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Binding affinity landscapes constrain the evolution of broadly neutralizing anti-influenza antibodies

Over the past two decades, several broadly neutralizing antibodies (bnAbs) that confer protection against diverse influenza strains have been isolated. Structural and biochemical characterization of these bnAbs has provided molecular insight into how they bind distinct antigens. However, our underst...

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Autores principales: Phillips, Angela M, Lawrence, Katherine R, Moulana, Alief, Dupic, Thomas, Chang, Jeffrey, Johnson, Milo S, Cvijovic, Ivana, Mora, Thierry, Walczak, Aleksandra M, Desai, Michael M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476123/
https://www.ncbi.nlm.nih.gov/pubmed/34491198
http://dx.doi.org/10.7554/eLife.71393
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author Phillips, Angela M
Lawrence, Katherine R
Moulana, Alief
Dupic, Thomas
Chang, Jeffrey
Johnson, Milo S
Cvijovic, Ivana
Mora, Thierry
Walczak, Aleksandra M
Desai, Michael M
author_facet Phillips, Angela M
Lawrence, Katherine R
Moulana, Alief
Dupic, Thomas
Chang, Jeffrey
Johnson, Milo S
Cvijovic, Ivana
Mora, Thierry
Walczak, Aleksandra M
Desai, Michael M
author_sort Phillips, Angela M
collection PubMed
description Over the past two decades, several broadly neutralizing antibodies (bnAbs) that confer protection against diverse influenza strains have been isolated. Structural and biochemical characterization of these bnAbs has provided molecular insight into how they bind distinct antigens. However, our understanding of the evolutionary pathways leading to bnAbs, and thus how best to elicit them, remains limited. Here, we measure equilibrium dissociation constants of combinatorially complete mutational libraries for two naturally isolated influenza bnAbs (CR9114, 16 heavy-chain mutations; CR6261, 11 heavy-chain mutations), reconstructing all possible evolutionary intermediates back to the unmutated germline sequences. We find that these two libraries exhibit strikingly different patterns of breadth: while many variants of CR6261 display moderate affinity to diverse antigens, those of CR9114 display appreciable affinity only in specific, nested combinations. By examining the extensive pairwise and higher order epistasis between mutations, we find key sites with strong synergistic interactions that are highly similar across antigens for CR6261 and different for CR9114. Together, these features of the binding affinity landscapes strongly favor sequential acquisition of affinity to diverse antigens for CR9114, while the acquisition of breadth to more similar antigens for CR6261 is less constrained. These results, if generalizable to other bnAbs, may explain the molecular basis for the widespread observation that sequential exposure favors greater breadth, and such mechanistic insight will be essential for predicting and eliciting broadly protective immune responses.
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spelling pubmed-84761232021-09-29 Binding affinity landscapes constrain the evolution of broadly neutralizing anti-influenza antibodies Phillips, Angela M Lawrence, Katherine R Moulana, Alief Dupic, Thomas Chang, Jeffrey Johnson, Milo S Cvijovic, Ivana Mora, Thierry Walczak, Aleksandra M Desai, Michael M eLife Evolutionary Biology Over the past two decades, several broadly neutralizing antibodies (bnAbs) that confer protection against diverse influenza strains have been isolated. Structural and biochemical characterization of these bnAbs has provided molecular insight into how they bind distinct antigens. However, our understanding of the evolutionary pathways leading to bnAbs, and thus how best to elicit them, remains limited. Here, we measure equilibrium dissociation constants of combinatorially complete mutational libraries for two naturally isolated influenza bnAbs (CR9114, 16 heavy-chain mutations; CR6261, 11 heavy-chain mutations), reconstructing all possible evolutionary intermediates back to the unmutated germline sequences. We find that these two libraries exhibit strikingly different patterns of breadth: while many variants of CR6261 display moderate affinity to diverse antigens, those of CR9114 display appreciable affinity only in specific, nested combinations. By examining the extensive pairwise and higher order epistasis between mutations, we find key sites with strong synergistic interactions that are highly similar across antigens for CR6261 and different for CR9114. Together, these features of the binding affinity landscapes strongly favor sequential acquisition of affinity to diverse antigens for CR9114, while the acquisition of breadth to more similar antigens for CR6261 is less constrained. These results, if generalizable to other bnAbs, may explain the molecular basis for the widespread observation that sequential exposure favors greater breadth, and such mechanistic insight will be essential for predicting and eliciting broadly protective immune responses. eLife Sciences Publications, Ltd 2021-09-07 /pmc/articles/PMC8476123/ /pubmed/34491198 http://dx.doi.org/10.7554/eLife.71393 Text en © 2021, Phillips et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Evolutionary Biology
Phillips, Angela M
Lawrence, Katherine R
Moulana, Alief
Dupic, Thomas
Chang, Jeffrey
Johnson, Milo S
Cvijovic, Ivana
Mora, Thierry
Walczak, Aleksandra M
Desai, Michael M
Binding affinity landscapes constrain the evolution of broadly neutralizing anti-influenza antibodies
title Binding affinity landscapes constrain the evolution of broadly neutralizing anti-influenza antibodies
title_full Binding affinity landscapes constrain the evolution of broadly neutralizing anti-influenza antibodies
title_fullStr Binding affinity landscapes constrain the evolution of broadly neutralizing anti-influenza antibodies
title_full_unstemmed Binding affinity landscapes constrain the evolution of broadly neutralizing anti-influenza antibodies
title_short Binding affinity landscapes constrain the evolution of broadly neutralizing anti-influenza antibodies
title_sort binding affinity landscapes constrain the evolution of broadly neutralizing anti-influenza antibodies
topic Evolutionary Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476123/
https://www.ncbi.nlm.nih.gov/pubmed/34491198
http://dx.doi.org/10.7554/eLife.71393
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