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The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo
Open accessAbstract
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.
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Cited by
International AIDS Society global scientific strategy: towards an HIV cure 2016
International AIDS Society Towards a Cure Working Group, Deeks, S. G., Lewin, S. R., Ross, A. L., Ananworanich, J., Benkirane, M., Cannon, P., Chomont, N., Douek, D., Lifson, J. D., et al. (2016) · Nature Medicine · doi:10.1038/nm.4108 · Cited by 425
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Parallel analysis of transcription, integration, and sequence of single HIV-1 proviruses
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Ait-Ammar, A., Kula, A., Darcis, G., Verdikt, R., De Wit, S., Gautier, V., Mallon, P. W. G., Marcello, A., Rohr, O., & Van Lint, C. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.03060 · Cited by 163
Metadata
- Authors
- Søgaard, O. S., Graversen, M. E., Leth, S., Olesen, R., Brinkmann, C. R., Nissen, S. K., Kjaer, A. S., Schleimann, M. H., Denton, P. W., Hey-Cunningham, W. J., Koelsch, K. K., Pantaleo, G., Krogsgaard, K., Sommerfelt, M., Fromentin, R., Chomont, N., Rasmussen, T. A., Østergaard, L., & Tolstrup, M.
- Venue
- PLOS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-09-17
- Volume
- 11
- Issue
- 9
- Pages
- e1005142
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- OpenAlex
- W2098194107
- Cited by
- 516
- References
- 8
- FWCI
- 29.92
- Type
- journal article
- Language
- en
- Open access
- gold
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- Søgaard, O. S., Graversen, M. E., Leth, S., Olesen, R., Brinkmann, C. R., Nissen, S. K., Kjaer, A. S., Schleimann, M. H., Denton, P. W., Hey-Cunningham, W. J., Koelsch, K. K., Pantaleo, G., Krogsgaard, K., Sommerfelt, M., Fromentin, R., Chomont, N., Rasmussen, T. A., Østergaard, L., & Tolstrup, M. (2015). The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo. PLOS Pathogens. https://doi.org/10.1371/journal.ppat.1005142
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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