Glycosylation changes in the globular head of H3N2 influenza hemagglutinin modulate
receptor binding without affecting virus virulence

Alymova, Irina V.; York, Ian A.; Air, Gillian M.; Cipollo, John F.; Gulati, Shelly; Baranovich, Tatiana; Kumar, Amrita; Zeng, Hui; Gansebom, Shane; McCullers, Jonathan A.

doi:10.1038/srep36216

Cited by 49 publications

(48 citation statements)

References 50 publications

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“…Accretion of conformationally flexible oligosaccharides on the HA further shields the antigenic sites to facilitate immune evasion [43, 59–62]. Nonetheless, the added N-glycosylation sites can also affect binding of the natural receptor when they are proximal to the RBS [54, 63–67]. The functional constraints of the RBS render it difficult, if not impossible, to be completely shielded by oligosaccharides.…”

Section: Antigenic Drift: Point Mutations and Glycosylationmentioning

confidence: 99%

A Perspective on the Structural and Functional Constraints for Immune Evasion: Insights from Influenza Virus

Wilson

2017

Journal of Molecular Biology

146

174

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Influenza virus evolves rapidly to constantly escape from natural immunity. Most humoral immune responses to influenza virus target the hemagglutinin glycoprotein (HA), which is the major antigen on the surface of the virus. The HA is comprised of a globular head domain for receptor binding and a stem domain for membrane fusion. The major antigenic sites of HA are located in the globular head subdomain, which is highly tolerant of amino-acid substitutions and continual addition of glycosylation sites. Nonetheless, the evolution of the receptor-binding site (RBS) and the stem region on HA is severely constrained by their functional roles in engaging the host receptor and in mediating membrane fusion, respectively. Here, we review how broadly neutralizing antibodies (bnAbs) exploit these evolutionary constraints to protect against diverse influenza strains. We also discuss the emerging role of other epitopes that are conserved only in subsets of viruses. This rapidly increasing knowledge of the evolutionary biology, immunology, structural biology, and virology of influenza virus is invaluable for development and design of more universal influenza vaccines as well as novel therapeutics.

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Section: Antigenic Drift: Point Mutations and Glycosylationmentioning

confidence: 99%

A Perspective on the Structural and Functional Constraints for Immune Evasion: Insights from Influenza Virus

Wilson

2017

Journal of Molecular Biology

146

174

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“…Alymova et al [66] also recently examined H3N2 with varying glycosylation levels, and concluded that glycosylation of the HA1 could decrease binding affinity, without reducing virulence. They further introduced the hypothesis, based on the consistent binding of the HAs to linear α2-6 sialylated polylactosamine glycans, that physiologically relevant receptor binding had not changed over the past 40 years.…”

Section: Impact Of Ha Glycosylation On Specificitymentioning

confidence: 99%

New insights into influenza A specificity: an evolution of paradigms

White

Hadden

et al. 2017

Current Opinion in Structural Biology

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Understanding the molecular origin of influenza receptor specificity is complicated by the paucity of quantitative affinity measurements, and the qualitative and variable nature of glycan array data. Further obstacles arise from the varied impact of viral glycosylation and the relatively narrow spectrum of biologically relevant receptors present on glycan arrays. A survey of receptor conformational properties is presented, leading to the conclusion that conformational entropy plays a key role in defining specificity, as does the newly reported ability of biantennary receptors that terminate in Siaα2-6Gal sequences to form bidentate interactions to two binding sites in a hemagglutinin trimer. Bidentate binding provides a functional explanation for the observation that Siaα2-6 receptors adopt an open-umbrella topology when bound to hemagglutinins from human-infective viruses, and calls for a reassessment of virus avidity and tissue tropism.

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“…HA surface antigenicity is affected strongly by the presence and types of N-glycosylation, which cannot be predicted from genetic sequence or 3D protein coordinates (13). N-Glycosylation sequons accumulate in the protein sequence, giving rise to increasing glycosylation as the strain evolves, shielding of antigenic sites (8,14,15), influencing receptor binding (16,17) and binding to innate immune system molecules (18,19).…”

Section: Introductionmentioning

confidence: 99%

Measuring site-specific glycosylation similarity between influenza A virus variants with statistical certainty

Chang

Hackett

Zhong

et al. 2020

Preprint

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The abbreviations used are: IAV, influenza A virus; HA, hemagglutinin; NA, neuraminidase; AGP, alpha-1-acid glycoprotein; AGPgal, asialo AGP with terminal galactose residues removed; Phil82, A/Philippines/2/1982; Phil82gal, Phil82 with terminal galactose residues removed; SWZ13, A/Switzerland/9715293/2013; 5B8, SWZ13 with amino acid substitutions Q132H, Y219S, and D225N in HA. AbstractInfluenza A virus (IAV) mutates rapidly, resulting in antigenic drift and poor year-to-year vaccine effectiveness. One challenge in designing effective vaccines is that genetic mutations frequently cause amino acid variations in IAV envelope protein hemagglutinin (HA) that create new N-glycosylation sequons; resulting N-glycans cause antigenic shielding, allowing viral escape from adaptive immune responses. Vaccine candidate strain selection currently involves correlating antigenicity with HA protein sequence among circulating strains, but quantitative comparison of site-specific glycosylation information may likely improve the ability to design vaccines with broader effectiveness against evolving strains. However, there is poor understanding of the influence of glycosylation on immunodominance, antigenicity, and immunogenicity of HA, and there are no well-tested methods for comparing glycosylation similarity among virus samples. Here, we present a method for statistically rigorous quantification of similarity between two related virus strains that considers the presence and Chang et al. p. 3 abundance of glycopeptide glycoforms. We demonstrate the strength of our approach by determining that there was a quantifiable difference in glycosylation at the protein level between wild-type IAV HA from A/Switzerland/9715293/2013 (SWZ13) and a mutant strain of SWZ13, even though no N-glycosylation sequons were changed. We determined site-specifically that WT and mutant HA have varying similarity at the glycosylation sites of the head domain, reflecting competing pressures to evade host immune response while retaining viral fitness. To our knowledge, our results are the first to quantify changes in glycosylation state that occur in related proteins of considerable glycan heterogeneity. Our results provide a method for understanding how changes in glycosylation state are correlated with variations in protein sequence, which is necessary for improving IAV vaccine strain selection. Understanding glycosylation will be especially important as we find new expression vectors for vaccine production, as glycosylation state depends greatly on the host species.

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Glycosylation changes in the globular head of H3N2 influenza hemagglutinin modulate receptor binding without affecting virus virulence

Cited by 49 publications

References 50 publications

A Perspective on the Structural and Functional Constraints for Immune Evasion: Insights from Influenza Virus

A Perspective on the Structural and Functional Constraints for Immune Evasion: Insights from Influenza Virus

New insights into influenza A specificity: an evolution of paradigms

Measuring site-specific glycosylation similarity between influenza A virus variants with statistical certainty

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