title: A single amino acid in the stalk region of the H1N1pdm influenza virus HA protein affects viral fusion, stability and infectivity.
abstract: The 2009 H1N1 pandemic (H1N1pdm) viruses have evolved to contain an E47K substitution in the HA2 subunit of the stalk region of the hemagglutinin (HA) protein. The biological significance of this single amino acid change was investigated by comparing A/California/7/2009 (HA2-E47) with a later strain, A/Brisbane/10/2010 (HA2-K47). The E47K change was found to reduce the threshold pH for membrane fusion from 5.4 to 5.0. An inter-monomer salt bridge between K47 in HA2 and E21 in HA1, a neighboring highly conserved residue, which stabilized the trimer structure, was found to be responsible for the reduced threshold pH for fusion. The higher structural and acid stability of the HA trimer caused by the E47K change also conferred higher viral thermal stability and infectivity in ferrets, suggesting a fitness advantage for the E47K evolutionary change in humans. Our study indicated that the pH of HA fusion activation is an important factor for influenza virus replication and host adaptation. The identification of this genetic signature in the HA stalk region that influences vaccine virus thermal stability also has significant implications for influenza vaccine production.
authors.affiliation: MedImmune LLC, Mountain View, California, United States of America.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Cotter
authors.affiliation: MedImmune LLC, Mountain View, California, United States of America.
authors.forename: Hong
authors.initials: H
authors.lastname: Jin
authors.affiliation: MedImmune LLC, Mountain View, California, United States of America.
authors.forename: Zhongying
authors.initials: Z
authors.lastname: Chen
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002462:Cell Membrane; D002642:Chick Embryo; D004285:Dogs; D005289:Ferrets; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000378:metabolism*; D006358:Hot Temperature; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053118:Influenza A Virus, H1N1 Subtype / Q000472:pathogenicity* / Q000502:physiology*; D007252:Influenza Vaccines / Q000235:genetics / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D020125:Mutation, Missense; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D053586:Virus Internalization; D014779:Virus Replication / Q000502:physiology*
chemical_list: C543345:H1N1 virus hemagglutinin; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines