The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo
AuthorSogaard, OS; Graversen, ME; Leth, S; Olesen, R; Brinkmann, CR; Nissen, SK; Kjaer, AS; Schleimann, MH; Denton, PW; Hey-Cunningham, WJ; ...
Source TitlePLoS Pathogens
PublisherPUBLIC LIBRARY SCIENCE
University of Melbourne Author/sRasmussen, Thomas
Document TypeJournal Article
CitationsSogaard, 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., Ostergaard, L. & Tolstrup, M. (2015). The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo. PLOS PATHOGENS, 11 (9), https://doi.org/10.1371/journal.ppat.1005142.
Access StatusOpen Access
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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