In vivo Effects of Romidepsin on T-Cell Activation, Apoptosis and Function in the BCN02 HIV-1 Kick&Kill Clinical Trial
Romidepsin (RMD) is a well-characterized histone deacetylase inhibitor approved for the treatment of cutaneous T-cell lymphoma. and studies have demonstrated that it is able to induce HIV-1 gene expression in latently infected CD4 T cells from HIV-1 individuals on suppressive antiretroviral therapy....
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| Published in | Frontiers in immunology Vol. 11; p. 418 |
|---|---|
| Main Authors | , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Switzerland
Frontiers Media S.A
20.03.2020
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| Subjects | |
| Online Access | Get full text |
| ISSN | 1664-3224 1664-3224 |
| DOI | 10.3389/fimmu.2020.00418 |
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| Abstract | Romidepsin (RMD) is a well-characterized histone deacetylase inhibitor approved for the treatment of cutaneous T-cell lymphoma.
and
studies have demonstrated that it is able to induce HIV-1 gene expression in latently infected CD4
T cells from HIV-1
individuals on suppressive antiretroviral therapy. However,
experiments suggested that RMD could also impair T-cell functionality, particularly of activated T cells. Thus, the usefulness of RMD in HIV-1 kick&kill strategies, that aim to enhance the immune system elimination of infected cells after inducing HIV-1 viral reactivation, may be limited. In order to address whether the
observations are replicated
, we determined the effects of RMD on the total and HIV-1-specific T-cell populations in longitudinal samples from the BCN02 kick&kill clinical trial (NCT02616874). BCN02 was a proof-of-concept study in 15 early treated HIV-1
individuals that combined MVA.HIVconsv vaccination with three weekly infusions of RMD given as a latency reversing agent. Our results show that RMD induced a transient increase in the frequency of apoptotic T cells and an enhanced activation of vaccine-induced T cells. Although RMD reduced the number of vaccine-elicited T cells secreting multiple cytokines, viral suppressive capacity of CD8
T cells was preserved over the RMD treatment. These observations have important implications for the design of effective kick&kill strategies for the HIV-1 cure. |
|---|---|
| AbstractList | Romidepsin (RMD) is a well-characterized histone deacetylase inhibitor approved for the treatment of cutaneous T-cell lymphoma.
in vitro
and
in vivo
studies have demonstrated that it is able to induce HIV-1 gene expression in latently infected CD4
+
T cells from HIV-1
+
individuals on suppressive antiretroviral therapy. However,
in vitro
experiments suggested that RMD could also impair T-cell functionality, particularly of activated T cells. Thus, the usefulness of RMD in HIV-1 kick&kill strategies, that aim to enhance the immune system elimination of infected cells after inducing HIV-1 viral reactivation, may be limited. In order to address whether the
in vitro
observations are replicated
in vivo
, we determined the effects of RMD on the total and HIV-1-specific T-cell populations in longitudinal samples from the BCN02 kick&kill clinical trial (NCT02616874). BCN02 was a proof-of-concept study in 15 early treated HIV-1
+
individuals that combined MVA.HIVconsv vaccination with three weekly infusions of RMD given as a latency reversing agent. Our results show that RMD induced a transient increase in the frequency of apoptotic T cells and an enhanced activation of vaccine-induced T cells. Although RMD reduced the number of vaccine-elicited T cells secreting multiple cytokines, viral suppressive capacity of CD8
+
T cells was preserved over the RMD treatment. These observations have important implications for the design of effective kick&kill strategies for the HIV-1 cure. Romidepsin (RMD) is a well-characterized histone deacetylase inhibitor approved for the treatment of cutaneous T-cell lymphoma. in vitro and in vivo studies have demonstrated that it is able to induce HIV-1 gene expression in latently infected CD4+ T cells from HIV-1+ individuals on suppressive antiretroviral therapy. However, in vitro experiments suggested that RMD could also impair T-cell functionality, particularly of activated T cells. Thus, the usefulness of RMD in HIV-1 kick&kill strategies, that aim to enhance the immune system elimination of infected cells after inducing HIV-1 viral reactivation, may be limited. In order to address whether the in vitro observations are replicated in vivo, we determined the effects of RMD on the total and HIV-1-specific T-cell populations in longitudinal samples from the BCN02 kick&kill clinical trial (NCT02616874). BCN02 was a proof-of-concept study in 15 early treated HIV-1+ individuals that combined MVA.HIVconsv vaccination with three weekly infusions of RMD given as a latency reversing agent. Our results show that RMD induced a transient increase in the frequency of apoptotic T cells and an enhanced activation of vaccine-induced T cells. Although RMD reduced the number of vaccine-elicited T cells secreting multiple