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Diversity of Functionally Permissive Sequences in the Receptor-Binding Site of Influenza Hemagglutinin
Nicholas C. Wu6
, Jia Xie6
, Tianqing Zheng
, Corwin M. Nycholat
, Geramie Grande
, James C. Paulson
, Richard A. Lerner
Correspondence information about the author Richard A. Lerner
Email the author Richard A. Lerner
, Ian A. Wilson7,Correspondence information about the author Ian A. WilsonEmail the author Ian A. Wilson
6These authors contributed equally
7Lead Contact
Highlights
Summary
Influenza A virus hemagglutinin (HA) initiates viral entry by engaging host receptor sialylated glycans via its receptor-binding site (RBS). The amino acid sequence of the RBS naturally varies across avian and human influenza virus subtypes and is also evolvable. However, functional sequence diversity in the RBS has not been fully explored. Here, we performed a large-scale mutational analysis of the RBS of A/WSN/33 (H1N1) and A/Hong Kong/1/1968 (H3N2) HAs. Many replication-competent mutants not yet observed in nature were identified, including some that could escape from an RBS-targeted broadly neutralizing antibody. This functional sequence diversity is made possible by pervasive epistasis in the RBS 220-loop and can be buffered by avidity in viral receptor binding. Overall, our study reveals that the HA RBS can accommodate a much greater range of sequence diversity than previously thought, which has significant implications for the complex evolutionary interrelationships between receptor specificity and immune escape.
Nicholas C. Wu6
, Jia Xie6
, Tianqing Zheng
, Corwin M. Nycholat
, Geramie Grande
, James C. Paulson
, Richard A. Lerner
Correspondence information about the author Richard A. LernerEmail the author Richard A. Lerner, Ian A. Wilson7,
Correspondence information about the author Ian A. WilsonEmail the author Ian A. Wilson6These authors contributed equally
7Lead Contact
Highlights
- ?Large-scale mutational analysis of influenza hemagglutinin receptor-binding site (RBS)
- ?Many new replication-competent RBS mutants were identified
- ?Some previously unobserved RBS mutants escape from a broadly neutralizing antibody
- ?Epistasis is common in the 220-loop of the hemagglutinin receptor-binding site
Summary
Influenza A virus hemagglutinin (HA) initiates viral entry by engaging host receptor sialylated glycans via its receptor-binding site (RBS). The amino acid sequence of the RBS naturally varies across avian and human influenza virus subtypes and is also evolvable. However, functional sequence diversity in the RBS has not been fully explored. Here, we performed a large-scale mutational analysis of the RBS of A/WSN/33 (H1N1) and A/Hong Kong/1/1968 (H3N2) HAs. Many replication-competent mutants not yet observed in nature were identified, including some that could escape from an RBS-targeted broadly neutralizing antibody. This functional sequence diversity is made possible by pervasive epistasis in the RBS 220-loop and can be buffered by avidity in viral receptor binding. Overall, our study reveals that the HA RBS can accommodate a much greater range of sequence diversity than previously thought, which has significant implications for the complex evolutionary interrelationships between receptor specificity and immune escape.
