The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo.

Détails

Ressource 1Télécharger: BIB_CFC707BF32ED.P001.pdf (1036.88 [Ko])
Etat: Public
Version: de l'auteur⸱e
ID Serval
serval:BIB_CFC707BF32ED
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo.
Périodique
Plos Pathogens
Auteur⸱e⸱s
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.
ISSN
1553-7374 (Electronic)
ISSN-L
1553-7366
Statut éditorial
Publié
Date de publication
2015
Peer-reviewed
Oui
Volume
11
Numéro
9
Pages
e1005142
Langue
anglais
Notes
Publication types: Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article ; Research Support, Non-U.S. Gov't Publication Status: epublish
Résumé
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.
Mots-clé
AIDS Vaccines/adverse effects, AIDS Vaccines/therapeutic use, Acetylation/drug effects, Adult, Anti-HIV Agents/administration & dosage, Anti-HIV Agents/adverse effects, Antiretroviral Therapy, Highly Active/adverse effects, Biomarkers/blood, Biomarkers/metabolism, Cohort Studies, Depsipeptides/administration & dosage, Depsipeptides/adverse effects, Drug Interactions, Female, Follow-Up Studies, HIV Infections/drug therapy, HIV Infections/immunology, HIV-1/drug effects, HIV-1/immunology, Histones/blood, Histones/metabolism, Humans, Infusions, Intravenous, Lymphocytes/drug effects, Lymphocytes/immunology, Male, Middle Aged, Protein Processing, Post-Translational/drug effects, RNA, Viral/blood, RNA, Viral/metabolism, Viral Load/drug effects, Virus Activation/drug effects, Virus Latency/drug effects
Pubmed
Web of science
Open Access
Oui
Création de la notice
27/10/2015 17:34
Dernière modification de la notice
20/08/2019 15:50
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