cytokines, viral suppressive capacity of CD8+ T cells was preserved over the RMD treatment. These observations have important implications for the design of effective kick&kill strategies for the HIV-1 cure.Romidepsin (RMD) is a well-characterized histone deacetylase inhibitor approved for the treatment of cutaneous T-cell lymphoma. in vitro and in vivo studies have demonstrated that it is able to induce HIV-1 gene expression in latently infected CD4+ T cells from HIV-1+ individuals on suppressive antiretroviral therapy. However, in vitro experiments suggested that RMD could also impair T-cell functionality, particularly of activated T cells. Thus, the usefulness of RMD in HIV-1 kick&kill strategies, that aim to enhance the immune system elimination of infected cells after inducing HIV-1 viral reactivation, may be limited. In order to address whether the in vitro observations are replicated in vivo, we determined the effects of RMD on the total and HIV-1-specific T-cell populations in longitudinal samples from the BCN02 kick&kill clinical trial (NCT02616874). BCN02 was a proof-of-concept study in 15 early treated HIV-1+ individuals that combined MVA.HIVconsv vaccination with three weekly infusions of RMD given as a latency reversing agent. Our results show that RMD induced a transient increase in the frequency of apoptotic T cells and an enhanced activation of vaccine-induced T cells. Although RMD reduced the number of vaccine-elicited T cells secreting multiple cytokines, viral suppressive capacity of CD8+ T cells was preserved over the RMD treatment. These observations have important implications for the design of effective kick&kill strategies for the HIV-1 cure. Romidepsin (RMD) is a well-characterized histone deacetylase inhibitor approved for the treatment of cutaneous T-cell lymphoma. and studies have demonstrated that it is able to induce HIV-1 gene expression in latently infected CD4 T cells from HIV-1 individuals on suppressive antiretroviral therapy. However, experiments suggested that RMD could also impair T-cell functionality, particularly of activated T cells. Thus, the usefulness of RMD in HIV-1 kick&kill strategies, that aim to enhance the immune system elimination of infected cells after inducing HIV-1 viral reactivation, may be limited. In order to address whether the observations are replicated , we determined the effects of RMD on the total and HIV-1-specific T-cell populations in longitudinal samples from the BCN02 kick&kill clinical trial (NCT02616874). BCN02 was a proof-of-concept study in 15 early treated HIV-1 individuals that combined MVA.HIVconsv vaccination with three weekly infusions of RMD given as a latency reversing agent. Our results show that RMD induced a transient increase in the frequency of apoptotic T cells and an enhanced activation of vaccine-induced T cells. Although RMD reduced the number of vaccine-elicited T cells secreting multiple cytokines, viral suppressive capacity of CD8 T cells was preserved over the RMD treatment. These observations have important implications for the design of effective kick&kill strategies for the HIV-1 cure. |
| Author | Marszalek, Marta Miró, José M. Coll, Pep Manzardo, Christian Clotet, Bonaventura Ruiz-Riol, Marta Brander, Christian Cedeño, Samandhy Hanke, Tomáš Rosás-Umbert, Miriam Moltó, José Fernández, Marco A. Mothe, Beatriz |
| AuthorAffiliation | Author Affiliations: IrsiCaixa AIDS Research Institute-HIVACAT, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Fundació Lluita contra la Sida, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Germans Trias i Pujol Research Institute, Badalona, Spain; Pharmacokinetic/pharmacodynamic modeling and simultation, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau-IIB Sant Pau, Barcelona, Spain; Hospital Clinic-HIVACAT, IDIBAPS, University of Barcelona, Spain; (currently working at Hospital Universitari Arnau de Vilanova, Lleida, Spain); Projecte dels noms, BCN Checkpoint, Barcelona, Spain; The Jenner Institute, The Nuffield Department of Medicine, University of Oxford, UK 1 IrsiCaixa AIDS Research Institute-HIVACAT , Badalona , Spain 4 Hospital Clinic- IDIBAPS, University of Barcelona , Barcelona , Spain 6 Department of Infectious Diseases, Hospital Germans Trias i Pujol , Badalona , Spain 10 ICREA, Pg. Lluis Companys , Barcelona , Spain 5 Fundació Lluita co |
| AuthorAffiliation_xml | – name: 4 Hospital Clinic- IDIBAPS, University of Barcelona , Barcelona , Spain – name: 5 Fundació Lluita contra la Sida, Hospital Universitari Germans Trias i Pujol , Badalona , Spain – name: 2 Department of Cellular Biology, Physiology and Immunology, Universitat Autònoma de Barcelona (UAB) , Barcelona , Spain – name: Author Affiliations: IrsiCaixa AIDS Research Institute-HIVACAT, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Fundació Lluita contra la Sida, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Germans Trias i Pujol Research Institute, Badalona, Spain; Pharmacokinetic/pharmacodynamic modeling and simultation, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau-IIB Sant Pau, Barcelona, Spain; Hospital