학술논문
Epigenetic landscape in the kick-and-kill therapeutic vaccine BCN02 clinical trial is associated with antiretroviral treatment interruption (ATI) outcome
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article
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Oriol-Tordera, Bruna; Esteve-Codina, Anna; Berdasco, María; Rosás-Umbert, Míriam; Gonçalves, Elena; Duran-Castells, Clara; Català-Moll, Francesc; Llano, Anuska; Cedeño, Samandhy; Puertas, Maria C; Tolstrup, Martin; Søgaard, Ole S; Clotet, Bonaventura; Martínez-Picado, Javier; Hanke, Tomáš; Combadiere, Behazine; Paredes, Roger; Hartigan-O'Connor, Dennis; Esteller, Manel; Meulbroek, Michael; Calle, María Luz; Sanchez-Pla, Alex; Moltó, José; Mothe, Beatriz; Brander, Christian; Ruiz-Riol, Marta
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Abstract
BackgroundThe BCN02-trial combined therapeutic vaccination with a viral latency reversing agent (romidepsin, RMD) in HIV-1-infected individuals and included a monitored antiretroviral pause (MAP) as an efficacy read-out identifying individuals with an early or late (< or > 4weeks) viral-rebound. Integrated -omics analyses were applied prior treatment interruption to identify markers of virus control during MAP.MethodsPBMC, whole-genome DNA methylation and transcriptomics were assessed in 14 BCN02 participants, including 8 Early and 4 Late viral-rebound individuals. Chromatin state, histone marks and integration analysis (histone-3 acetylation (H3Ac), viral load, proviral levels and HIV-specific T cells responses) were included. REDUC-trial samples (n = 5) were included as a control group for RMD administration alone.FindingsDNA methylation imprints after receiving the complete intervention discriminated Early versus Late viral-rebound individuals before MAP. Also, differential chromatin accessibility and histone marks at DNA methylation level were detected. Importantly, the differential DNA methylation positions (DMPs) between Early and Late rebounders before MAP were strongly associated with viral load, proviral levels as well as the HIV-specific T-cell responses. Most of these DMPs were already present prior to the intervention and accentuated after RMD infusion.InterpretationThis study identifies host DNA methylation profiles and epigenetic cascades that are predictive of subsequent virus control in a kick-and-kill HIV cure strategy.FundingEuropean Union Horizon 2020 Framework Programme for Research and Innovation under Grant Agreement N°681137-EAVI2020 and N°847943-MISTRAL, the Ministerio de Ciencia e Innovación (SAF2017_89726_R), and the National Institutes of Health-National Institute of Allergy and Infectious Diseases Program Grant P01-AI131568.