title: Sequential treatment with 5-aza-2'-deoxycytidine and deacetylase inhibitors reactivates HIV-1.
abstract: Reactivation of HIV gene expression in latently infected cells together with an efficient cART has been proposed as an adjuvant therapy aimed at eliminating/decreasing the reservoir size. Results from HIV clinical trials using deacetylase inhibitors (HDACIs) question the efficiency of these latency-reversing agents (LRAs) used alone and underline the need to evaluate other LRAs in combination with HDACIs. Here, we evaluated the therapeutic potential of a demethylating agent (5-AzadC) in combination with clinically tolerable HDACIs in reactivating HIV-1 from latency first in vitro and next ex vivo. We showed that a sequential treatment with 5-AzadC and HDACIs was more effective than the corresponding simultaneous treatment both in vitro and ex vivo. Interestingly, only two of the sequential LRA combinatory treatments tested induced HIV-1 particle recovery in a higher manner than the drugs alone ex vivo and at concentrations lower than the human tolerable plasmatic concentrations. Taken together, our data reveal the benefit of using combinations of 5-AzadC with an HDACI and, for the first time, the importance of treatment time schedule for LRA combinations in order to reactivate HIV.
authors.affiliation: Service of Molecular Virology, Department of Molecular Biology (DBM), Université Libre de Bruxelles (ULB), Gosselies, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Bouchat
authors.affiliation: Service of Molecular Virology, Department of Molecular Biology (DBM), Université Libre de Bruxelles (ULB), Gosselies, Belgium.
authors.forename: Nadège
authors.initials: N
authors.lastname: Delacourt
authors.affiliation: Service of Molecular Virology, Department of Molecular Biology (DBM), Université Libre de Bruxelles (ULB), Gosselies, Belgium.
authors.forename: Anna
authors.initials: A
authors.lastname: Kula
authors.affiliation: Service of Molecular Virology, Department of Molecular Biology (DBM), Université Libre de Bruxelles (ULB), Gosselies, Belgium Service des Maladies Infectieuses, Centre Hospitalier Universitaire (CHU) de Liège, Domaine Universitaire du Sart-Tilman, Université de Liège, Liège, Belgium.
authors.forename: Gilles
authors.initials: G
authors.lastname: Darcis
authors.affiliation: Service of Molecular Virology, Department of Molecular Biology (DBM), Université Libre de Bruxelles (ULB), Gosselies, Belgium.
authors.forename: Benoit
authors.initials: B
authors.lastname: Van Driessche
authors.affiliation: Laboratory of Immunology, IRISLab, CHU-Brugmann, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Francis
authors.initials: F
authors.lastname: Corazza
authors.affiliation: Service of Molecular Virology, Department of Molecular Biology (DBM), Université Libre de Bruxelles (ULB), Gosselies, Belgium.
authors.forename: Jean-Stéphane
authors.initials: JS
authors.lastname: Gatot
authors.affiliation: Service de Virologie, EA7327, AP-HP, Hôpital Necker-Enfants-Malades, Université Paris-Descartes, Paris, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Melard
authors.affiliation: Service of Molecular Virology, Department of Molecular Biology (DBM), Université Libre de Bruxelles (ULB), Gosselies, Belgium.
authors.forename: Caroline
authors.initials: C
authors.lastname: Vanhulle
authors.affiliation: Service des Maladies Infectieuses, CHU St-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Kabamba
authors.initials: K
authors.lastname: Kabeya
authors.affiliation: Service of Molecular Virology, Department of Molecular Biology (DBM), Université Libre de Bruxelles (ULB), Gosselies, Belgium.
authors.forename: Marion
authors.initials: M
authors.lastname: Pardons
authors.affiliation: Service de Virologie, EA7327, AP-HP, Hôpital Necker-Enfants-Malades, Université Paris-Descartes, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Avettand-Fenoel
authors.affiliation: Service des Maladies Infectieuses, CHU St-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Nathan
authors.initials: N
authors.lastname: Clumeck
authors.affiliation: Service des Maladies Infectieuses, CHU St-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Stéphane
authors.initials: S
authors.lastname: De Wit
authors.affiliation: IUT Louis Pasteur de Schiltigheim, University of Strasbourg, Schiltigheim, France Institut Universitaire de France (IUF), Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Rohr
authors.affiliation: Service de Virologie, EA7327, AP-HP, Hôpital Necker-Enfants-Malades, Université Paris-Descartes, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Rouzioux
authors.affiliation: Service of Molecular Virology, Department of Molecular Biology (DBM), Université Libre de Bruxelles (ULB), Gosselies, Belgium cvlint@ulb.ac.be.
authors.forename: Carine
authors.initials: C
authors.lastname: Van Lint
mesh_terms: D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D002478:Cells, Cultured; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D012367:RNA, Viral / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014775:Virus Activation / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D012367:RNA, Viral; D000077209:Decitabine; D001374:Azacitidine
keywords: HDACIs; HIV latency; HIV reservoir; demethylating agent; epigenetics