Clinic-HIVACAT, IDIBAPS, University of Barcelona, Spain; (currently working at Hospital Universitari Arnau de Vilanova, Lleida, Spain); Projecte dels noms, BCN Checkpoint, Barcelona, Spain; The Jenner Institute, The Nuffield Department of Medicine, University of Oxford, UK – name: 1 IrsiCaixa AIDS Research Institute-HIVACAT , Badalona , Spain – name: 7 Centre for Health and Social Care Research (CESS), Faculty of Medicine, University of Vic – Central University of Catalonia (UVic – UCC) , Vic , Spain – name: 3 Flow Cytometry Facility, Health Sciences Research Institute Germans Trias i Pujol , Badalona , Spain – name: 8 The Jenner Institute, University of Oxford , Oxford , United Kingdom – name: 6 Department of Infectious Diseases, Hospital Germans Trias i Pujol , Badalona , Spain – name: 9 Joint Research Center for Human Retrovirus Infection, Kumamoto University , Kumamoto , Japan – name: 10 ICREA, Pg. Lluis Companys , Barcelona , Spain |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/32265913$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Contributor | Llano, Anuksa Martinez-Picado, Javier Ambrosioni, Juan Coll, Pep Perez-Alvarez, Nuria Saz, Jorge Clotet, Bonaventura Brander, Christian Ruiz-Riol, Marta Barriocanal, Ana Maria Revollo, Boris Paredes, Roger Moltó, José Mothe, Beatriz Farré, Magi Morón-López, Sara Miro, Jose M Muñoz, Jose Valle, Marta Borthwick, Nicola Marszalek, Marta Rovira, Cristina Wee, Edmund G Escrig, Roser Gel, Silvia Miranda, Cristina Manzardo, Christian Carrillo, Antonio Toro, Jessica Crook, Alison Cedeño, Samandhy Puertas, Maria C Meulbroek, Michael Hanke, Tomáš Ruiz, Irene Benet, Susana Rosás-Umbert, Miriam López, Miriam Perez-Reche, Cristina Puig, Jordi Pujol, Ferran |
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| Copyright | Copyright © 2020 Rosás-Umbert, Ruiz-Riol, Fernández, Marszalek, Coll, Manzardo, Cedeño, Miró, Clotet, Hanke, Moltó, Mothe, Brander and the BCN02 study group. Copyright © 2020 Rosás-Umbert, Ruiz-Riol, Fernández, Marszalek, Coll, Manzardo, Cedeño, Miró, Clotet, Hanke, Moltó, Mothe, Brander and the BCN02 study group. 2020 Rosás-Umbert, Ruiz-Riol, Fernández, Marszalek, Coll, Manzardo, Cedeño, Miró, Clotet, Hanke, Moltó, Mothe, Brander and the BCN02 study group |
| Copyright_xml | – notice: Copyright © 2020 Rosás-Umbert, Ruiz-Riol, Fernández, Marszalek, Coll, Manzardo, Cedeño, Miró, Clotet, Hanke, Moltó, Mothe, Brander and the BCN02 study group. – notice: Copyright © 2020 Rosás-Umbert, Ruiz-Riol, Fernández, Marszalek, Coll, Manzardo, Cedeño, Miró, Clotet, Hanke, Moltó, Mothe, Brander and the BCN02 study group. 2020 Rosás-Umbert, Ruiz-Riol, Fernández, Marszalek, Coll, Manzardo, Cedeño, Miró, Clotet, Hanke, Moltó, Mothe, Brander and the BCN02 study group |
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| Keywords | therapeutic vaccine HDAC inhibitor kick&kill strategy latency reversing agent (LRA) romidepsin |
| Language | English |
| License | Copyright © 2020 Rosás-Umbert, Ruiz-Riol, Fernández, Marszalek, Coll, Manzardo, Cedeño, Miró, Clotet, Hanke, Moltó, Mothe, Brander and the BCN02 study group. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by: Carolina Garrido, University of North Carolina at Chapel Hill, United States Reviewed by: R. Brad Jones, Cornell University, United States; Thomas Aagaard Rasmussen, Peter Doherty Institute for Infection and Immunity, Australia This article was submitted to Vaccines and Molecular Therapeutics, a section of the journal Frontiers in Immunology |
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B27 article-title: Therapeutic vaccines after early ART: impact on reservoir |
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| Snippet | Romidepsin (RMD) is a well-characterized histone deacetylase inhibitor approved for the treatment of cutaneous T-cell lymphoma.
and
studies have demonstrated... Romidepsin (RMD) is a well-characterized histone deacetylase inhibitor approved for the treatment of cutaneous T-cell lymphoma. in vitro and in vivo studies... Romidepsin (RMD) is a well-characterized histone deacetylase inhibitor approved for the treatment of cutaneous T-cell lymphoma. in vitro and in vivo studies... |
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| SubjectTerms | AIDS Vaccines - immunology Apoptosis - drug effects CD8-Positive T-Lymphocytes - drug effects CD8-Positive T-Lymphocytes - immunology Depsipeptides - pharmacology Depsipeptides - therapeutic use Follow-Up Studies Histone Code Histone Deacetylase Inhibitors - pharmacology Histone Deacetylase Inhibitors - therapeutic use HIV Infections - drug therapy HIV Infections - immunology HIV-1 Humans Immunization, Secondary Immunogenicity, Vaccine Immunologic Memory Immunology Lymphocyte Activation - drug effects Programmed Cell Death 1 Receptor - biosynthesis Programmed Cell Death 1 Receptor - genetics Proof of Concept Study RNA, Viral - genetics Virus Latency - drug effects Virus Replication |
| Title | In vivo Effects of Romidepsin on T-Cell Activation, Apoptosis and Function in the BCN02 HIV-1 Kick&Kill Clinical Trial |
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