Details

Autor(en) / Beteiligte

• 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
• Sommer, Peter

Titel

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

Ist Teil von

• PloS one, 2009-06, Vol.4 (6), p.e6093

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2009

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.