RT Journal Article T1 Evolution of human H3N2 influenza virus receptor specificity has substantially expanded the receptor-binding domain site A1 Thompson, Andrew J. A1 Wu, Nicholas C. A1 Canales Mayordomo, María Ángeles A1 Kikuchi, Chika A1 Zhu, Xueyong A1 Fernadez de Toro, Beatriz A1 Cañada, Francisco J. A1 Worth, Charli A1 Wang, Shengyang A1 Mcbride, Ryan A1 Peng, Wenjie A1 Nycholat, Corwin M. A1 Jimenez-Barbero, Jesus A1 Wilson, Ian A. A1 Paulson, James C. AB Hemagglutinins (HAs) from human influenza viruses descend from avian progenitors that bind α2–3-linked sialosides, and must adapt to glycans with α2–6-linked sialic acids on human airway cells to transmit within the human population. Since their introduction during the 1968 pandemic, H3N2 viruses have evolved over the past five decades to preferentially recognize α2–6-sialoside receptors that are elongated through addition of poly-LacNAc. Using STD-NMR, X-ray crystallography, and solid-phase glycan microarrays, we show that more recent H3N2 viruses now make increasingly complex interactions with elongated receptors, while continuously selecting for strains maintaining this phenotype. This change is accompanied by an extension of the traditional receptor binding site to include residues in key antigenic sites on the surface of HA trimers. These results help explain the propensity for selection of antigenic variants, leading to vaccine mismatching, when H3N2 viruses are propagated in chicken eggs or cells that do not contain such receptors. PB Cell Press SN 1934-6069 SN 1931-3128 YR 2024 FD 2024-04-29 LK https://hdl.handle.net/20.500.14352/107749 UL https://hdl.handle.net/20.500.14352/107749 LA eng NO Thompson A J, Wu N C, Canales A, Kikuchi C, Zhu X , Fernández de Toro B, Cañada F J, Worth C, Wang S , McBride R , Peng W , Nycholat C M , Jiménez-Barbero J, Wilson I A, Paulson J C. Evolution of human H3N2 influenza virus receptor specificity has substantially expanded the receptor-binding domain site. Cell Host Microbe. 2024 Feb 14; 32(2): 261–275.e4. NO Bill and Melinda Gates Foundation, Ministerio de Ciencia e Innovación de España, Kwang Hua Educational Foundation, NIH NIAID Centers of Excellence for Influenza Research DS Docta Complutense RD 7 abr 2025