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; Maria Berdasco; Míriam Rosás-Umbert; Elena Gonçalves; Clara Duran-Castells; Francesc Català-Moll; Anuska Llano Montero; Samandhy Cedeño; Maria C. Puertas; Martin Tolstrup; Ole S. Søgaard; Bonaventura Clotet Sala; Javier Martínez-Picado; Tomáš Hanke; Behazine Combadiere; Roger Paredes; Dennis Hartigan-O'Connor; M Esteller; Michael Meulbroek; M. Luz Calle; Alex Sánchez; José Moltó; Beatriz Mothe; Christian Brander; Marta Ruiz-Riol

doi:10.1016/j.ebiom.2022.103956

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, Maria Berdasco, Míriam Rosás-Umbert, Elena Gonçalves, Clara Duran-Castells, Francesc Català-Moll, Anuska Llano Montero, Samandhy Cedeño, Maria C. Puertas, Martin Tolstrup, Ole S. Søgaard, Bonaventura Clotet Sala, Javier Martínez-Picado, Tomáš Hanke, Behazine Combadiere, Roger Paredes, Dennis Hartigan-O'Connor, M Esteller, Michael MeulbroekM. Luz Calle, Alex Sánchez, José Moltó, Beatriz Mothe, Christian Brander, Marta Ruiz-Riol

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Resum

European Commission. Horizon 2020 $a El BCN02-trial va combinar la vacunació terapèutica amb un agent de latència viral (romidepsin, RMD) en individus infectats pel VIH-1 i va incloure una pausa antiretroviral monitoritzada (MAP) com a lectura d'eficàcia que identificava els individus amb un rebot viral precoç o tardà (< o > 4 setmanes). Es van aplicar anàlisis integrades -òmics abans de la interrupció del tractament per identificar marcadors de control del virus durant el MAP. Es va avaluar PBMC, metilació d'ADN genòmic complet i transcriptòmica en 14 participants BCN02, inclosos 8 individus amb rebot viral precoç o tardà (4 setmanes) . Estat de la cromatina, marques d'histones i anàlisi d'integració (acetilació d'histonina-3 (H3Ac), càrrega viral, nivells provirals i respostes T específiques del VIH) es van incloure. Es van incloure mostres REDUC-trial (n = 5) com a grup de control per a l'administració RMD en solitari. Les empremtes de metilació d'ADN després de rebre la intervenció completa discriminaven els individus amb rebot viral precoç o tardà abans del MAP. A més, es va detectar una accessibilitat diferencial de cromatina i marques d'histones al nivell de metilació d'ADN. És important destacar que les posicions de metilació d'ADN (DMP) entre els rebotadors precoços i tardans abans del MAP estaven fortament associades amb la càrrega viral, nivells provirals així com respostes T específiques del VIH. La majoria d'aquestes DMP ja eren presents abans de la intervenció i es van accentuar després de la infusió RMD. Aquest estudi identifica perfils epigenètics predictius del control posterior del virus en una estratègia de curació del VIH basada en el principi "treat and kill". Programa Marc de Recerca i Innovació Horitzó 2020 de la Unió Europea sota l'Acord N°681137-EAVI2020 i N°847943-MISTRAL, el Ministerio de Ciencia e Innovación (SAF2017_89726_R), i els Instituts Nacionals de Salut - Programa d'Infeccions Al·lèrgiques i Infeccioses Subvenció 536 __ $f 681137-EAVI2020

Idioma original	Anglès
Revista	EBioMedicine
Volum	78
DOIs	https://doi.org/10.1016/j.ebiom.2022.103956
Estat de la publicació	Publicada - 2022

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10.1016/j.ebiom.2022.103956

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Oriol-Tordera, B., Esteve-Codina, A., Berdasco, M., Rosás-Umbert, M., Gonçalves, E., Duran-Castells, C., Català-Moll, F., Llano Montero, A., Cedeño, S., Puertas, M. C., Tolstrup, M., Søgaard, O. S., Clotet Sala, B., Martínez-Picado, J., Hanke, T., Combadiere, B., Paredes, R., Hartigan-O'Connor, D., Esteller, M., ... Ruiz-Riol, M. (2022). Epigenetic landscape in the kick-and-kill therapeutic vaccine BCN02 clinical trial is associated with antiretroviral treatment interruption (ATI) outcome. EBioMedicine, 78. https://doi.org/10.1016/j.ebiom.2022.103956

