The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo

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  • 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
  • ,
  • William J Hey-Cunningham, Kirby Institute, University of New South Wales Medicine, University of New South Wales, Australia
  • Kersten K Koelsch, Kirby Institute, University of New South Wales Medicine, University of New South Wales, Australia
  • Giuseppe Pantaleo, Division of Immunology and Allergy, Lausanne University Hospital, Lausanne, Switzerland
  • Kim Krogsgaard, Bionor Pharma ASA, Oslo, Norway, Norway
  • Maja Sommerfelt, Bionor Pharma ASA, Oslo, Norway, Norway
  • Remi Fromentin, Centre de Recherche du CHUM, Montreal, Quebec, Canada, Canada
  • Nicolas Chomont, Centre de Recherche du CHUM, Montreal, Quebec, Canada, Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Faculty of Medicine, Montreal, Quebec, Canada, Canada
  • Thomas A Rasmussen
  • ,
  • Lars Jørgen Østergaard
  • Martin Tolstrup
Pharmacologically-induced activation of replication competent proviruses from latency inthe presence of antiretroviral treatment (ART) has been proposed as a step towards curingHIV-1 infection. However, until now, approaches to reverse HIV-1 latency in humans haveyielded mixed results. Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremicHIV-1 infected adults received intravenous 5 mg/m2 romidepsin (Celgene) once weekly for3 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-1RNA 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 quantifi-able 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, romidepsinsafely 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.

Original languageEnglish
Article numbere1005142
JournalP L o S Pathogens
Pages (from-to)1-22
Number of pages22
Publication statusPublished - 2015

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