Journal Article

Synergistic Activation of HIV-1 Expression by Deacetylase Inhibitors and Prostratin: Implications for Treatment of Latent Infection

de Launoit, Yvan, Herbein, Georges, Martinelli, Valérie, Guiguen, Allan, Poutrel, Solène, Van Lint, Carine, Piette, Jacques, Demonte, Dominique, De Wit, Stéphane, Clumeck, Nathan, Vanhulle, Caroline, Lambotte, Olivier, Calao, Miriam, Burny, Arsène, Reuse, Sophie, Rohr, Olivier, Cherrier, Thomas, Rouzioux, Christine, Collette, Yves, Quivy, Vincent, Veithen, Emmanuelle, Moutschen, Michel, Kabeya, Kabamba, Lamine, Aurélia, Avettand, Véronique, Gatot, Jean-Stéphane, Vaira, Dolores

2009

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acquired immune deficiency syndrome / Activation / Adult / Aged / AIDS / Anti-HIV Agents / Anti-HIV Agents - pharmacology / Antiretroviral agents / Antiretroviral drugs / Biochemistry, biophysics & molecular biology / Biochimie, biophysique & biologie moléculaire / CD4 antigen / CD8 antigen / CD8-Positive T-Lymphocytes / CD8-Positive T-Lymphocytes - metabolism / Cell growth / Cell Nucleus / Cell Nucleus - metabolism / Combined treatment / Control / Cytoplasm / Cytoplasm - metabolism / Deoxyribonucleic acid / DNA / DNA-directed RNA polymerase / Drug Synergism / Elongation / Enzyme Inhibitors / Enzyme Inhibitors - pharmacology / Gene expression / Genetic research / Health aspects / Highly active antiretroviral therapy / Histone deacetylase / HIV / HIV Infections / HIV Infections - drug therapy / HIV-1 / HIV-1 - enzymology / HIV-1 - metabolism / HIV-1/enzymology/metabolism / Human immunodeficiency virus / Humans / I-kappa B Proteins / I-kappa B Proteins - metabolism / Infections / Infectious Diseases/HIV Infection and AIDS / Inhibitors / Laboratories / Latent infection / Leukocytes (mononuclear) / Life Sciences / Long terminal repeat / Lymphocytes / Lymphocytes T / Microbiology and Parasitology / Middle Aged / Molecular Biology/Transcription Initiation and Activation / Monocytes / Monocytes - virology / NF-kappa B / NF-kappa B - antagonists & inhibitors / NF-KappaB Inhibitor alpha / NF-κB protein / Nucleosomes / Nucleosomes - metabolism / Oxidative stress / Patients / Peripheral blood mononuclear cells / Phorbol Esters / Phorbol Esters - pharmacology / Physiological aspects / Replication / Reservoirs / Ribonucleic acid / RNA / RNA polymerase II / Sciences du vivant / Synergism / T cells / Therapy / Transcription / Transcription (Genetics) / Transfection / Virology / Virology/Persistence and Latency / Virology/Viral and Gene Regulation / Virus Latency / Virus Latency - drug effects / Virus replication / Viruses