Abstract
During circulation in humans and natural selection to escape antibody recognition for decades, A/H3N2 influenza viruses emerged with altered receptor specificities. These viruses lost the ability to agglutinate erythrocytes critical for antigenic characterization and give low yields and acquire adaptive mutations when cultured in eggs and cells, contributing to recent vaccine challenges. Examination of receptor specificities of A/H3N2 viruses reveals that recent viruses compensated for decreased binding of the prototypic human receptor by recognizing α2,6-sialosides on extended LacNAc moieties. Erythrocyte glycomics shows an absence of extended glycans providing a rationale for lack of agglutination by recent A/H3N2 viruses. A glycan remodeling approach installing functional receptors on erythrocytes, allows antigenic characterization of recent A/H3N2 viruses confirming the cocirculation of antigenically different viruses in humans. Computational analysis of HAs in complex with sialosides having extended LacNAc moieties reveals that mutations distal to the RBD reoriented the Y159 side chain resulting in an extended receptor binding site.
Highlights
During circulation in humans and natural selection to escape antibody recognition for decades, A/H3N2 influenza viruses emerged with altered receptor specificities
Glycan microarray technology has been used to examine receptor requirements of HAs24, these were not populated with biologically relevant glycans to establish minimal receptor requirements. This information is, critical to understand how receptor binding has evolved over time and how a lack of expression of specific glycans by erythrocytes or laboratory hosts may have resulted in a loss of agglutination or a lack of propagation, respectively
They resemble structures found on human respiratory tissue, which abundantly expresses N-glycans having multiple consecutive LacNAc repeating units that can be capped by sialic acid[25,26]
Summary
During circulation in humans and natural selection to escape antibody recognition for decades, A/H3N2 influenza viruses emerged with altered receptor specificities These viruses lost the ability to agglutinate erythrocytes critical for antigenic characterization and give low yields and acquire adaptive mutations when cultured in eggs and cells, contributing to recent vaccine challenges. Human influenza A viruses have a remarkable ability to evolve and evade neutralization by antibodies elicited by prior infections or vaccinations[1,2] This antigenic evolution, or drift, is mainly caused by amino acid substitutions in the globular head of the hemagglutinin (HA) protein where binding occurs with sialic acid receptors of host cells[3,4]. The difficulties to antigenically characterize circulating A/H3N2 viruses, in particular those belonging to the dominant 3C.2a clade, and the inability of large-scale virus production without eggadaptation has led to serious problems with A/H3N2 influenza vaccine production and effectiveness[1,11]
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