Histone methyltransferase inhibitors induce HIV-1 recovery in resting CD4(+) T cells from HIV-1-infected HAART-treated patients

AIDS. 2012 Jul 31;26(12):1473-82. doi: 10.1097/QAD.0b013e32835535f5.


Objective: Reactivation of HIV-1 expression in persistent reservoirs together with an efficient HAART has been proposed as an adjuvant therapy aimed at reaching a functional cure for HIV. Previously, H3K9 methylation was shown to play a major role in chromatin-mediated repression of the HIV-1 promoter. Here, we evaluated the therapeutic potential of histone methyltransferase inhibitors (HMTIs) in reactivating HIV-1 from latency.

Design: We evaluated the reactivation potential of two specific HMTIs (chaetocin and BIX-01294, two specific inhibitors of Suv39H1 and G9a, respectively) in ex-vivo cultures of resting CD4 T cells isolated from HIV-1-infected HAART-treated individuals.

Methods: We measured HIV-1 recovery in ex-vivo cultures treated with an HMTI alone or in combination with other HIV-1 inducers (in absence of IL-2 and of allogenic stimulation) of CD8-depleted peripheral blood mononuclear cells (PBMCs) or of resting CD4 T cells isolated from 67 HIV-infected, HAART-treated patients with undetectable viral load.

Results: We demonstrated, for the first time, that chaetocin induced HIV-1 recovery in 50% of CD8-depleted PBMCs cultures and in 86% of resting CD4 T-cell cultures isolated from HIV-1-infected, HAART-treated patients, whereas BIX-01294 reactivated HIV-1 expression in 80% of resting CD4 T-cell cultures isolated from similar patients. Moreover, we showed that combinatory treatments including one HMTI and either the histone deacetylase inhibitor suberoylanilide hydroxamic acid or the non-tumor-promoting NF-κB inducer prostratin had a higher reactivation potential than these compounds alone.

Conclusion: Our results constitute a proof-of-concept for the therapeutic potential of HMTIs in strategies aiming at reducing the pool of latent reservoirs in HIV-infected, HAART-treated patient.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiretroviral Therapy, Highly Active
  • Azepines / pharmacology*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / virology*
  • Disease Reservoirs
  • HIV Infections / drug therapy
  • HIV Infections / immunology
  • HIV Infections / virology*
  • HIV-1 / immunology*
  • HIV-1 / physiology
  • Histocompatibility Antigens
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
  • Humans
  • Leukocytes, Mononuclear / immunology
  • Methyltransferases / antagonists & inhibitors
  • Piperazines / pharmacology
  • Quinazolines / pharmacology*
  • Repressor Proteins / antagonists & inhibitors
  • Virus Latency / drug effects


  • Azepines
  • BIX 01294
  • Histocompatibility Antigens
  • Piperazines
  • Quinazolines
  • Repressor Proteins
  • chaetocin
  • SUV39H1 protein, human
  • Histone Methyltransferases
  • Methyltransferases
  • EHMT2 protein, human
  • Histone-Lysine N-Methyltransferase