title: An inhibitory activity in human cells restricts the function of an avian-like influenza virus polymerase.
abstract: Transmission of avian influenza virus into human populations has the potential to cause pandemic outbreaks. A major determinant of species tropism is the identity of amino acid 627 in the PB2 subunit of the heterotrimeric influenza polymerase; glutamic acid predominates in avian PB2, whereas lysine occupies this position in human isolates. We show that a dominant inhibitory activity in human cells potently and selectively restricts the function of polymerases containing an avian-like PB2 with glutamic acid at residue 627. Restricted polymerases fail to assemble into ribonucleoprotein complexes, resulting in decreased genome transcription, replication, and virus production without any significant effect on relative viral infectivity. Understanding the molecular basis of this species-specific restriction should provide strategies to prevent and treat avian influenza outbreaks in humans.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Mehle
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Doudna
mesh_terms: D000818:Animals; D001717:Birds / Q000821:virology; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology; D004285:Dogs; D054884:Host-Pathogen Interactions; D006801:Humans; D009980:Influenza A virus / Q000201:enzymology* / Q000235:genetics / Q000502:physiology; D005585:Influenza in Birds / Q000821:virology*; D007251:Influenza, Human / Q000821:virology*; D020125:Mutation, Missense; D011485:Protein Binding; D012324:RNA-Dependent RNA Polymerase / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D012261:Ribonucleoproteins / Q000378:metabolism; D013045:Species Specificity; D014764:Viral Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D019065:Virus Assembly
chemical_list: C057027:PB2 protein, Influenzavirus A; D012261:Ribonucleoproteins; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase