title: The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo.
abstract: 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.
  
  
  BACKGROUND
  clinicaltrials.gov NTC02092116.
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Ole S
authors.initials: OS
authors.lastname: Søgaard
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Mette E
authors.initials: ME
authors.lastname: Graversen
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Steffen
authors.initials: S
authors.lastname: Leth
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Rikke
authors.initials: R
authors.lastname: Olesen
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Christel R
authors.initials: CR
authors.lastname: Brinkmann
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Sara K
authors.initials: SK
authors.lastname: Nissen
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Anne Sofie
authors.initials: AS
authors.lastname: Kjaer
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Mariane H
authors.initials: MH
authors.lastname: Schleimann
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark; Aarhus Institute for Advanced Studies, Aarhus University, Denmark.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Denton
authors.affiliation: Kirby Institute, University of New South Wales Medicine, University of New South Wales Australia, Sydney, Australia.
authors.forename: William J
authors.initials: WJ
authors.lastname: Hey-Cunningham
authors.affiliation: Kirby Institute, University of New South Wales Medicine, University of New South Wales Australia, Sydney, Australia.
authors.forename: Kersten K
authors.initials: KK
authors.lastname: Koelsch
authors.affiliation: Division of Immunology and Allergy, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pantaleo
authors.affiliation: Bionor Pharma ASA, Oslo, Norway.
authors.forename: Kim
authors.initials: K
authors.lastname: Krogsgaard
authors.affiliation: Bionor Pharma ASA, Oslo, Norway.
authors.forename: Maja
authors.initials: M
authors.lastname: Sommerfelt
authors.affiliation: Centre de Recherche du CHUM, Montreal, Quebec, Canada.
authors.forename: Remi
authors.initials: R
authors.lastname: Fromentin
authors.affiliation: Centre de Recherche du CHUM, Montreal, Quebec, Canada; Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Faculty of Medicine, Montreal, Quebec, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chomont
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Rasmussen
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Østergaard
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Tolstrup
mesh_terms: D016915:AIDS Vaccines / Q000009:adverse effects / Q000627:therapeutic use; D000107:Acetylation / Q000187:drug effects; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D015331:Cohort Studies; D047630:Depsipeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004347:Drug Interactions; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology / Q000302:isolation & purification / Q000502:physiology; D006657:Histones / Q000097:blood / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012367:RNA, Viral / Q000097:blood* / Q000378:metabolism; D019562:Viral Load / Q000187:drug effects; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects*
chemical_list: D016915:AIDS Vaccines; D019380:Anti-HIV Agents; D015415:Biomarkers; D047630:Depsipeptides; D006657:Histones; D012367:RNA, Viral; C494182:Vacc-4x; C087123:romidepsin