@article{02464599eee441e3a6cb82550b4005e7,

title = "Epigenetic landscape in the kick-and-kill therapeutic vaccine BCN02 clinical trial is associated with antiretroviral treatment interruption (ATI) outcome",

abstract = "European Commission. Horizon 2020 \$a 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 (< or > 4weeks) viral-rebound. Integrated -omics analyses were applied prior treatment interruption to identify markers of virus control during MAP. 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. 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. 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. 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 Innovaci{\'o}n (SAF2017\_89726\_R), and the National Institutes of Health-National Institute of Allergy and Infectious Diseases Program Grant 536 \_\_ \$f 681137-EAVI2020",

keywords = "HIV-1 vaccine, Epigenetics, DNA methylation",

author = "Bruna Oriol-Tordera and Anna Esteve-Codina and Maria Berdasco and M{\'i}riam Ros{\'a}s-Umbert and Elena Gon{\c c}alves and Clara Duran-Castells and Francesc Catal{\`a}-Moll and \{Llano Montero\}, Anuska and Samandhy Cede{\~n}o and Puertas, \{Maria C.\} and Martin Tolstrup and S{\o}gaard, \{Ole S.\} and \{Clotet Sala\}, Bonaventura and Javier Mart{\'i}nez-Picado and Tom{\'a}{\v s} Hanke and Behazine Combadiere and Roger Paredes and Dennis Hartigan-O'Connor and M Esteller and Michael Meulbroek and Calle, \{M. Luz\} and Alex S{\'a}nchez and Jos{\'e} Molt{\'o} and Beatriz Mothe and Christian Brander and Marta Ruiz-Riol",

year = "2022",

doi = "10.1016/j.ebiom.2022.103956",

language = "English",

volume = "78",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier BV",

}

Oriol-Tordera, B, Esteve-Codina, A, Berdasco, M, Rosás-Umbert, M, Gonçalves, E, Duran-Castells, C, Català-Moll, F, Llano Montero, A, Cedeño, S, Puertas, MC, Tolstrup, M, Søgaard, OS, Clotet Sala, B, Martínez-Picado, J, Hanke, T, Combadiere, B, Paredes, R, Hartigan-O'Connor, D, Esteller, M, Meulbroek, M, Calle, ML, Sánchez, A, Moltó, J, Mothe, B, Brander, C & Ruiz-Riol, M 2022, 'Epigenetic landscape in the kick-and-kill therapeutic vaccine BCN02 clinical trial is associated with antiretroviral treatment interruption (ATI) outcome', EBioMedicine, vol. 78. https://doi.org/10.1016/j.ebiom.2022.103956

TY - JOUR

T1 - Epigenetic landscape in the kick-and-kill therapeutic vaccine BCN02 clinical trial is associated with antiretroviral treatment interruption (ATI) outcome

AU - Oriol-Tordera, Bruna

AU - Esteve-Codina, Anna

AU - Berdasco, Maria

AU - Rosás-Umbert, Míriam

AU - Gonçalves, Elena

AU - Duran-Castells, Clara

AU - Català-Moll, Francesc

AU - Llano Montero, Anuska

AU - Cedeño, Samandhy

AU - Puertas, Maria C.

AU - Tolstrup, Martin

AU - Søgaard, Ole S.

AU - Clotet Sala, Bonaventura

AU - Martínez-Picado, Javier

AU - Hanke, Tomáš

AU - Combadiere, Behazine

AU - Paredes, Roger

AU - Hartigan-O'Connor, Dennis

AU - Esteller, M

AU - Meulbroek, Michael

AU - Calle, M. Luz

AU - Sánchez, Alex

AU - Moltó, José

AU - Mothe, Beatriz

AU - Brander, Christian

AU - Ruiz-Riol, Marta

PY - 2022

Y1 - 2022

N2 - European Commission. Horizon 2020 $a 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 (< or > 4weeks) viral-rebound. Integrated -omics analyses were applied prior treatment interruption to identify markers of virus control during MAP. 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. 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. 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. 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 536 __ $f 681137-EAVI2020

AB - European Commission. Horizon 2020 $a 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 (< or > 4weeks) viral-rebound. Integrated -omics analyses were applied prior treatment interruption to identify markers of virus control during MAP. 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. 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. 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. 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 536 __ $f 681137-EAVI2020

KW - HIV-1 vaccine

KW - Epigenetics

KW - DNA methylation

UR - https://www.scopus.com/pages/publications/85126590337

U2 - 10.1016/j.ebiom.2022.103956

DO - 10.1016/j.ebiom.2022.103956

M3 - Article

C2 - 35325780

SN - 2352-3964

VL - 78

JO - EBioMedicine

JF - EBioMedicine

ER -

Epigenetic landscape in the kick-and-kill therapeutic vaccine BCN02 clinical trial is associated with antiretroviral treatment interruption (ATI) outcome

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