The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo
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 r...
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Published in | PLoS pathogens Vol. 11; no. 9; p. e1005142 |
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Main Authors | , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Public Library of Science
01.09.2015
Public Library of Science (PLoS) |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 Conceived and designed the experiments: OSS TAR LØ MT SL. Performed the experiments: OSS SL MEG CRB RO ASK MHS PWD SKN WJHC KKK GP MS KK RF NC TAR MT. Analyzed the data: OSS SL CRB RO ASK MHS PWD SKN WJHC KKK GP RF NC TAR MT. Contributed reagents/materials/analysis tools: CRB RO ASK MHS PWD SKN WJHC KKK GP MS KK RF NC. Wrote the paper: OSS TAR LØ MT RO PWD. I have read the journal's policy and the authors of this manuscript have the following competing interests: MS is an employee of Bionor Pharma ASA and has shares in the company. KK is a consultant to Bionor Pharma ASA. The other authors declare no competing interests. This does not alter our adherence to all PLOS policies on sharing data and materials. |
ISSN: | 1553-7374 1553-7366 1553-7374 |
DOI: | 10.1371/journal.ppat.1005142 |