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- Title
Synergistic activation of HIV-1 expression by deacetylase inhibitors and prostratin: implications for treatment of latent infection.
- Authors
Reuse, Sophie; Calao, Miriam; Kabeya, Kabamba; Guiguen, Allan; Gatot, Jean-Stéphane; Quivy, Vincent; Vanhulle, Caroline; Lamine, Aurélia; Vaira, Dolores; Demonte, Dominique; Martinelli, Valérie; Veithen, Emmanuelle; Cherrier, Thomas; Avettand, Véronique; Poutrel, Solène; Piette, Jacques; de Launoit, Yvan; Moutschen, Michel; Burny, Arsène; Rouzioux, Christine; De Wit, Stéphane; Herbein, Georges; Rohr, Olivier; Collette, Yves; Lambotte, Olivier; Clumeck, Nathan; Van Lint, Carine
- Abstract
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.
- Publication
PloS one, 2009, Vol 4, Issue 6, pe6093
- ISSN
1932-6203
- Publication type
Journal Article
- DOI
10.1371/journal.pone.0006093