In Vitro Evolution of an Influenza Broadly Neutralizing Antibody is Modulated by Hemagglutinin Receptor Specificity

Overview

Journal Nat Commun

Specialty Biology

Date 2017 May 16

PMID 28504265

Citations 46

Authors

Nicholas C Wu

Geramie Grande

Hannah L Turner

Andrew B Ward

Jia Xie

Richard A Lerner

Ian A Wilson

Affiliations

Soon will be listed here.

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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