EBioMedicine (Apr 2022)
Epigenetic landscape in the kick-and-kill therapeutic vaccine BCN02 clinical trial is associated with antiretroviral treatment interruption (ATI) outcome
- Bruna Oriol-Tordera,
- Anna Esteve-Codina,
- María Berdasco,
- Míriam Rosás-Umbert,
- Elena Gonçalves,
- Clara Duran-Castells,
- Francesc Català-Moll,
- Anuska Llano,
- Samandhy Cedeño,
- Maria C. Puertas,
- Martin Tolstrup,
- Ole S. Søgaard,
- Bonaventura Clotet,
- Javier Martínez-Picado,
- Tomáš Hanke,
- Behazine Combadiere,
- Roger Paredes,
- Dennis Hartigan-O'Connor,
- Manel Esteller,
- Michael Meulbroek,
- María Luz Calle,
- Alex Sanchez-Pla,
- José Moltó,
- Beatriz Mothe,
- Christian Brander,
- Marta Ruiz-Riol
Affiliations
- Bruna Oriol-Tordera
- IrsiCaixa, AIDS Research Institute, Institute for Health Science Research Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, 2nd floor, Ctra del canyet s/n, Badalona, Barcelona 08916, Spain; Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia, Universitat Autònoma de Barcelona, Av. de Can Domènech 737, Cerdanyola del Vallès, Barcelona 08193, Spain
- Anna Esteve-Codina
- Centro Nacional de Análisis Genómico (CNAG), Barcelona Science Park - Tower I, Carrer de Baldiri Reixac 4, Barcelona 08028, Spain; Universitat Pompeu Fabra (UPF), Plaça de la Mercè 10-12, Barcelona 08002, Spain
- María Berdasco
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute, Vinguda de la Granvia de l'Hospitalet 199, L'Hospitalet de Llobregat, Barcelona 08907, Spain; Epigenetic Therapies Group, Experimental and Clinical Hematology Program (PHEC), Josep Carreras Leukaemia Research Institute, Ctra de Can Ruti - Camí de les Escoles, s/n, Badalona, Barcelona 08916, Spain
- Míriam Rosás-Umbert
- IrsiCaixa, AIDS Research Institute, Institute for Health Science Research Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, 2nd floor, Ctra del canyet s/n, Badalona, Barcelona 08916, Spain; Department of Clinical Medicine - Department of Infectious Disease, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, East Jutland, Aarhus 8200, Denmark
- Elena Gonçalves
- Centre d'Immunologie et des Maladies Infectieuses – Paris (Cimi-Paris), INSERM U1135, Sorbonne Université, Bd de l'Hôpital 91, Paris, Île de France 75013, France
- Clara Duran-Castells
- IrsiCaixa, AIDS Research Institute, Institute for Health Science Research Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, 2nd floor, Ctra del canyet s/n, Badalona, Barcelona 08916, Spain; Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia, Universitat Autònoma de Barcelona, Av. de Can Domènech 737, Cerdanyola del Vallès, Barcelona 08193, Spain
- Francesc Català-Moll
- IrsiCaixa, AIDS Research Institute, Institute for Health Science Research Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, 2nd floor, Ctra del canyet s/n, Badalona, Barcelona 08916, Spain
- Anuska Llano
- IrsiCaixa, AIDS Research Institute, Institute for Health Science Research Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, 2nd floor, Ctra del canyet s/n, Badalona, Barcelona 08916, Spain
- Samandhy Cedeño
- IrsiCaixa, AIDS Research Institute, Institute for Health Science Research Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, 2nd floor, Ctra del canyet s/n, Badalona, Barcelona 08916, Spain
- Maria C. Puertas
- IrsiCaixa, AIDS Research Institute, Institute for Health Science Research Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, 2nd floor, Ctra del canyet s/n, Badalona, Barcelona 08916, Spain; CIBERINFEC, Madrid, Spain
- Martin Tolstrup
- Department of Clinical Medicine - Department of Infectious Disease, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, East Jutland, Aarhus 8200, Denmark
- Ole S. Søgaard
- Department of Clinical Medicine - Department of Infectious Disease, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, East Jutland, Aarhus 8200, Denmark
- Bonaventura Clotet
- IrsiCaixa, AIDS Research Institute, Institute for Health Science Research Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, 2nd floor, Ctra del canyet s/n, Badalona, Barcelona 08916, Spain; CIBERINFEC, Madrid, Spain; Fundació Lluita contra la Sida, Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, Ctra del Canyet s/n, Badalona, Barcelona 08916, Spain; Centre for Health and Social Care Research (CESS), Faculty of Medicine, University of Vic - Central University of Catalonia (UVic - UCC), Carrer Miquel Martí i Pol, 1, Vic, Barcelona 08500, Spain
- Javier Martínez-Picado
- IrsiCaixa, AIDS Research Institute, Institute for Health Science Research Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, 2nd floor, Ctra del canyet s/n, Badalona, Barcelona 08916, Spain; CIBERINFEC, Madrid, Spain; Centre for Health and Social Care Research (CESS), Faculty of Medicine, University of Vic - Central University of Catalonia (UVic - UCC), Carrer Miquel Martí i Pol, 1, Vic, Barcelona 08500, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig de Lluís Companys, 23, Barcelona 08010, Spain
