2005) Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet. 366:549–55.CrossRefPubMedGoogle Scholar
  35. 35.
    Siliciano JD, et al. (2007) Stability of the latent reservoir for HIV-1 in patients receiving valproic acid. J. Infect. Dis. 195:833–36.CrossRefPubMedGoogle Scholar
  36. 36.
    Sagot-Lerolle N, et al. (2008) Prolonged valproic acid treatment does not reduce the size of latent HIV reservoir. Aids. 22:1125–9.CrossRefPubMedGoogle Scholar
  37. 37.
    Archin NM, et al. (2008) Valproic acid without intensified antiviral therapy has limited impact on persistent HIV infection of resting CD4+ T cells. Aids. 22:1131–5.CrossRefPubMedGoogle Scholar
  38. 38.
    Archin NM, et al. (2010) Antiretroviral intensification and valproic acid lack sustained effect on residual HIV-1 viremia or resting CD4+ cell infection. PLoS One. 5:e9390.CrossRefPubMedGoogle Scholar
  39. 39.
    Matalon S, et al. (2010) The histone deacetylase inhibitor ITF2357 decreases surface CXCR4 and CCR5 expression on CD4(+) T-cells and monocytes and is superior to valproic acid for latent HIV-1 expression in vitro. J. Acquir. Immune Defic. Syndr. 54:1–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R. (2007) FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist. 12:1247–52.CrossRefPubMedGoogle Scholar
  41. 41.
    Archin NM, et al. (2009) Expression of latent HIV induced by the potent HDAC inhibitor suberoylanilide hydroxamic acid. AIDS Res. Hum. Retroviruses. 25:207–12.CrossRefPubMedGoogle Scholar
  42. 42.
    Edelstein LC, Micheva-Viteva S, Phelan BD, Dougherty JP. (2009) Short communication: activation of latent HIV type 1 gene expression by suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor approved for use to treat cutaneous T cell lymphoma. AIDS Res. Hum. Retroviruses. 25:883–7.CrossRefPubMedGoogle Scholar
  43. 43.
    Furlan A, et al. (2011) Pharmacokinetics, safety and inducible cytokine responses during a phase 1 trial of the oral histone deacetylase inhibitor ITF2357 (givinostat). Mol. Med. 17:353–362.CrossRefPubMedGoogle Scholar
  44. 44.
    Vojinovic J, Damjanov N. (2011) HDAC inhibition in rheumatoid arthritis and juvenile idiopathic arthritis. Mol. Med. 17:397–403.CrossRefPubMedGoogle Scholar
  45. 45.
    Khan N, et al. (2008) Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors. Biochem. J. 409:581–9.CrossRefPubMedGoogle Scholar
  46. 46.
    Gimsing P, et al. (2008) A phase I clinical trial of the histone deacetylase inhibitor belinostat in patients with advanced hematological neoplasia. Eur. J. Haematol. 81:170–6.CrossRefPubMedGoogle Scholar
  47. 47.
    Mackay HJ, et al. Phase II trial of the histone deacetylase inhibitor belinostat in women with platinum resistant epithelial ovarian cancer and micropapillary (LMP) ovarian tumours. Eur. J. Cancer. 46:1573-9.CrossRefPubMedGoogle Scholar
  48. 48.
    Archin NM, et al. (2009) Expression of latent human immunodeficiency type 1 is induced by novel and selective histone deacetylase inhibitors. Aids. 23:1799–806.CrossRefPubMedGoogle Scholar
  49. 49.
    Valenzuela-Fernandez A, et al. (2005) Histone deacetylase 6 regulates human immunodeficiency virus type 1 infection. Mol. Biol. Cell 16:5445–54.CrossRefPubMedGoogle Scholar
  50. 50.
    Morselli PL, Franco-Morselli R. (1980) Clinical pharmacokinetics of antiepileptic drugs in adults. Pharmacol. Ther. 10:65–101.CrossRefPubMedGoogle Scholar
  51. 51.
    Kuller LH, et al. (2008) Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 5:e203.CrossRefPubMedGoogle Scholar
  52. 52.
    Baker JV, et al. (2011) Changes in inflammatory and coagulation biomarkers: a randomized comparison of immediate versus deferred antiretroviral therapy in patients with HIV infection. J. Acquir. Immune Defic. Syndr. 56:36–43.CrossRefPubMedGoogle Scholar
  53. 53.
    Laughlin MA, et al. (1993) Sodium butyrate treatment of cells latently infected with HIV-1 results in the expression of unspliced viral RNA. Virology. 196:496–505.CrossRefPubMedGoogle Scholar
  54. 54.
    Van Lint C, Emiliani S, Ott M, Verdin E. (1996) Transcriptional activation and chromatin remodeling of the HIV-1 promoter in response to histone acetylation. EMBO J. 15:1112–20.CrossRefPubMedGoogle Scholar
  55. 55.
    Witvrouw M, et al. (1997) Cell type-dependent effect of sodium valproate on human immunodeficiency virus type 1 replication in vitro. AIDS Res. Hum. Retroviruses. 13:187–92.CrossRefPubMedGoogle Scholar
  56. 56.
    El Kharroubi A, Piras G, Zensen R, Martin MA. (1998) Transcriptional activation of the integrated chromatin-associated human immunodeficiency virus type 1 promoter. Mol. Cell. Biol. 18:2535–44.CrossRefPubMedGoogle Scholar
  57. 57.
    Ylisastigui L, Archin NM, Lehrman G, Bosch RJ, Margolis DM. (2004) Coaxing HIV-1 from resting CD4 T cells: histone deacetylase inhibition allows latent viral expression. Aids. 18:1101–8.CrossRefPubMedGoogle Scholar
  58. 58.
    Contreras X, et al. (2009) Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells. J. Biol. Chem. 284:6782–9.CrossRefPubMedGoogle Scholar
  59. 59.
    Savarino A, et al. (2009) “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. Retrovirology. 6:52.CrossRefPubMedGoogle Scholar
  60. 60.
    Reuse S, et al. (2009) Synergistic activation of HIV-1 expression by deacetylase inhibitors and prostratin: implications for treatment of latent infection. PLoS One. 4:e6093.CrossRefPubMedGoogle Scholar
  61. 61.
    Shehu-Xhilaga M, et al. (2009) The novel histone deacetylase inhibitors metacept-1 and metacept-3 potently increase HIV-1 transcription in latently infected cells. Aids. 23:2047–50.CrossRefPubMedGoogle Scholar
  62. 62.
    Choi BS, et al. Novel histone deacetylase inhibitors CG05 and CG06 effectively reactivate latently infected HIV-1. Aids. 24:609-11.CrossRefPubMedGoogle Scholar
  63. 63.
    Yin H, Zhang Y, Zhou X, Zhu H. (2010) Histonedeacetylase inhibitor Oxamflatin increase HIV-1 transcription by inducing histone modification in latently infected cells. Mol. Biol. Rep. 2010, Dec 23 [Epub ahead of print].Google Scholar
  64. 64.
    Colin L, Van Lint C. (2009) Molecular control of HIV-1 postintegration latency: implications for the development of new therapeutic strategies. Retrovirology. 6:111.CrossRefPubMedGoogle Scholar

Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • Shay Matalon
    • 1
  • Thomas A Rasmussen
    • 2
  • Charles A Dinarello
    • 1
  1. 1.Department of Medicine, Division of Infectious DiseasesUniversity of Colorado DenverAuroraUSA
  2. 2.Department of Infectious DiseasesAarhus University HospitalSkejbyDenmark

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