The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo

PLoS Pathog. 2015 Sep 17;11(9):e1005142. doi: 10.1371/journal.ppat.1005142. eCollection 2015 Sep.

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.

Trial registration: clinicaltrials.gov NTC02092116.

Trial registration: ClinicalTrials.gov NCT02092116.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AIDS Vaccines / adverse effects
  • AIDS Vaccines / therapeutic use
  • Acetylation / drug effects
  • Adult
  • 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
  • Depsipeptides / administration & dosage
  • Depsipeptides / adverse effects
  • Depsipeptides / therapeutic use*
  • Drug Interactions
  • Female
  • Follow-Up Studies
  • 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
  • Histones / blood
  • Histones / metabolism
  • Humans
  • Infusions, Intravenous
  • Lymphocytes / drug effects
  • Lymphocytes / immunology
  • Lymphocytes / metabolism
  • Male
  • Middle Aged
  • Protein Processing, Post-Translational / drug effects
  • RNA, Viral / blood*
  • RNA, Viral / metabolism
  • Viral Load / drug effects
  • Virus Activation / drug effects*
  • Virus Latency / drug effects*

Substances

  • AIDS Vaccines
  • Anti-HIV Agents
  • Biomarkers
  • Depsipeptides
  • Histones
  • RNA, Viral
  • Vacc-4x
  • romidepsin

Associated data

  • ClinicalTrials.gov/NCT02092116

Grant support

This study was funded by a grant from the Research Council of Norway (GLOBVAC) program (Nr: 235955) and Bionor Pharma ASA. The Research Council of Norway had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Bionor Pharma ASA contributed to the study design and the preparation of the manuscript.