The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo

PLoS Pathogens

Remi Fromentin¹  Martin Tolstrup²  Rikke Olesen³  Paul W. Denton³  Ole S. Søgaard³  Kersten K. Koelsch³  Mette E. Graversen³  Mariane H. Schleimann³  Anne Sofie Kjaer³  Sara K. Nissen³  Kim Krogsgaard³  Lars Østergaard⁴  Steffen Leth⁵  Maja Sommerfelt⁵  Giuseppe Pantaleo⁵  Christel R. Brinkmann⁵  William J. Hey-Cunningham⁵  Nicolas Chomont⁶  Thomas A. Rasmussen⁶ 

[1] Aarhus Institute for Advanced Studies, Aarhus University, Denmark;Bionor Pharma ASA, Oslo, Norway;Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark;Division of Immunology and Allergy, Lausanne University Hospital, Lausanne, Switzerland;Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark;Kirby Institute, University of New South Wales Medicine, University of New South Wales Australia, Sydney, Australia

关键词: HIV-1;    T cells;    Cytotoxic T cells;    Memory T cells;    HIV;    Blood plasma;    Lymphocytes;    Viral persistence;    latency;   

DOI  :  10.1371/journal.ppat.1005142

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY