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

Autor:	Phillips AM; Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, United States., Lawrence KR; Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, United States.; NSF-Simons Center for Mathematical and Statistical Analysis of Biology, Harvard University, Cambridge, United States.; Quantitative Biology Initiative, Harvard University, Cambridge, United States.; Department of Physics, Massachusetts Institute of Technology, Cambridge, United States., Moulana A; Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, United States., Dupic T; Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, United States., Chang J; Department of Physics, Harvard University, Cambridge, United States., Johnson MS; Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, United States., Cvijovic I; Department of Applied Physics, Stanford University, Stanford, United States., Mora T; Laboratoire de physique de ÍÉcole Normale Supérieure, CNRS, PSL University, Sorbonne Université, and Université de Paris, Paris, France., Walczak AM; Laboratoire de physique de ÍÉcole Normale Supérieure, CNRS, PSL University, Sorbonne Université, and Université de Paris, Paris, France., Desai MM; Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, United States.; NSF-Simons Center for Mathematical and Statistical Analysis of Biology, Harvard University, Cambridge, United States.; Quantitative Biology Initiative, Harvard University, Cambridge, United States.; Department of Physics, Harvard University, Cambridge, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2021 Sep 07; Vol. 10. Date of Electronic Publication: 2021 Sep 07.
DOI:	10.7554/eLife.71393
Abstrakt:	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. Competing Interests: AP, KL, AM, TD, JC, MJ, IC, TM, MD No competing interests declared, AW Senior editor, eLife (© 2021, Phillips et al.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu