Sequential treatment with 5‐aza‐2′‐deoxycytidine and deacetylase inhibitors reactivates HIV‐1. Issue 2 (17th December 2015)

• Record Type: Journal Article
• Authors: Bouchat, Sophie; Delacourt, Nadège; Kula, Anna; Darcis, Gilles; Van Driessche, Benoit; Corazza, Francis; Gatot, Jean‐Stéphane; Melard, Adeline; Vanhulle, Caroline; Kabeya, Kabamba; Pardons, Marion; Avettand‐Fenoel, Véronique; Clumeck, Nathan; De Wit, Stéphane; Rohr, Olivier; Rouzioux, Christine; Van Lint, Carine
• Is Part Of: EMBO molecular medicine. Volume 8:Issue 2(2016)
• Page Start: 117
• Page End: 138
• Publication Date: 2015-12-17
• Subjects: demethylating agent -- epigenetics -- HDACIs -- HIV latency -- HIV reservoir; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201505557
• Languages: English
• ISSNs: 1757-4676

Abstract

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. Synopsis: Sequential administration of latency‐reversing agents (LRAs), namely deacetylase inhibitors (HDACIs) and demethylating agents, together with an efficient cART, could represent an adjuvant anti‐HIV‐1 therapy to induce viral production and possibly reduce the size of latent HIV‐1 reservoirs. A sequential treatment with 5‐AzadC and HDACIs is more effective both in vitro and ex vivo at inducing HIV gene expression than the corresponding simultaneous treatments, highlighting for the first time the importance of treatment schedule for LRAs combinations. Combining 5‐AzadC + panobinostat and 5‐AzadC + romidepsin show reactivation potentials at concentrations lower than the human tolerable plasmatic concentrations. These findings are valuable for designing future anti‐latency therapeutic strategies and thereby constitute a step forward in achieving HIV remission. Abstract : Sequential administration of latency‐reversing agents (LRAs), namely deacetylase inhibitors (HDACIs) and demethylating agents, together with an efficient cART, could represent an adjuvant anti‐HIV‐1 therapy to induce viral production and possibly reduce the size of latent HIV‐1 reservoirs.