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

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, 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 MeulbroekMaría Luz Calle, Alex Sanchez-Pla, José Moltó, Beatriz Mothe, Christian Brander, Marta Ruiz-Riol^*

^*Corresponding author for this work

Department of Clinical Medicine - Department of Infectious Diseases

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

9 Citations (Scopus)

Abstract

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 (< or > 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.

Original language	English
Article number	103956
Journal	EBioMedicine
Volume	78
Number of pages	19
DOIs	https://doi.org/10.1016/j.ebiom.2022.103956
Publication status	Published - Apr 2022

Keywords

DNA methylation
Epigenetics
HIV-1 vaccine

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Oriol-Tordera, B., Esteve-Codina, A., Berdasco, M., Rosás-Umbert, M., Gonçalves, E., Duran-Castells, C., Català-Moll, F., Llano, A., Cedeño, S., Puertas, M. C., Tolstrup, M., Søgaard, O. S., Clotet, 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, Article 103956. https://doi.org/10.1016/j.ebiom.2022.103956

@article{82a32920c0e34b3aa419a49d5c43c0d8,

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

abstract = "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 (< or > 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 Innovaci{\'o}n (SAF2017_89726_R), and the National Institutes of Health–National Institute of Allergy and Infectious Diseases Program Grant P01-AI131568.",

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

author = "Bruna Oriol-Tordera and Anna Esteve-Codina and Mar{\'i}a 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 Anuska Llano and Samandhy Cede{\~n}o and Puertas, {Maria C.} and Martin Tolstrup and S{\o}gaard, {Ole S.} and Bonaventura Clotet and Javier Mart{\'i}nez-Picado and Tom{\'a}{\v s} Hanke and Behazine Combadiere and Roger Paredes and Dennis Hartigan-O'Connor and Manel Esteller and Michael Meulbroek and Calle, {Mar{\'i}a Luz} and Alex Sanchez-Pla and Jos{\'e} Molt{\'o} and Beatriz Mothe and Christian Brander and Marta Ruiz-Riol",

year = "2022",

month = apr,

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

language = "English",

volume = "78",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier B.V.",

}

Oriol-Tordera, B, Esteve-Codina, A, Berdasco, M, Rosás-Umbert, M, Gonçalves, E, Duran-Castells, C, Català-Moll, F, Llano, A, Cedeño, S, Puertas, MC, Tolstrup, M , Søgaard, OS, Clotet, B, Martínez-Picado, J, Hanke, T, Combadiere, B, Paredes, R, Hartigan-O'Connor, D, Esteller, M, Meulbroek, M, Calle, ML, Sanchez-Pla, 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, 103956. https://doi.org/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. / Oriol-Tordera, Bruna; Esteve-Codina, Anna; Berdasco, María et al.
In: EBioMedicine, Vol. 78, 103956, 04.2022.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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, María

AU - Rosás-Umbert, Míriam

AU - Gonçalves, Elena

AU - Duran-Castells, Clara

AU - Català-Moll, Francesc

AU - Llano, Anuska

AU - Cedeño, Samandhy

AU - Puertas, Maria C.

AU - Tolstrup, Martin

AU - Søgaard, Ole S.

AU - Clotet, Bonaventura

AU - Martínez-Picado, Javier

AU - Hanke, Tomáš

AU - Combadiere, Behazine

AU - Paredes, Roger

AU - Hartigan-O'Connor, Dennis

AU - Esteller, Manel

AU - Meulbroek, Michael

AU - Calle, María Luz

AU - Sanchez-Pla, Alex

AU - Moltó, José

AU - Mothe, Beatriz

AU - Brander, Christian

AU - Ruiz-Riol, Marta

PY - 2022/4

Y1 - 2022/4

N2 - 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 (< or > 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.

AB - 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 (< or > 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.

KW - DNA methylation

KW - Epigenetics

KW - HIV-1 vaccine

UR - http://www.scopus.com/inward/record.url?scp=85126590337&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2022.103956

DO - 10.1016/j.ebiom.2022.103956

M3 - Journal article

C2 - 35325780

AN - SCOPUS:85126590337

SN - 2352-3964

VL - 78

JO - EBioMedicine

JF - EBioMedicine

M1 - 103956

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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Keywords

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