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

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...

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Main Authors: Sophie Bouchat, Nadège Delacourt, Anna Kula, Gilles Darcis, Benoit Van Driessche, Francis Corazza, Jean‐Stéphane Gatot, Adeline Melard, Caroline Vanhulle, Kabamba Kabeya, Marion Pardons, Véronique Avettand‐Fenoel, Nathan Clumeck, Stéphane De Wit, Olivier Rohr, Christine Rouzioux, Carine Van Lint
Format: Article
Language:English
Published: Springer Nature 2015-12-01
Series:EMBO Molecular Medicine
Subjects:
demethylating agent
epigenetics
HDACIs
HIV latency
HIV reservoir
Online Access:https://doi.org/10.15252/emmm.201505557
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Summary: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.
ISSN:1757-4676
1757-4684

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