The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo.

• Main Authors: 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, Kersten K Koelsch, Giuseppe Pantaleo, Kim Krogsgaard, Maja Sommerfelt, Remi Fromentin, Nicolas Chomont, Thomas A Rasmussen, Lars Østergaard, Martin Tolstrup
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2015-09-01
• Series: PLoS Pathogens
• Online Access: https://doi.org/10.1371/journal.ppat.1005142
• ISSN: 1553-7366; 1553-7374

<h4>Unlabelled</h4>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.<h4>Trial registration</h4>clinicaltrials.gov NTC02092116.