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Characterization of CD8 T Cell-Mediated Mutations in the Immunodominant Epitope GP33-41 of Lymphocytic Choriomeningitis Virus

Cytotoxic T lymphocytes (CTLs) represent key immune effectors of the host response against chronic viruses, due to their cytotoxic response to virus-infected cells. In response to this selection pressure, viruses may accumulate escape mutations that evade CTL-mediated control. To study the emergence...

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Autores principales: Smyth, Mark, Khamina, Kseniya, Popa, Alexandra, Gudipati, Venugopal, Agerer, Benedikt, Lercher, Alexander, Kosack, Lindsay, Endler, Lukas, Baazim, Hatoon, Viczenczova, Csilla, Huppa, Johannes B., Bergthaler, Andreas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236698/
https://www.ncbi.nlm.nih.gov/pubmed/34194424
http://dx.doi.org/10.3389/fimmu.2021.638485
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author Smyth, Mark
Khamina, Kseniya
Popa, Alexandra
Gudipati, Venugopal
Agerer, Benedikt
Lercher, Alexander
Kosack, Lindsay
Endler, Lukas
Baazim, Hatoon
Viczenczova, Csilla
Huppa, Johannes B.
Bergthaler, Andreas
author_facet Smyth, Mark
Khamina, Kseniya
Popa, Alexandra
Gudipati, Venugopal
Agerer, Benedikt
Lercher, Alexander
Kosack, Lindsay
Endler, Lukas
Baazim, Hatoon
Viczenczova, Csilla
Huppa, Johannes B.
Bergthaler, Andreas
author_sort Smyth, Mark
collection PubMed
description Cytotoxic T lymphocytes (CTLs) represent key immune effectors of the host response against chronic viruses, due to their cytotoxic response to virus-infected cells. In response to this selection pressure, viruses may accumulate escape mutations that evade CTL-mediated control. To study the emergence of CTL escape mutations, we employed the murine chronic infection model of lymphocytic choriomeningitis virus (LCMV). We developed an amplicon-based next-generation sequencing pipeline to detect low frequency mutations in the viral genome and identified non-synonymous mutations in the immunodominant LCMV CTL epitope, GP33-41, in infected wildtype mice. Infected Rag2-deficient mice lacking CTLs did not contain such viral mutations. By using transgenic mice with T cell receptors specific to GP33-41, we characterized the emergence of viral mutations in this epitope under varying selection pressure. We investigated the two most abundant viral mutations by employing reverse genetically engineered viral mutants encoding the respective mutations. These experiments provided evidence that these mutations prevent activation and expansion of epitope-specific CD8 T cells. Our findings on the mutational dynamics of CTL escape mutations in a widely-studied viral infection model contributes to our understanding of how chronic viruses interact with their host and evade the immune response. This may guide the development of future treatments and vaccines against chronic infections.
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spelling pubmed-82366982021-06-29 Characterization of CD8 T Cell-Mediated Mutations in the Immunodominant Epitope GP33-41 of Lymphocytic Choriomeningitis Virus Smyth, Mark Khamina, Kseniya Popa, Alexandra Gudipati, Venugopal Agerer, Benedikt Lercher, Alexander Kosack, Lindsay Endler, Lukas Baazim, Hatoon Viczenczova, Csilla Huppa, Johannes B. Bergthaler, Andreas Front Immunol Immunology Cytotoxic T lymphocytes (CTLs) represent key immune effectors of the host response against chronic viruses, due to their cytotoxic response to virus-infected cells. In response to this selection pressure, viruses may accumulate escape mutations that evade CTL-mediated control. To study the emergence of CTL escape mutations, we employed the murine chronic infection model of lymphocytic choriomeningitis virus (LCMV). We developed an amplicon-based next-generation sequencing pipeline to detect low frequency mutations in the viral genome and identified non-synonymous mutations in the immunodominant LCMV CTL epitope, GP33-41, in infected wildtype mice. Infected Rag2-deficient mice lacking CTLs did not contain such viral mutations. By using transgenic mice with T cell receptors specific to GP33-41, we characterized the emergence of viral mutations in this epitope under varying selection pressure. We investigated the two most abundant viral mutations by employing reverse genetically engineered viral mutants encoding the respective mutations. These experiments provided evidence that these mutations prevent activation and expansion of epitope-specific CD8 T cells. Our findings on the mutational dynamics of CTL escape mutations in a widely-studied viral infection model contributes to our understanding of how chronic viruses interact with their host and evade the immune response. This may guide the development of future treatments and vaccines against chronic infections. Frontiers Media S.A. 2021-06-14 /pmc/articles/PMC8236698/ /pubmed/34194424 http://dx.doi.org/10.3389/fimmu.2021.638485 Text en Copyright © 2021 Smyth, Khamina, Popa, Gudipati, Agerer, Lercher, Kosack, Endler, Baazim, Viczenczova, Huppa and Bergthaler https://creativecommons.org/licenses/by/4.0/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.
spellingShingle Immunology
Smyth, Mark
Khamina, Kseniya
Popa, Alexandra
Gudipati, Venugopal
Agerer, Benedikt
Lercher, Alexander
Kosack, Lindsay
Endler, Lukas
Baazim, Hatoon
Viczenczova, Csilla
Huppa, Johannes B.
Bergthaler, Andreas
Characterization of CD8 T Cell-Mediated Mutations in the Immunodominant Epitope GP33-41 of Lymphocytic Choriomeningitis Virus
title Characterization of CD8 T Cell-Mediated Mutations in the Immunodominant Epitope GP33-41 of Lymphocytic Choriomeningitis Virus
title_full Characterization of CD8 T Cell-Mediated Mutations in the Immunodominant Epitope GP33-41 of Lymphocytic Choriomeningitis Virus
title_fullStr Characterization of CD8 T Cell-Mediated Mutations in the Immunodominant Epitope GP33-41 of Lymphocytic Choriomeningitis Virus
title_full_unstemmed Characterization of CD8 T Cell-Mediated Mutations in the Immunodominant Epitope GP33-41 of Lymphocytic Choriomeningitis Virus
title_short Characterization of CD8 T Cell-Mediated Mutations in the Immunodominant Epitope GP33-41 of Lymphocytic Choriomeningitis Virus
title_sort characterization of cd8 t cell-mediated mutations in the immunodominant epitope gp33-41 of lymphocytic choriomeningitis virus
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236698/
https://www.ncbi.nlm.nih.gov/pubmed/34194424
http://dx.doi.org/10.3389/fimmu.2021.638485
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