title: Novel residues in avian influenza virus PB2 protein affect virulence in mammalian hosts.
abstract: Highly pathogenic avian H5N1 influenza viruses have sporadically transmitted to humans causing high mortality. The mechanistic basis for adaptation is still poorly understood, although several residues in viral protein PB2 are known to be important for this event. Here, we demonstrate that three residues, 147T, 339T and 588T, in PB2 play critical roles in the virulence of avian H5N1 influenza viruses in a mammalian host in vitro and in vivo and, together, result in a phenotype comparable to that conferred by the previously known PB2-627K mutation with respect to virus polymerase activity. A virus with the three residues and 627K in PB2, as has been isolated from a lethal human case, is more pathogenic than viruses with only the three residues or 627K in PB2. Importantly, H5N1 viruses bearing the former three PB2 residues have circulated widely in recent years in avian species in nature.
authors.affiliation: Influenza Research Institute, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA.
authors.forename: Shufang
authors.initials: S
authors.lastname: Fan
authors.affiliation: Influenza Research Institute, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA.
authors.forename: Masato
authors.initials: M
authors.lastname: Hatta
authors.affiliation: Influenza Research Institute, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA.
authors.forename: Jin Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Influenza Research Institute, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Halfmann
authors.affiliation: Influenza Research Institute, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA.
authors.forename: Masaki
authors.initials: M
authors.lastname: Imai
authors.affiliation: Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico NM 87545, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Macken
authors.affiliation: Department of Virology, National Institute of Hygiene and Epidemiology, 1 Yersin Street, Hai Ba Trung, Hanoi 10000, Vietnam.
authors.forename: Mai Quynh
authors.initials: MQ
authors.lastname: Le
authors.affiliation: Department of Animal Health, National Centre for Veterinary Diagnostics, 78/11 Giai Phong Rd, Hanoi 10000, Vietnam.
authors.forename: Tung
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Influenza Research Institute, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Neumann
authors.affiliation: 1] Influenza Research Institute, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA [2] Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan [3] International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan [4] Infection-Induced Host Responses Project, Exploratory Research for Advanced Technology, Saitama 332-0012, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016000:Cluster Analysis; D019295:Computational Biology; D017931:DNA Primers / Q000235:genetics; D004285:Dogs; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics* / Q000472:pathogenicity*; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010641:Phenotype; D010802:Phylogeny; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics*; D059386:Reverse Genetics / Q000379:methods; D016415:Sequence Alignment; D014764:Viral Proteins / Q000235:genetics*; D014774:Virulence
chemical_list: D017931:DNA Primers; C057027:PB2 protein, Influenzavirus A; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase