Major antigenic site B of human influenza H3N2 viruses has an evolving local fitness landscape

Nicholas C Wu,Armita Nourmohammad,Andrew J Thompson,Jakub Otwinowski,Corwin M Nycholat,Ian A Wilson

doi:10.1038/s41467-020-15102-5

Abstract

Antigenic drift of influenza virus hemagglutinin (HA) is enabled by facile evolvability. However, HA antigenic site B, which has become immunodominant in recent human H3N2 influenza viruses, is also evolutionarily constrained by its involvement in receptor binding. Here, we employ deep mutational scanning to probe the local fitness landscape of HA antigenic site B in six different human H3N2 strains spanning from 1968 to 2016. We observe that the fitness landscape of HA antigenic site B can be very different between strains. Sequence variants that exhibit high fitness in one strain can be deleterious in another, indicating that the evolutionary constraints of antigenic site B have changed over time. Structural analysis suggests that the local fitness landscape of antigenic site B can be reshaped by natural mutations via modulation of the receptor-binding mode. Overall, these findings elucidate how influenza virus continues to explore new antigenic space despite strong functional constraints.

Highlights

Antigenic drift of influenza virus hemagglutinin (HA) is enabled by facile evolvability
A total of 4 × 4 × 3 × 2 × 3 × 2 = 576 amino acid combinations are possible across these six residues. These 576 variants were introduced into the HA of 6 different strains from 1968 to 2016, namely, A/ Hong Kong/1/1968 (HK68), A/Bangkok/1/1979 (Bk79), A/Beijing/353/1989 (Bei89), A/Moscow/10/1999 (Mos99), A/Brisbane/ 10/2007 (Bris07), and A/North Dakota/26/2016 (NDako16), which were isolated approximately 10 years apart
HK68, Bk79, Bei[89], Mos[99], and Bris[07] are all historical vaccine strains, whereas NDako[16] is almost identical to A/Switzerland/9715293/ 2013 (Switz13), which was the vaccine strain for the 2015–2016 influenza season

Summary

Introduction

Antigenic drift of influenza virus hemagglutinin (HA) is enabled by facile evolvability. We employ deep mutational scanning to probe the local fitness landscape of HA antigenic site B in six different human H3N2 strains spanning from 1968 to 2016. Structural analysis suggests that the local fitness landscape of antigenic site B can be reshaped by natural mutations via modulation of the receptor-binding mode. Overall, these findings elucidate how influenza virus continues to explore new antigenic space despite strong functional constraints. We are interested in understanding how the local fitness landscape of antigenic site B in human H3N2 virus has changed over time due to epistasis when the genetic backgrounds differ for the rest of the protein. The replication fitness of 576 variants of interest in antigenic site B is measured by deep mutational scanning in each of the six different H3N2 genetic backgrounds, namely, A/Hong Kong/1/1968 (HK68), A/Bangkok/1/

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