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Author Notes:

Address correspondence to Richard D. Cummings, rcummin1@bidmc.harvard.edu, or David A. Steinhauer (requests for materials), dsteinh@emory.edu

L.B.-L., C.G., J.T., and N.J. performed the experiments, with the assistance of S.F.C. and J.H.-M. L.B.-L. and C.G. analyzed the data, with the assistance of A.Y.M. D.A.S. and R.D.C. supervised the experiments. L.B.-L., R.D.C., and D.A.S. wrote the manuscript.

We declare that we have no competing interests.


Research Funding:

We acknowledge support from the U.S. Department of Health and Human Services (contract HHSN272201400004C) (National Institute for Allergy and Infectious Diseases [NIAID] Centers of Excellence for Influenza Research and Surveillance) and National Institutes of Health (NIH) award P41GM103694 (National Center for Functional Glycomics), which supports the use of the Consortium for Functional Glycomics (CFG) glycan microarrays. J.T. was supported by the NIAID of the NIH under award T32AI106699.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Virology
  • phosphorylated glycans
  • receptor binding
  • sialylated glycans
  • antigenic drift
  • influenza

Antigenic Pressure on H3N2 Influenza Virus Drift Strains Imposes Constraints on Binding to Sialylated Receptors but Not Phosphorylated Glycans


Journal Title:

Journal of Virology


Volume 93, Number 22


Type of Work:

Article | Final Publisher PDF


H3N2 strains of influenza A virus emerged in humans in 1968 and have continued to circulate, evolving in response to human immune pressure. During this process of "antigenic drift," viruses have progressively lost the ability to agglutinate erythrocytes of various species and to replicate efficiently under the established conditions for amplifying clinical isolates and generating vaccine candidates. We have determined the glycome profiles of chicken and guinea pig erythrocytes to gain insights into reduced agglutination properties displayed by drifted strains and show that both chicken and guinea pig erythrocytes contain complex sialylated N-glycans but that they differ with respect to the extent of branching, core fucosylation, and the abundance of poly-N-acetyllactosamine (PL) [-3Galβ1-4GlcNAcβ1-]n structures. We also examined binding of the H3N2 viruses using three different glycan microarrays: The synthetic Consortium for Functional Glycomics array; the defined N-glycan array designed to reveal contributions to binding based on sialic acid linkage type, branched structures, and core modifications; and the human lung shotgun glycan microarray. The results demonstrate that H3N2 viruses have progressively lost their capacity to bind nearly all canonical sialylated receptors other than a selection of biantennary structures and PL structures with or without sialic acid. Significantly, all viruses displayed robust binding to nonsialylated high-mannose phosphorylated glycans, even as the recognition of sialylated structures is decreased through antigenic drift. IMPORTANCE Influenza subtype H3N2 viruses have circulated in humans for over 50 years, continuing to cause annual epidemics. Such viruses have undergone antigenic drift in response to immune pressure, reducing the protective effects of preexisting immunity to previously circulating H3N2 strains. The changes in hemagglutinin (HA) affiliated with drift have implications for the receptor binding properties of these viruses, affecting virus replication in the culture systems commonly used to generate and amplify vaccine strains. Therefore, the antigenic properties of the vaccines may not directly reflect those of the circulating strains from which they were derived, compromising vaccine efficacy. In order to reproducibly provide effective vaccines, it will be critical to understand the interrelationships between binding, antigenicity, and replication properties in different growth substrates.

Copyright information:

© 2019 American Society for Microbiology.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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