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The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo (Romidepsin Reverses HIV-1 Latency In Vivo)

Søgaard, Ole S ; Graversen, Mette E ; Leth, Steffen ; Olesen, Rikke ; Brinkmann, Christel R ; Nissen, Sara K ; Kjaer, Anne Sofie ; Schleimann, Mariane H ; Denton, Paul W ; Hey-Cunningham, William J ; Koelsch, Kersten K ; Pantaleo, Giuseppe ; Krogsgaard, Kim ; Sommerfelt, Maja ; Fromentin, Remi ; Chomont, Nicolas ; Rasmussen, Thomas A ; Østergaard, Lars ; Tolstrup, Martin Siliciano, Robert F. (Editor)

2015, Vol.11(9), p.e1005142 [Periódico revisado por pares]

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  • Título:
    The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo (Romidepsin Reverses HIV-1 Latency In Vivo)
  • Autor: Søgaard, Ole S ; Graversen, Mette E ; Leth, Steffen ; Olesen, Rikke ; Brinkmann, Christel R ; Nissen, Sara K ; Kjaer, Anne Sofie ; Schleimann, Mariane H ; Denton, Paul W ; Hey-Cunningham, William J ; Koelsch, Kersten K ; Pantaleo, Giuseppe ; Krogsgaard, Kim ; Sommerfelt, Maja ; Fromentin, Remi ; Chomont, Nicolas ; Rasmussen, Thomas A ; Østergaard, Lars ; Tolstrup, Martin
  • Siliciano, Robert F. (Editor)
  • Assuntos: Research Article
  • É parte de: 2015, Vol.11(9), p.e1005142
  • Descrição: 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/m 2 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 ; One proposed way of curing HIV is to activate virus transcription and kill latently infected cells while the presence of antiretroviral therapy prevents spreading the infection. Induction of global T cell activation by mitogenic or other potent activators effectively reverses HIV-1 from latency ex vivo , but such compounds are generally too toxic for clinical use. Therefore, investigating the capacity of small molecule latency reversing agents to induce production of virus without causing global T cell activation has been a top research priority for scientists in recent years. In the present clinical trial, we demonstrate that significant viral reactivation can be safely induced using the depsipeptide romidepsin (HDAC inhibitor) in long-term suppressed HIV-1 individuals on antiretroviral therapy. Following each romidepsin infusion, we observed clear increases in lymphocyte H3 acetylation, HIV-1 transcription, and plasma HIV-1 RNA. Importantly, this reversal of HIV-1 latency could be measured using standard clinical assays for detection of plasma HIV-1 RNA. Furthermore, romidepsin did not alter the proportion of HIV-specific T cells or inhibit T cell cytokine production which is critically important for future trials combining HDAC inhibitors with interventions (e.g. therapeutic HIV-1 vaccination) designed to enhance killing of latently infected cells.
  • Idioma: Inglês

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