Article (Scientific journals)
Synergistic activation of HIV-1 expression by deacetylase inhibitors and prostratin: implications for treatment of latent infection
Reuse, sophie; Calao, Miriam; Kabeya, Kabamba et al.
2009In PLoS ONE, 4 (6), p. 6093
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Keywords :
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
Abstract :
[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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
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 
Quivy, Vincent
Vanhulle, Caroline
Lamine, Aurelia
Vaira, Dolorès ;  Centre Hospitalier Universitaire de Liège - CHU > Hématologie biologique et immuno hématologie
Demonte, Dominique
Martinelli, Valerie
Veithen, Emmanuelle
Cherrier, Thomas ;  Université de Liège - ULiège > GIGA Research
Avettand, Veronique
Poutrel, Solene
Piette, Jacques ;  Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Virologie - Immunologie - GIGA-Research
de Launoit, Yvan
Moutschen, Michel  ;  Centre Hospitalier Universitaire de Liège - CHU > Maladies infectieuses et médecine interne générale
Burny, Arsène ;  Université de Liège - ULiège > Agro Biotech Gembloux
Rouzioux, Christine
De Wit, Stephane
Herbein, Georges
Rohr, Olivier
Collette, Yves
Lambotte, Olivier
Clumeck, Nathan
Van Lint, Carine
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Synergistic activation of HIV-1 expression by deacetylase inhibitors and prostratin: implications for treatment of latent infection
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Public Library of Science, San Franscisco, United States
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