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The inhibitor of apoptosis proteins antagonist Debio 1143 promotes the PD-1 blockade-mediated HIV load reduction in blood and tissues of humanized mice

The immune checkpoint programmed cell death protein 1 (PD-1) plays a major role in T cell exhaustion in cancer and chronic HIV infection. The inhibitor of apoptosis protein antagonist Debio 1143 (D1143) enhances tumor cell death and synergizes with anti-PD-1 agents to promote tumor immunity and disp...

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Autores principales: Bobardt, Michael, Kuo, Joseph, Chatterji, Udayan, Wiedemann, Norbert, Vuagniaux, Gregoire, Gallay, Philippe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980394/
https://www.ncbi.nlm.nih.gov/pubmed/31978106
http://dx.doi.org/10.1371/journal.pone.0227715
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author Bobardt, Michael
Kuo, Joseph
Chatterji, Udayan
Wiedemann, Norbert
Vuagniaux, Gregoire
Gallay, Philippe
author_facet Bobardt, Michael
Kuo, Joseph
Chatterji, Udayan
Wiedemann, Norbert
Vuagniaux, Gregoire
Gallay, Philippe
author_sort Bobardt, Michael
collection PubMed
description The immune checkpoint programmed cell death protein 1 (PD-1) plays a major role in T cell exhaustion in cancer and chronic HIV infection. The inhibitor of apoptosis protein antagonist Debio 1143 (D1143) enhances tumor cell death and synergizes with anti-PD-1 agents to promote tumor immunity and displayed HIV latency reversal activity in vitro. We asked in this study whether D1143 would stimulate the potency of an anti-human PD-1 monoclonal antibody (mAb) to reduce HIV loads in humanized mice. Anti-PD-1 mAb treatment decreased PD-1+ CD8+ cell population by 32.3% after interruption of four weeks treatment, and D1143 co-treatment further reduced it from 32.3 to 73%. Anti-PD-1 mAb administration reduced HIV load in blood by 94%, and addition of D1143 further enhanced this reduction from 94 to 97%. D1143 also more profoundly promoted with the anti-PD-1-mediated reduction of HIV loads in all tissues analyzed including spleen (71 to 96.4%), lymph nodes (64.3 to 80%), liver (64.2 to 94.4), lung (64.3 to 80.1%) and thymic organoid (78.2 to 98.2%), achieving a >5 log reduction of HIV loads in CD4+ cells isolated from tissues 2 weeks after drug treatment interruption. Ex vivo anti-CD3/CD28 stimulation increased the ability to activate exhausted CD8+ T cells in infected mice having received in vivo anti-PD-1 treatment by 7.9-fold (5 to 39.6%), and an additional increase by 1.7-fold upon D1143 co-treatment (39.6 to 67.3%). These findings demonstrate for the first time that an inhibitor of apoptosis protein antagonist enhances in a statistically manner the effects of an immune check point inhibitor on antiviral immunity and on HIV load reduction in tissues of humanized mice, suggesting that the combination of two distinct classes of immunomodulatory agents constitutes a promising anti-HIV immunotherapeutic approach.
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spelling pubmed-69803942020-02-07 The inhibitor of apoptosis proteins antagonist Debio 1143 promotes the PD-1 blockade-mediated HIV load reduction in blood and tissues of humanized mice Bobardt, Michael Kuo, Joseph Chatterji, Udayan Wiedemann, Norbert Vuagniaux, Gregoire Gallay, Philippe PLoS One Research Article The immune checkpoint programmed cell death protein 1 (PD-1) plays a major role in T cell exhaustion in cancer and chronic HIV infection. The inhibitor of apoptosis protein antagonist Debio 1143 (D1143) enhances tumor cell death and synergizes with anti-PD-1 agents to promote tumor immunity and displayed HIV latency reversal activity in vitro. We asked in this study whether D1143 would stimulate the potency of an anti-human PD-1 monoclonal antibody (mAb) to reduce HIV loads in humanized mice. Anti-PD-1 mAb treatment decreased PD-1+ CD8+ cell population by 32.3% after interruption of four weeks treatment, and D1143 co-treatment further reduced it from 32.3 to 73%. Anti-PD-1 mAb administration reduced HIV load in blood by 94%, and addition of D1143 further enhanced this reduction from 94 to 97%. D1143 also more profoundly promoted with the anti-PD-1-mediated reduction of HIV loads in all tissues analyzed including spleen (71 to 96.4%), lymph nodes (64.3 to 80%), liver (64.2 to 94.4), lung (64.3 to 80.1%) and thymic organoid (78.2 to 98.2%), achieving a >5 log reduction of HIV loads in CD4+ cells isolated from tissues 2 weeks after drug treatment interruption. Ex vivo anti-CD3/CD28 stimulation increased the ability to activate exhausted CD8+ T cells in infected mice having received in vivo anti-PD-1 treatment by 7.9-fold (5 to 39.6%), and an additional increase by 1.7-fold upon D1143 co-treatment (39.6 to 67.3%). These findings demonstrate for the first time that an inhibitor of apoptosis protein antagonist enhances in a statistically manner the effects of an immune check point inhibitor on antiviral immunity and on HIV load reduction in tissues of humanized mice, suggesting that the combination of two distinct classes of immunomodulatory agents constitutes a promising anti-HIV immunotherapeutic approach. Public Library of Science 2020-01-24 /pmc/articles/PMC6980394/ /pubmed/31978106 http://dx.doi.org/10.1371/journal.pone.0227715 Text en © 2020 Bobardt et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Bobardt, Michael
Kuo, Joseph
Chatterji, Udayan
Wiedemann, Norbert
Vuagniaux, Gregoire
Gallay, Philippe
The inhibitor of apoptosis proteins antagonist Debio 1143 promotes the PD-1 blockade-mediated HIV load reduction in blood and tissues of humanized mice
title The inhibitor of apoptosis proteins antagonist Debio 1143 promotes the PD-1 blockade-mediated HIV load reduction in blood and tissues of humanized mice
title_full The inhibitor of apoptosis proteins antagonist Debio 1143 promotes the PD-1 blockade-mediated HIV load reduction in blood and tissues of humanized mice
title_fullStr The inhibitor of apoptosis proteins antagonist Debio 1143 promotes the PD-1 blockade-mediated HIV load reduction in blood and tissues of humanized mice
title_full_unstemmed The inhibitor of apoptosis proteins antagonist Debio 1143 promotes the PD-1 blockade-mediated HIV load reduction in blood and tissues of humanized mice
title_short The inhibitor of apoptosis proteins antagonist Debio 1143 promotes the PD-1 blockade-mediated HIV load reduction in blood and tissues of humanized mice
title_sort inhibitor of apoptosis proteins antagonist debio 1143 promotes the pd-1 blockade-mediated hiv load reduction in blood and tissues of humanized mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980394/
https://www.ncbi.nlm.nih.gov/pubmed/31978106
http://dx.doi.org/10.1371/journal.pone.0227715
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