title: The R292K mutation that confers resistance to neuraminidase inhibitors leads to competitive fitness loss of A/Shanghai/1/2013 (H7N9) influenza virus in ferrets.
abstract: BACKGROUND
  Neuraminidase (NA) inhibitors are the only licensed therapeutic option for human zoonotic H7N9 infections. An NA-R292K mutation that confers broad-spectrum resistance to NA inhibitors has been documented in H7N9 patients after treatment.
  
  
  METHODS
  We evaluated the transmission potential of a human influenza A H7N9 isolate with a NA-R292K mutation in the ferret model followed by genotyping assay to monitor its competitive fitness in vivo.
  
  
  RESULTS
  Plaque-purified A/Shanghai/1/2013 wild-type and NA-R292K viruses transmitted at comparable efficiency to direct or respiratory droplet contact ferrets. In ferrets inoculated with the plaque-purified A/Shanghai/1/2013 NA-R292K virus with dominant K292 (94%), the resistant K292 genotype was outgrown by the wild-type R292 genotype during the course of infection. Transmission of the resistant K292 genotype was detected in 3/4 direct contact and 3/4 respiratory droplet contact ferrets at early time points but was gradually replaced by the wild-type genotype. In the respiratory tissues of inoculated or infected ferrets, the wild-type R292 genotype dominated in the nasal turbinate, whereas the resistant K292 genotype was more frequently detected in the lungs.
  
  
  CONCLUSIONS
  The NA inhibitor-resistant H7N9 virus with the NA-R292K mutation may transmit among ferrets but showed compromised fitness in vivo while in competition with the wild-type virus.
authors.affiliation: School of Public Health.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Yen
authors.affiliation: School of Public Health.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: School of Public Health.
authors.forename: Ka-Tim
authors.initials: KT
authors.lastname: Choy
authors.affiliation: School of Public Health.
authors.forename: Sin Fun
authors.initials: SF
authors.lastname: Sia
authors.affiliation: School of Public Health.
authors.forename: Ooiean
authors.initials: O
authors.lastname: Teng
authors.affiliation: School of Public Health.
authors.forename: Iris H
authors.initials: IH
authors.lastname: Ng
authors.affiliation: School of Public Health.
authors.forename: Vicky J
authors.initials: VJ
authors.lastname: Fang
authors.affiliation: Shanghai Public Health Clinical Center, China.
authors.forename: Yunwen
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Shanghai Public Health Clinical Center, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: School of Public Health.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Cowling
authors.affiliation: Department of Pathology, LKS Faculty of Medicine, University of Hong Kong, Hong Kong SAR.
authors.forename: John M
authors.initials: JM
authors.lastname: Nicholls
authors.affiliation: School of Public Health.
authors.forename: Yi
authors.initials: Y
authors.lastname: Guan
authors.affiliation: School of Public Health.
authors.forename: Joseph Sriyal Malik
authors.initials: JS
authors.lastname: Peiris
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D024882:Drug Resistance, Viral; D005289:Ferrets; D064766:Influenza A Virus, H7N9 Subtype / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development / Q000502:physiology*; D008297:Male; D020125:Mutation, Missense; D009439:Neuraminidase / Q000235:genetics* / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000635:transmission / Q000821:virology*; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D014764:Viral Proteins; C487630:NA protein, influenza A virus; D009439:Neuraminidase
keywords: H7N9 influenza virus; R292K NA mutation; ferrets; neuraminidase inhibitors; resistance; transmission