title: Identification of mammalian-adapting mutations in the polymerase complex of an avian H5N1 influenza virus.
abstract: Avian influenza viruses of the H5N1 subtype pose a serious global health threat due to the high mortality (>60%) associated with the disease caused by these viruses and the lack of protective antibodies to these viruses in the general population. The factors that enable avian H5N1 influenza viruses to replicate in humans are not completely understood. Here we use a high-throughput screening approach to identify novel mutations in the polymerase genes of an avian H5N1 virus that confer efficient polymerase activity in mammalian cells. Several of the identified mutations (which have previously been found in natural isolates) increase viral replication in mammalian cells and virulence in infected mice compared with the wild-type virus. The identification of amino-acid mutations in avian H5N1 influenza virus polymerase complexes that confer increased replication and virulence in mammals is important for the identification of circulating H5N1 viruses with an increased potential to infect humans.
authors.affiliation: Influenza Research Institute, School of Veterinary Medicine, Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Taft
authors.affiliation: 1] Laboratory of Animal Hygiene, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan [2] Transboundary Animal Diseases Center, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ozawa
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Fitch
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Jay V
authors.initials: JV
authors.lastname: Depasse
authors.affiliation: Influenza Research Institute, School of Veterinary Medicine, Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Halfmann
authors.affiliation: Influenza Research Institute, School of Veterinary Medicine, Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Hill-Batorski
authors.affiliation: Influenza Research Institute, School of Veterinary Medicine, Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA.
authors.forename: Masato
authors.initials: M
authors.lastname: Hatta
authors.affiliation: 1] Wisconsin National Primate Research Center, Madison Wisconsin 53715, USA [2] Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison WI 53711, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Friedrich
authors.affiliation: 1] Influenza Research Institute, School of Veterinary Medicine, Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA [2] Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Tiago J S
authors.initials: TJ
authors.lastname: Lopes
authors.affiliation: Influenza Research Institute, School of Veterinary Medicine, Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA.
authors.forename: Eileen A
authors.initials: EA
authors.lastname: Maher
authors.affiliation: 1] University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA [2] Department of Biology, New York University, New York, New York 10003, USA.
authors.forename: Elodie
authors.initials: E
authors.lastname: Ghedin
authors.affiliation: Bioinformatics Institute, University of Auckland, Auckland 1010, New Zealand.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Macken
authors.affiliation: Influenza Research Institute, School of Veterinary Medicine, Department of Pathobiological Sciences, 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, Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA [2] Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan [3] 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: D000220:Adaptation, Biological; D000818:Animals; D004285:Dogs; D005260:Female; D017930:Genes, Reporter; D059014:High-Throughput Nucleotide Sequencing; D057166:High-Throughput Screening Assays; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics* / Q000472:pathogenicity; D061985:Madin Darby Canine Kidney Cells; D008807:Mice, Inbred BALB C; D009154:Mutation; D014764:Viral Proteins / Q000235:genetics*; D014779:Virus Replication
chemical_list: D014764:Viral Proteins