In vitro evolution of an influenza broadly neutralizing antibody is modulated by hemagglutinin receptor specificity

Nature Communications
Nicholas C WuIan A Wilson

Abstract

The relatively recent discovery and characterization of human broadly neutralizing antibodies (bnAbs) against influenza virus provide valuable insights into antiviral and vaccine development. However, the factors that influence the evolution of high-affinity bnAbs remain elusive. We therefore explore the functional sequence space of bnAb C05, which targets the receptor-binding site (RBS) of influenza haemagglutinin (HA) via a long CDR H3. We combine saturation mutagenesis with yeast display to enrich for C05 variants of CDR H3 that bind to H1 and H3 HAs. The C05 variants evolve up to 20-fold higher affinity but increase specificity to each HA subtype used in the selection. Structural analysis reveals that the fine specificity is strongly influenced by a highly conserved substitution that regulates receptor binding in different subtypes. Overall, this study suggests that subtle natural variations in the HA RBS between subtypes and species may differentially influence the evolution of high-affinity bnAbs.

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Citations

Jan 16, 2019·Proceedings of the National Academy of Sciences of the United States of America·Alexander M SevyJens Meiler
Oct 2, 2019·PLoS Computational Biology·Shenshen Wang, Lei Dai
Jan 9, 2019·The Journal of Immunology : Official Journal of the American Association of Immunologists·James E Crowe
Feb 5, 2019·The Journal of Infectious Diseases·James E Crowe
Jul 22, 2020·Proceedings of the National Academy of Sciences of the United States of America·Yao YaoDennis W Wolan
Sep 27, 2019·Evolutionary Bioinformatics Online·Khanh Pb LeLy Le
Jul 15, 2020·Science·Meng YuanIan A Wilson
Mar 12, 2021·Biochemistry·Clara T SchoederRocco Moretti
Mar 23, 2021·PLoS Pathogens·Chang-Chun D LeeIan A Wilson
Apr 29, 2021·ELife·Oskar H Schnaack, Armita Nourmohammad
Oct 24, 2018·Journal of Medicinal Chemistry·Cy V CredilleSeth M Cohen

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Datasets Mentioned

BETA
PRJNA326694
EMD-8578

Methods Mentioned

BETA
phage
fluorescence-activated cell sorting
size exclusion chromatography
PCR
PCRs
fluorescence-activated
Flow Cytometry
transfection
biolayer interferometry
biosensors

Clinical Trials Mentioned

NCT02371668
NCT01938352

Software Mentioned

ImageJ
DogPicker
Chimera
EMAN2
Coot
Appion
Refmac5
Leginon

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