Recent H3N2 Viruses Have Evolved Specificity for Extended, Branched Human-type Receptors, Conferring Potential for Increased Avidity

Human and avian influenza viruses recognize different sialic acid-containing receptors, referred to as human-type (NeuAcα2-6Gal) and avian-type (NeuAcα2-3Gal), respectively. This presents a species barrier for aerosol droplet transmission of avian viruses in humans and ferrets. Recent reports have suggested that current human H3N2 viruses no longer have strict specificity toward human-type receptors. Using an influenza receptor glycan microarray with extended airway glycans, we find that H3N2 viruses have in fact maintained human-type specificity, but they have evolved preference for a subset of receptors comprising branched glycans with extended poly-N-acetyl-lactosamine (poly-LacNAc) chains, a specificity shared with the 2009 pandemic H1N1 (Cal/04) hemagglutinin. Lipid-linked versions of extended sialoside receptors can restore susceptibility of sialidase-treated MDCK cells to infection by both recent (A/Victoria/361/11) and historical (A/Hong Kong/8/1968) H3N2 viruses. Remarkably, these human-type receptors with elongated branches have the potential to increase avidity by simultaneously binding to two subunits of a single hemagglutinin trimer. [Display omitted] •All H3N2 influenza viruses recognize human-type receptors with extended glycan chains•Recent H3 and pandemic H1 hemagglutinins prefer extended, branched N-glycan receptors•Lipid-linked glycan receptors restore infectivity to receptor-deficient MDCK cells•Molecular dynamics simulation shows bidentate binding of N-glycans to one HA trimer To clarify H3N2 human influenza virus receptor specificity, Peng et al. developed a glycan array that included extended glycans. Recent H3N2 and 2009 pandemic H1N1 viruses share specificity for human-type receptors with extended glycan chains, conferring potential for increased avidity by simultaneously binding two subunits of a single hemagglutinin trimer.