Sequential treatment with 5‐aza‐2′‐deoxycytidine and deacetylase inhibitors reactivates HIV‐1

EMBO Molecular Medicine - Tập 8 Số 2 - Trang 117-138 - 2016
Sophie Bouchat1, Nadège Delacourt1, Anna Kula1, Gilles Darcis2,1, Benoît Van Driessche1, Francis Corazza3, Jean‐Stéphane Gatot1, Adeline Mélard4, Caroline Vanhulle1, Kabamba Kabeya5, Marion Pardons1, Véronique Avettand-Fènoël4, Nathan Clumeck5, Stéphane De Wit5, Olivier Rohr6,7, Christine Katlama4, Carine Van Lint1
1Service of Molecular Virology, Department of Molecular Biology (DBM), Université Libre de Bruxelles (ULB), Gosselies, Belgium
2Service des Maladies Infectieuses Centre Hospitalier Universitaire (CHU) de Liège Domaine Universitaire du Sart‐Tilman Université de Liège Liège Belgium
3Laboratory of Immunology IRISLab CHU‐Brugmann Université Libre de Bruxelles (ULB) Brussels Belgium
4Service de Virologie EA7327 AP‐HP Hôpital Necker‐Enfants‐Malades Université Paris‐Descartes Paris France
5Service des Maladies Infectieuses CHU St‐Pierre Université Libre de Bruxelles (ULB) Brussels Belgium
6IUT Louis Pasteur de Schiltigheim, University of Strasbourg, Schiltigheim, France
7Institut Universitaire de France (IUF), Paris, France

Tóm tắt

AbstractReactivation 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.

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EMBO Molecular Medicine

Tập 8 Số 2

117-138

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