How single mutations affect viral escape from broad and narrow antibodies to H1 influenza hemagglutinin

Michael B Doud,Juhye M Lee,Jesse D Bloom

doi:10.1038/s41467-018-03665-3

Michael B Doud, Juhye M Lee + Show 1 more

Open Access

https://doi.org/10.1038/s41467-018-03665-3

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Abstract

Influenza virus can escape most antibodies with single mutations. However, rare antibodies broadly neutralize many viral strains. It is unclear how easily influenza virus might escape such antibodies if there was strong pressure to do so. Here, we map all single amino-acid mutations that increase resistance to broad antibodies to H1 hemagglutinin. Our approach not only identifies antigenic mutations but also quantifies their effect sizes. All antibodies select mutations, but the effect sizes vary widely. The virus can escape a broad antibody to hemagglutinin’s receptor-binding site the same way it escapes narrow strain-specific antibodies: via single mutations with huge effects. In contrast, broad antibodies to hemagglutinin’s stalk only select mutations with small effects. Therefore, among the antibodies we examine, breadth is an imperfect indicator of the potential for viral escape via single mutations. Antibodies targeting the H1 hemagglutinin stalk are quantifiably harder to escape than the other antibodies tested here.

Highlights

Influenza virus can escape most antibodies with single mutations
Human influenza virus undergoes rapid antigenic drift because most neutralizing antibodies target epitopes on the viral hemagglutinin (HA) protein that are highly tolerant of mutational change
The epitopes of broad antibodies could come under stronger antigenic selection in human influenza virus

Summary

Introduction

Influenza virus can escape most antibodies with single mutations. rare antibodies broadly neutralize many viral strains. One possible reason that viruses exhibit different amounts of antigenic variation is that they have disparate evolutionary capacities to escape the immunodominant antibodies generated by natural immune responses[13,14,15] According to this explanation, human influenza virus undergoes rapid antigenic drift because most neutralizing antibodies target epitopes on the viral hemagglutinin (HA) protein that are highly tolerant of mutational change. Verifying this corollary has become of practical importance with the discovery of broadly neutralizing antibodies against influenza virus These antibodies typically target conserved epitopes in HA’s stalk[24,25,26] or receptor-binding site[27,28,29], and neutralize a wide range of viral strains. Perhaps broad antibodies are broad because the virus has difficulty escaping them regardless of selection from host immunity

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