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 and Ian A. Wilson ()
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Nicholas C. Wu: The Scripps Research Institute
Andrew J. Thompson: The Scripps Research Institute
Jia Xie: The Scripps Research Institute
Chih-Wei Lin: The Scripps Research Institute
Corwin M. Nycholat: The Scripps Research Institute
Xueyong Zhu: The Scripps Research Institute
Richard A. Lerner: The Scripps Research Institute
James C. Paulson: The Scripps Research Institute
Ian A. Wilson: The Scripps Research Institute

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03663-5

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