The depsipeptide romidepsin reverses HIV-1 latency in vivo.

September 24, 2015 at 7:44 am

PLoS Pathog 2015 Sep 17; 11:e1005142.

Ole S. Søgaard, Mette E. Graversen, Steffen Leth, Rikke Olesen, Christel R. Brinkmann, Sara K. Nissen, Anne Sofie Kjaer, Mariane H. Schleimann, Paul W. Denton, Thomas A. Rasmussen, Lars Østergaard, Martin Tolstrup

Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark

Mette E. Graversen, Steffen Leth, Anne Sofie Kjaer, Mariane H. Schleimann, Paul W. Denton, Lars Østergaard, Martin Tolstrup

Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark

Paul W. Denton

Aarhus Institute for Advanced Studies, Aarhus University, Denmark

William J. Hey-Cunningham, Kersten K. Koelsch

Kirby Institute, University of New South Wales Medicine, University of New South Wales Australia, Sydney, Australia

Giuseppe Pantaleo

Division of Immunology and Allergy, Lausanne University Hospital, Lausanne, Switzerland

Kim Krogsgaard, Maja Sommerfelt

Bionor Pharma ASA, Oslo, Norway

Remi Fromentin, Nicolas Chomont

Centre de Recherche du CHUM, Montreal, Quebec, Canada

Nicolas Chomont

Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Faculty of Medicine, Montreal, Quebec, Canada

Corresponding Author: olesoega@rm.dk   

Pharmacologically-induced activation of replication competent proviruses from latency in the presence of antiretroviral treatment (ART) has been proposed as a step towards curing HIV-1 infection.

However, until now, approaches to reverse HIV-1 latency in humans have yielded mixed results.

Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremic HIV-1 infected adults received intravenous 5 mg/m2 romidepsin (Celgene) once weekly for 3 weeks while maintaining ART.

Lymphocyte histone H3 acetylation, a cellular measure of the pharmacodynamic response to romidepsin, increased rapidly (maximum fold range: 3.7–7.7 relative to baseline) within the first hours following each romidepsin administration.

Concurrently, HIV-1 transcription quantified as copies of cell-associated un-spliced HIV-1 RNA increased significantly from baseline during treatment (range of fold-increase: 2.4–5.0; p = 0.03).

Plasma HIV-1 RNA increased from <20 copies/mL at baseline to readily quantifiable levels at multiple post-infusion time-points in 5 of 6 patients (range 46–103 copies/mL following the second infusion, p = 0.04). Importantly, romidepsin did not decrease the number of HIV-specific T cells or inhibit T cell cytokine production.

Adverse events (all grade 1–2) were consistent with the known side effects of romidepsin. In conclusion, romidepsin safely induced HIV-1 transcription resulting in plasma HIV-1 RNA that was readily detected with standard commercial assays demonstrating that significant reversal of HIV-1 latency in vivo is possible without blunting T cell-mediated immune responses.

These finding have major implications for future trials aiming to eradicate the HIV-1 reservoir.

Trial Registration clinicaltrials.gov NTC02092116

FULL TEXT

http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1005142

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Entry filed under: HIV/SIDA.

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