Sequential treatment with 5‐aza‐2′‐deoxycytidine and deacetylase inhibitors reactivates <scp>HIV</scp>‐1

Bouchat, Sophie; Delacourt, Nadège; Kula, Anna; Darcis, Gilles; Driessche, Benoît Van; Corazza, Francis; Gatot, Jean-Stéphane; Mélard, Adeline; Vanhulle, Caroline; Kabeya, Kabamba; Pardons, Marion; Avettand-Fènoël, Véronique; Clumeck, Nathan; Wit, Stéphane De; Rohr, Olivier; Rouzioux, Christine; Lint, Carine Van

doi:10.15252/emmm.201505557

Cited by 72 publications

(88 citation statements)

References 77 publications

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“…Numerous studies indicate that combinations of different LRAs are more effective than single agents in reactivating latent HIV-1 reservoirs (22, 46). This is also true of the histone methyltransferase inhibitors, which exhibit synergistic effects when used combinatorially with other agents, such as IL-15 or SAHA.…”

Section: Discussionmentioning

confidence: 99%

Multiple Histone Lysine Methyltransferases Are Required for the Establishment and Maintenance of HIV-1 Latency

Nguyen

Das

Dobrowolski

et al. 2017

mBio

164

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We showed previously that the histone lysine methyltransferase (HKMT) H3K27me3 (EZH2) is the catalytic subunit of Polycomb repressive complex 2 (PRC2) and is required for the maintenance of HIV-1 latency in Jurkat T cells. Here we show, by using chromatin immunoprecipitation experiments, that both PRC2 and euchromatic histone-lysine N-methyltransferase 2 (EHMT2), the G9a H3K9me2-3 methyltransferase, are highly enriched at the proviral 5′ long terminal repeat (LTR) and rapidly displaced upon proviral reactivation. Clustered regularly interspaced short palindromic repeat(s) (CRISPR)-mediated knockout of EZH2 caused depletion of both EZH2 and EHMT2, but CRISPR-mediated knockout of EHMT2 was selective for EHMT2, consistent with the failure of EHMT2 knockouts to induce latent proviruses in this system. Either (i) knockout of methyltransferase by short hairpin RNA in Jurkat T cells prior to HIV-1 infection or (ii) inhibition of the enzymes with drugs significantly reduced the levels of the resulting silenced viruses, demonstrating that both enzymes are required to establish latency. To our surprise, inhibition of EZH2 (by GSK-343 or EPZ-6438) or inhibition of EHMT2 (by UNC-0638) in the Th17 primary cell model of HIV latency or resting memory T cells isolated from HIV-1-infected patients receiving highly active antiretroviral therapy, was sufficient to induce the reactivation of latent proviruses. The methyltransferase inhibitors showed synergy with interleukin-15 and suberanilohydroxamic acid. We conclude that both PRC2 and EHMT2 are required for the establishment and maintenance of HIV-1 proviral silencing in primary cells. Furthermore, EZH2 inhibitors such as GSK-343 and EPZ-6438 and the EHMT2 inhibitor UNC-0638 are strong candidates for use as latency-reversing agents in clinical studies.

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Section: Discussionmentioning

confidence: 99%

Multiple Histone Lysine Methyltransferases Are Required for the Establishment and Maintenance of HIV-1 Latency

Nguyen

Das

Dobrowolski

et al. 2017

mBio

164

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“…An inhibitor of transcriptional activator Runx1 called R05-3335 demonstrated synergy with vorinostat in patient PBMCs ex vivo (89). Panobinostat and romidepsin synergized with 5-azadC, a DNA demethylating agent (90). A human lectin, galectin-9, synergized in patient cells ex vivo with vorinostat and JQ1 (91).…”

Section: Lra Combination Therapymentioning

confidence: 99%

Novel Latency Reversal Agents for HIV-1 Cure

2018

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Antiretroviral therapy (ART) has rendered HIV-1 infection a treatable illness, however ART is not curative due to the persistence of replication-competent, latent proviruses in long-lived resting T cells. Strategies that target these latently infected cells and allow for immune recognition and clearance of this reservoir will be necessary to eradicate HIV-1 in infected individuals. This review describes current pharmacologic approaches to reactivate the latent reservoir in a manner that infected cells can be recognized and targeted, with the ultimate goal of achieving an HIV-1 cure.

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“…Some types of anticancer chemotherapy can have antilatency effects (228,229). Further studies are needed to evaluate the effects of chemotherapy on HIV reservoirs.…”

Section: Total Hiv Dna Can Be Used To Evaluate Treatment Strategies mentioning

confidence: 99%

Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

et al. 2016

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SUMMARYHIV-1 DNA persists in infected cells despite combined antiretroviral therapy (cART), forming viral reservoirs. Recent trials of strategies targeting latent HIV reservoirs have rekindled hopes of curing HIV infection, and reliable markers are thus needed to evaluate viral reservoirs. Total HIV DNA quantification is simple, standardized, sensitive, and reproducible. Total HIV DNA load influences the course of the infection and is therefore clinically relevant. In particular, it is predictive of progression to AIDS and death, independently of HIV RNA load and the CD4 cell count. Baseline total HIV DNA load is predictive of the response to cART. It declines during cART but remains quantifiable, at a level that reflects both the history of infection (HIV RNA zenith, CD4 cell count nadir) and treatment efficacy (residual viremia, cumulative viremia, immune restoration, immune cell activation). Total HIV DNA load in blood is also predictive of the presence and severity of some HIV-1-associated end-organ disorders. It can be useful to guide individual treatment, notably, therapeutic de-escalation. Although it does not distinguish between replication-competent and -defective latent viruses, the total HIV DNA load in blood, tissues, and cells provides insights into HIV pathogenesis, probably because all viral forms participate in host cell activation and HIV pathogenesis. Total HIV DNA is thus a biomarker of HIV reservoirs, which can be defined as all infected cells and tissues containing all forms of HIV persistence that participate in pathogenesis. This participation may occur through the production of new virions, creating new cycles of infection and disseminating infected cells; maintenance or amplification of reservoirs by homeostatic cell proliferation; and viral transcription and synthesis of viral proteins without new virion production. These proteins can induce immune activation, thus participating in the vicious circle of HIV pathogenesis.

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

Cited by 72 publications

References 77 publications

Multiple Histone Lysine Methyltransferases Are Required for the Establishment and Maintenance of HIV-1 Latency

Multiple Histone Lysine Methyltransferases Are Required for the Establishment and Maintenance of HIV-1 Latency

Novel Latency Reversal Agents for HIV-1 Cure

Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

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