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

Nat Commun. 2020 Mar 6;11(1):1233. doi: 10.1038/s41467-020-15102-5.

Authors

Nicholas C Wu¹, Jakub Otwinowski², Andrew J Thompson³, Corwin M Nycholat³, Armita Nourmohammad^{2

4}, Ian A Wilson^{5

6}

Affiliations

¹ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
² Max Planck Institute for Dynamics and Self-Organization, 37077, Göttingen, Germany.
³ Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA.
⁴ Department of Physics, University of Washington, Seattle, WA, 98195, USA.
⁵ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA. wilson@scripps.edu.
⁶ The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA. wilson@scripps.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, Viral / genetics*
Antigens, Viral / immunology
Antigens, Viral / metabolism
Binding Sites / genetics
Crystallography, X-Ray
DNA Mutational Analysis
Dogs
Evolution, Molecular*
HEK293 Cells
Hemagglutinin Glycoproteins, Influenza Virus / genetics*
Hemagglutinin Glycoproteins, Influenza Virus / immunology
Hemagglutinin Glycoproteins, Influenza Virus / metabolism
Humans
Influenza A Virus, H3N2 Subtype / genetics*
Influenza A Virus, H3N2 Subtype / immunology
Influenza A Virus, H3N2 Subtype / metabolism
Madin Darby Canine Kidney Cells
Mutation
Protein Domains / genetics
Protein Domains / immunology
RNA, Viral / genetics
RNA, Viral / isolation & purification
Receptors, Cell Surface / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Sequence Analysis, DNA

Substances

Antigens, Viral
Hemagglutinin Glycoproteins, Influenza Virus
RNA, Viral
Receptors, Cell Surface
sialic acid receptor

Abstract

Publication types

MeSH terms

Substances

Grants and funding