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

Nicholas C. Wu; Geramie Grande; Hannah L. Turner; Andrew B. Ward; Jia Xie; Richard A. Lerner; Ian A. Wilson

doi:10.1038/ncomms15371

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

Nicholas C. Wu, Geramie Grande, Hannah L. Turner, Andrew B. Ward, Jia Xie, Richard A. Lerner, Ian A. Wilson

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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.

Original language	English (US)
Article number	15371
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15371
State	Published - May 15 2017
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/ncomms15371

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title = "In vitro evolution of an influenza broadly neutralizing antibody is modulated by hemagglutinin receptor specificity",

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.",

author = "Wu, {Nicholas C.} and Geramie Grande and Turner, {Hannah L.} and Ward, {Andrew B.} and Jia Xie and Lerner, {Richard A.} and Wilson, {Ian A.}",

note = "Funding Information: We acknowledge NIH R56 AI117675 for support. N.C.W. was supported by the Croucher Foundation Fellowship. Publisher Copyright: {\textcopyright} The Author(s) 2017.",

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doi = "10.1038/ncomms15371",

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AU - Wu, Nicholas C.

AU - Grande, Geramie

AU - Turner, Hannah L.

AU - Ward, Andrew B.

AU - Xie, Jia

AU - Lerner, Richard A.

AU - Wilson, Ian A.

PY - 2017/5/15

Y1 - 2017/5/15

N2 - 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.

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

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