- Tomáš Hanke
- The Jenner Institute, University of Oxford, Old Road Campus Research Build, Roosevelt Dr, Headington, Oxford, Oxfordshire OX3 7DQ, UK; Joint Research Center for Human Retrovirus Infection, Kumamoto University, Honjo 2-2-1, Kumamoto City, Chuo-ku 860-0811, Japan
- Behazine Combadiere
- Centre d'Immunologie et des Maladies Infectieuses – Paris (Cimi-Paris), INSERM U1135, Sorbonne Université, Bd de l'Hôpital 91, Paris, Île de France 75013, France
- Roger Paredes
- IrsiCaixa, AIDS Research Institute, Institute for Health Science Research Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, 2nd floor, Ctra del canyet s/n, Badalona, Barcelona 08916, Spain; CIBERINFEC, Madrid, Spain; Fundació Lluita contra la Sida, Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, Ctra del Canyet s/n, Badalona, Barcelona 08916, Spain; Centre for Health and Social Care Research (CESS), Faculty of Medicine, University of Vic - Central University of Catalonia (UVic - UCC), Carrer Miquel Martí i Pol, 1, Vic, Barcelona 08500, Spain
- Dennis Hartigan-O'Connor
- Department of Medical Microbiology and Immunology, University of California, Veterinary Medicine 3A, Davis, CA 95616, USA; Division of Experimental Medicine, UC Davis School of Medicine, 4610 X Street, Sacramento, CA 95817, USA
- Manel Esteller
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig de Lluís Companys, 23, Barcelona 08010, Spain; Cancer and Leukemia Epigenetics and Biology Program (PEBCL), Josep Carreras Leukaemia Research Institute, Ctra de Can Ruti - Camí de les Escoles, s/n, Badalona, Barcelona 08916, Spain; Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Av. Monforte de Lemos 3-5. Pabellón 11. Planta 0, Madrid 28029, Spain; Department of Physiological Sciences II, School of Medicine, University of Barcelona, Feixa Llarga, s/n, L'Hospitalet de Llobregat, Barcelona 08907, Spain
- Michael Meulbroek
- Projecte dels NOMS-Hispanosida, BCN Checkpoint, Carrer del Comte Borrell, 164-166, Barcelona 08015, Spain
- María Luz Calle
- Biosciences Department, Faculty of Sciences and Technology, University of Vic-Central University of Catalonia, Carrer de la Laura 13 – Torre dels Frares, Vic, Barcelona 08500, Spain
- Alex Sanchez-Pla
- Statistics Department, Biology Faculty, University of Barcelona, Diagonal 643, Barcelona 08028, Spain; Statistics and Bioinformatics Unit Vall d'Hebron Institut de Recerca (VHIR), Passeig de la Vall d'Hebron, 129, Barcelona 08035, Spain
- José Moltó
- CIBERINFEC, Madrid, Spain; Fundació Lluita contra la Sida, Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, Ctra del Canyet s/n, Badalona, Barcelona 08916, Spain
- Beatriz Mothe
- IrsiCaixa, AIDS Research Institute, Institute for Health Science Research Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, 2nd floor, Ctra del canyet s/n, Badalona, Barcelona 08916, Spain; CIBERINFEC, Madrid, Spain; Fundació Lluita contra la Sida, Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, Ctra del Canyet s/n, Badalona, Barcelona 08916, Spain; Centre for Health and Social Care Research (CESS), Faculty of Medicine, University of Vic - Central University of Catalonia (UVic - UCC), Carrer Miquel Martí i Pol, 1, Vic, Barcelona 08500, Spain
- Christian Brander
- IrsiCaixa, AIDS Research Institute, Institute for Health Science Research Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, 2nd floor, Ctra del canyet s/n, Badalona, Barcelona 08916, Spain; Centre for Health and Social Care Research (CESS), Faculty of Medicine, University of Vic - Central University of Catalonia (UVic - UCC), Carrer Miquel Martí i Pol, 1, Vic, Barcelona 08500, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig de Lluís Companys, 23, Barcelona 08010, Spain
- Marta Ruiz-Riol
- IrsiCaixa, AIDS Research Institute, Institute for Health Science Research Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, 2nd floor, Ctra del canyet s/n, Badalona, Barcelona 08916, Spain; CIBERINFEC, Madrid, Spain; Corresponding author at: IrsiCaixa, AIDS Research Institute, Institute for Health Science Research Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, 2nd floor, Ctra del canyet s/n, Badalona, Barcelona 08916, Spain.
- Journal volume & issue
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Vol. 78
p. 103956
Abstract
Summary: Background: The 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 ( 4weeks) viral-rebound. Integrated -omics analyses were applied prior treatment interruption to identify markers of virus control during MAP. Methods: PBMC, 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. Findings: DNA 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. Interpretation: This study identifies host DNA methylation profiles and epigenetic cascades that are predictive of subsequent virus control in a kick-and-kill HIV cure strategy. Funding: European 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.
