title: Histone methyltransferase inhibitors induce HIV-1 recovery in resting CD4(+) T cells from HIV-1-infected HAART-treated patients.
abstract: 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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Service of Molecular Virology, Institute of Molecular Biology and Medicine, University of Brussels, Gosselies, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Bouchat
authors.forename: Jean-Stéphane
authors.initials: JS
authors.lastname: Gatot
authors.forename: Kabamba
authors.initials: K
authors.lastname: Kabeya
authors.forename: Christelle
authors.initials: C
authors.lastname: Cardona
authors.forename: Laurence
authors.initials: L
authors.lastname: Colin
authors.forename: Georges
authors.initials: G
authors.lastname: Herbein
authors.forename: Stéphane
authors.initials: S
authors.lastname: De Wit
authors.forename: Nathan
authors.initials: N
authors.lastname: Clumeck
authors.forename: Olivier
authors.initials: O
authors.lastname: Lambotte
authors.forename: Christine
authors.initials: C
authors.lastname: Rouzioux
authors.forename: Olivier
authors.initials: O
authors.lastname: Rohr
authors.forename: Carine
authors.initials: C
authors.lastname: Van Lint
mesh_terms: D023241:Antiretroviral Therapy, Highly Active; D001381:Azepines / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D004197:Disease Reservoirs; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology; D006649:Histocompatibility Antigens; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008780:Methyltransferases / Q000037:antagonists & inhibitors; D010879:Piperazines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors; D017735:Virus Latency / Q000187:drug effects
chemical_list: D001381:Azepines; C518299:BIX 01294; D006649:Histocompatibility Antigens; D010879:Piperazines; D011799:Quinazolines; D012097:Repressor Proteins; C002511:chaetocin; C407843:SUV39H1 protein, human; D000076983:Histone Methyltransferases; D008780:Methyltransferases; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase