A complex epistatic network limits the mutational reversibility in the influenza hemagglutinin receptor-binding site

Nicholas C. Wu, Andrew J. Thompson, Jia Xie, Chih Wei Lin, Corwin M. Nycholat, Xueyong Zhu, Richard A. Lerner, James C. Paulson, Ian A. Wilson

Research output: Contribution to journalArticlepeer-review

Abstract

The hemagglutinin (HA) receptor-binding site (RBS) in human influenza A viruses is critical for attachment to host cells, which imposes a functional constraint on its natural evolution. On the other hand, being part of the major antigenic sites, the HA RBS of human H3N2 viruses needs to constantly mutate to evade the immune system. From large-scale mutagenesis experiments, we here show that several of the natural RBS substitutions become integrated into an extensive epistatic network that prevents substitution reversion. X-ray structural analysis reveals the mechanistic consequences as well as changes in the mode of receptor binding. Further studies are necessary to elucidate whether such entrenchment limits future options for immune escape or adversely affect long-term viral fitness.

Original languageEnglish (US)
Article number1264
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018
Externally publishedYes

ASJC Scopus subject areas

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

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