title: Three amino acid changes in PB1-F2 of highly pathogenic H5N1 avian influenza virus affect pathogenicity in mallard ducks.
abstract: Despite reports that the PB1-F2 protein contributes to influenza virus pathogenicity in the mouse model, little is known about its significance in avian hosts. In our previous study, the A/Vietnam/1203/04 (H5N1) wild-type virus (wtVN1203) was more lethal to mallard ducks than a reverse genetics (rg)-derived VN1203. In search of potential viral factors responsible for this discrepancy, we found that synonymous mutations (SMs) had been inadvertently introduced into three genes of the rgVN1203 (rgVN1203/SM-3). Of 11 SMs in the PB1 gene, three resided in the PB1-F2 open reading frame, caused amino acid (aa) substitutions in the PB1-F2 protein, and reduced virus lethality in mallard ducks. The wtVN1203 and recombinant viruses with repairs to these three aa's (rgVN1203/R-PB1-F2) or with repairs to all 11 SMs (rgVN1203/R-PB1) were significantly more pathogenic than rgVN1203/SM-3. In cultured cells, repairing three mutations in PB1-F2 increased viral polymerase activity and expression levels of viral RNA.
authors.affiliation: Division of Virology, Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, 262 Danny Thomas Place, Memphis, TN 38105-3678, USA.
authors.forename: Henju
authors.initials: H
authors.lastname: Marjuki
authors.forename: Christoph
authors.initials: C
authors.lastname: Scholtissek
authors.forename: John
authors.initials: J
authors.lastname: Franks
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Negovetich
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Aldridge
authors.forename: Rachelle
authors.initials: R
authors.lastname: Salomon
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.forename: Robert G
authors.initials: RG
authors.lastname: Webster
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D002645:Chickens; D004372:Ducks / Q000821:virology*; D005347:Fibroblasts / Q000821:virology; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics / Q000472:pathogenicity*; D005585:Influenza in Birds / Q000503:physiopathology* / Q000821:virology; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics*; D014774:Virulence
chemical_list: C442816:PB1-F2 protein, Influenza A virus; D014764:Viral Proteins
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