Reference : Synergistic activation of HIV-1 expression by deacetylase inhibitors and prostratin: ...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Synergistic activation of HIV-1 expression by deacetylase inhibitors and prostratin: implications for treatment of latent infection
Reuse, sophie [Université Libre de Bruxelles - ULB > IBMM > Laboratoire de virologie moléculaire > >]
Calao, Miriam [Université Libre de Bruxelles - ULB > > >IBMM > Laboratoire de virologie moléculaire > >]
Kabeya, Kabamba [> >]
Guiguen, Allan [> >]
GATOT, Jean-Stéphane mailto [> >]
Quivy, Vincent [> >]
Vanhulle, Caroline [> >]
Lamine, Aurelia [> >]
Vaira, Dolorès mailto [Centre Hospitalier Universitaire de Liège - CHU > > Hématologie biologique et immuno hématologie >]
Demonte, Dominique [> >]
Martinelli, Valerie [> >]
Veithen, Emmanuelle [> >]
Cherrier, Thomas mailto [Université de Liège - ULiège > GIGA Research > > >]
Avettand, Veronique [> >]
Poutrel, Solene [> >]
Piette, Jacques mailto [Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Virologie - Immunologie - GIGA-Research >]
de Launoit, Yvan [> >]
Moutschen, Michel mailto [Centre Hospitalier Universitaire de Liège - CHU > > Maladies infectieuses et médecine interne générale >]
Burny, Arsene [> >]
Rouzioux, Christine [> >]
De Wit, Stephane [> >]
Herbein, Georges [> >]
Rohr, Olivier [> >]
Collette, Yves [> >]
Lambotte, Olivier [> >]
Clumeck, Nathan [> >]
Van Lint, Carine [> >]
Public Library of Science
Yes (verified by ORBi)
San Franscisco
United States
[en] Adult ; Aged ; Anti-HIV Agents/pharmacology ; CD8-Positive T-Lymphocytes/metabolism ; Cell Nucleus/metabolism ; Cytoplasm/metabolism ; Drug Synergism ; Enzyme Inhibitors/pharmacology ; HIV Infections/drug therapy ; HIV-1/enzymology/metabolism ; Humans ; I-kappa B Proteins/metabolism ; Middle Aged ; Monocytes/virology ; NF-kappa B/antagonists & inhibitors ; Nucleosomes/metabolism ; Phorbol Esters/pharmacology ; Virus Latency/drug effects
[en] 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.
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