Prediction of PD-L1 inhibition effects for HIV-infected individuals

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• dc.contributor.author Zheltkova, Valerya
• dc.contributor.author Argilaguet Marqués, Jordi, 1977-
• dc.contributor.author Peligero Cruz, Cristina, 1986-
• dc.contributor.author Bocharov, Gennady A.
• dc.contributor.author Meyerhans, Andreas
• dc.date.accessioned 2019-11-12T11:43:48Z
• dc.date.available 2019-11-12T11:43:48Z
• dc.date.issued 2019
• dc.description.abstract The novel therapies with immune checkpoint inhibitors hold great promises for patients with chronic virus infections and cancers. This is based mainly on the partial reversal of the exhausted phenotype of antigen-specific cytotoxic CD8 T cells (CTL). Recently, we have shown that the restoration of HIV-specific T cell function depends on the HIV infection stage of an infected individual. Here we aimed to answer two fundamental questions: (i) Can one estimate growth parameters for the HIV-specific proliferative responsiveness upon PD-L1 blockade ex vivo? (ii) Can one use these parameter estimates to predict clinical benefit for HIV-infected individuals displaying diverse infection phenotypes? To answer these questions, we first analyzed HIV-1 Gag-specific CD8 T cell proliferation by time-resolved CFSE assays and estimated the effect of PD-L1 blockade on division and death rates, and specific precursor frequencies. These values were then incorporated into a model for CTL-mediated HIV control and the effects on CTL frequencies, viral loads and CD4 T cell counts were predicted for different infection phenotypes. The biggest absolute increase in CD4 T cell counts was in the group of slow progressors while the strongest reduction in virus loads was observed in progressor patients. These results suggest a significant clinical benefit only for a subgroup of HIV-infected individuals. However, as PD1 is a marker of lymphocyte activation and expressed on several lymphocyte subsets including also CD4 T cells and B cells, we subsequently examined the multiple effects of anti-PD-L1 blockade beyond those on CD8 T cells. This extended model then predicts that the net effect on HIV load and CD4 T cell number depends on the interplay between positive and negative effects of lymphocyte subset activation. For a physiologically relevant range of affected model parameters, PD-L1 blockade is likely to be overall beneficial for HIV-infected individuals.
• dc.description.sponsorship This work is supported by the Russian Science Foundation (http://rscf.ru/en/) (grant 18-11-00171). JA and AM are also supported by a grant from the Spanish Ministry of Economy, Industry and Competitiveness (http://www.mineco.gob.es) and FEDER grant no. SAF2016-75505-R (AEI/MINEICO/FEDER, UE) and the “María de Maeztu” Programme for Units of Excellence in R&D (MDM-2014-0370). VZ is also partially supported by RFBR project 18-31-00356. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• dc.format.mimetype application/pdf
• dc.identifier.citation Zheltkova V, Argilaguet J, Peligero C, Bocharov G, Meyerhans A. Prediction of PD-L1 inhibition effects for HIV-infected individuals. PLoS Comput Biol. 2019;15(11):e1007401. DOI: 10.1371/journal.pcbi.1007401
• dc.identifier.doi http://dx.doi.org/10.1371/journal.pcbi.1007401
• dc.identifier.issn 1553-734X
• dc.identifier.uri http://hdl.handle.net/10230/42824
• dc.language.iso eng
• dc.publisher Public Library of Science (PLoS)
• dc.relation.ispartof PLOS Computational Biology. 2019;15(11):e1007401
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016-75505-R
• dc.rights © 2019 Zheltkova et al. 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.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword T cells
• dc.subject.keyword T helper cells
• dc.subject.keyword HIV
• dc.subject.keyword Cytotoxic T cells
• dc.subject.keyword HIV infections
• dc.subject.keyword Viral load
• dc.subject.keyword Cell cycle and cell division
• dc.subject.keyword Antibodies
• dc.title Prediction of PD-L1 inhibition effects for HIV-infected individuals
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion