The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo.
- Søgaard OS Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
- Graversen ME Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
- Leth S Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
- Olesen R Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
- Brinkmann CR Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
- Nissen SK Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
- Kjaer AS Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
- Schleimann MH Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
- Denton PW 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.
- Hey-Cunningham WJ Kirby Institute, University of New South Wales Medicine, University of New South Wales Australia, Sydney, Australia.
- Koelsch KK Kirby Institute, University of New South Wales Medicine, University of New South Wales Australia, Sydney, Australia.
- Pantaleo G Division of Immunology and Allergy, Lausanne University Hospital, Lausanne, Switzerland.
- Krogsgaard K Bionor Pharma ASA, Oslo, Norway.
- Sommerfelt M Bionor Pharma ASA, Oslo, Norway.
- Fromentin R Centre de Recherche du CHUM, Montreal, Quebec, Canada.
- Chomont N Centre de Recherche du CHUM, Montreal, Quebec, Canada; Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Faculty of Medicine, Montreal, Quebec, Canada.
- Rasmussen TA Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
- Østergaard L Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
- Tolstrup M Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
- 2015-09-18
Published in:
- PLoS pathogens. - 2015
AIDS Vaccines
Acetylation
Adult
Anti-HIV Agents
Antiretroviral Therapy, Highly Active
Biomarkers
Cohort Studies
Depsipeptides
Drug Interactions
Female
Follow-Up Studies
HIV Infections
HIV-1
Histones
Humans
Infusions, Intravenous
Lymphocytes
Male
Middle Aged
Protein Processing, Post-Translational
RNA, Viral
Viral Load
Virus Activation
Virus Latency
English
UNLABELLED
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.
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.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1371/journal.ppat.1005142
- PMID 26379282
- Persistent URL
- https://sonar.ch/global/documents/265225
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