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

• Published in: EMBO molecular medicine Vol. 8; no. 2; pp. 117 - 138
• Main 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
• Format: Journal Article Web Resource
• Language: English
• Published: London Nature Publishing Group UK 01-02-2016; John Wiley & Sons, Inc; EMBO Press; Wiley Open Access; Wiley-Blackwell; John Wiley and Sons Inc; Springer Nature
• Subjects: Antimitotic agents; Antineoplastic agents; Azacitidine - analogs & derivatives; Azacitidine - pharmacology; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - virology; Cell culture; Cells, Cultured; Clinical trials; Cooperation; Decitabine; demethylating agent; Deoxyribonucleic acid; DNA; DNA methylation; EMBO23; EMBO28; Enzyme Inhibitors - pharmacology; epigenetics; Gene expression; Genetics & genetic processes; Génétique & processus génétiques; HDACIs; Health aspects; Histone Deacetylase Inhibitors - pharmacology; HIV; HIV (Viruses); HIV latency; HIV reservoir; HIV testing; HIV-1 - physiology; Human health and pathology; Human immunodeficiency virus; Humans; Immune system; Infectious diseases; Latency; Latent infection; Life Sciences; Metabolism; Microbiology and Parasitology; Pharmaceutical sciences; Pharmacology; Public health; Real-Time Polymerase Chain Reaction; Research Article; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral - analysis; Sciences du vivant; Studies; Virology; Virus Activation - drug effects; HDACIs; demethylating agent; HIV latency; HIV reservoir; epigenetics
• ISSN: 1757-4676; 1757-4684; 1757-4684
• DOI: 10.15252/emmm.201505557

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.
Graphical 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.