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Article Dans Une Revue PLoS ONE Année : 2009

Synergistic activation of HIV-1 expression by deacetylase inhibitors and prostratin: implications for treatment of latent infection.

Sophie Reuse
  • Fonction : Auteur
Miriam Calao
  • Fonction : Auteur
Kabamba Kabeya
  • Fonction : Auteur
Jean-Stéphane Gatot
  • Fonction : Auteur
Vincent Quivy
  • Fonction : Auteur
Caroline Vanhulle
  • Fonction : Auteur
Aurélia Lamine
  • Fonction : Auteur
Dolores Vaira
  • Fonction : Auteur
Dominique Demonte
  • Fonction : Auteur
Valérie Martinelli
  • Fonction : Auteur
Emmanuelle Veithen
  • Fonction : Auteur
Thomas Cherrier
  • Fonction : Auteur
Véronique Avettand
  • Fonction : Auteur
Solène Poutrel
  • Fonction : Auteur
Jacques Piette
  • Fonction : Auteur
Michel Moutschen
  • Fonction : Auteur
Arsène Burny
  • Fonction : Auteur
Stéphane de Wit
  • Fonction : Auteur
Olivier Rohr
  • Fonction : Auteur
Yves Collette
Carine van Lint
  • Fonction : Auteur

Résumé

The persistence of transcriptionally silent but replication-competent HIV-1 reservoirs in Highly Active Anti-Retroviral Therapy (HAART)-treated infected individuals, represents a major hurdle to virus eradication. Activation of HIV-1 gene expression in these cells together with an efficient HAART has been proposed as an adjuvant therapy aimed at decreasing the pool of latent viral reservoirs. Using the latently-infected U1 monocytic cell line and latently-infected J-Lat T-cell clones, we here demonstrated a strong synergistic activation of HIV-1 production by clinically used histone deacetylase inhibitors (HDACIs) combined with prostratin, a non-tumor-promoting nuclear factor (NF)- kappaB inducer. In J-Lat cells, we showed that this synergism was due, at least partially, to the synergistic recruitment of unresponsive cells into the expressing cell population. A combination of prostratin+HDACI synergistically activated the 5' Long Terminal Repeat (5'LTR) from HIV-1 Major group subtypes representing the most prevalent viral genetic forms, as shown by transient transfection reporter assays. Mechanistically, HDACIs increased prostratin-induced DNA-binding activity of nuclear NF-kappaB and degradation of cytoplasmic NF-kappaB inhibitor, IkappaBalpha . Moreover, the combined treatment prostratin+HDACI caused a more pronounced nucleosomal remodeling in the U1 viral promoter region than the treatments with the compounds alone. This more pronounced remodeling correlated with a synergistic reactivation of HIV-1 transcription following the combined treatment prostratin+HDACI, as demonstrated by measuring recruitment of RNA polymerase II to the 5'LTR and both initiated and elongated transcripts. The physiological relevance of the prostratin+HDACI synergism was shown in CD8(+)-depleted peripheral blood mononuclear cells from HAART-treated patients with undetectable viral load. Moreover, this combined treatment reactivated viral replication in resting CD4(+) T cells isolated from similar patients. Our results suggest that combinations of different kinds of proviral activators may have important implications for reducing the size of latent HIV-1 reservoirs in HAART-treated patients.

Domaines

Virologie

Dates et versions

hal-00464770 , version 1 (17-03-2010)

Identifiants

Citer

Sophie Reuse, Miriam Calao, Kabamba Kabeya, Allan Guiguen, Jean-Stéphane Gatot, et al.. Synergistic activation of HIV-1 expression by deacetylase inhibitors and prostratin: implications for treatment of latent infection.. PLoS ONE, 2009, 4 (6), pp.e6093. ⟨10.1371/journal.pone.0006093⟩. ⟨hal-00464770⟩
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