The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo

• Published in: PLoS pathogens Vol. 11; no. 9; p. e1005142
• Main Authors: Søgaard, Ole S, Graversen, Mette E, Leth, Steffen, Olesen, Rikke, Brinkmann, Christel R, Nissen, Sara K, Kjaer, Anne Sofie, Schleimann, Mariane H, Denton, Paul W, Hey-Cunningham, William J, Koelsch, Kersten K, Pantaleo, Giuseppe, Krogsgaard, Kim, Sommerfelt, Maja, Fromentin, Remi, Chomont, Nicolas, Rasmussen, Thomas A, Østergaard, Lars, Tolstrup, Martin
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.09.2015; Public Library of Science (PLoS)
• Subjects: Acetylation - drug effects; Acquired immune deficiency syndrome; Adult; AIDS; AIDS Vaccines - adverse effects; AIDS Vaccines - therapeutic use; Anti-HIV Agents - administration & dosage; Anti-HIV Agents - adverse effects; Anti-HIV Agents - therapeutic use; Antiretroviral Therapy, Highly Active - adverse effects; Biomarkers - blood; Biomarkers - metabolism; Cohort Studies; Curing; Cytokines; Depsipeptides - administration & dosage; Depsipeptides - adverse effects; Depsipeptides - therapeutic use; Drug Interactions; Drug therapy; Female; Follow-Up Studies; Histones - blood; Histones - metabolism; HIV; HIV Infections - drug therapy; HIV Infections - immunology; HIV Infections - metabolism; HIV Infections - virology; HIV-1 - drug effects; HIV-1 - immunology; HIV-1 - isolation & purification; HIV-1 - physiology; Human immunodeficiency virus; Humans; Infections; Infusions, Intravenous; Lymphocytes; Lymphocytes - drug effects; Lymphocytes - immunology; Lymphocytes - metabolism; Male; Middle Aged; Plasma; Protein Processing, Post-Translational - drug effects; RNA, Viral - blood; RNA, Viral - metabolism; Studies; Viral Load - drug effects; Virus Activation - drug effects; Virus Latency - drug effects
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1005142

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. clinicaltrials.gov NTC02092116.