tetano
Editor, Senior Moderator
J Virol. 2015 Feb 11. pii: JVI.02473-14. [Epub ahead of print]
[h=1]Competitive Fitness of Influenza B Viruses with Neuraminidase Inhibitor-Resistant Substitutions in a Co-infection Model of the Human Airway Epithelium.[/h] Burnham AJ[SUP]1[/SUP], Armstrong J[SUP]1[/SUP], Lowen AC[SUP]2[/SUP], Webster RG[SUP]1[/SUP], Govorkova EA[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Influenza A and B viruses are regarded almost equally as human pathogens with significant disease burden. Neuraminidase (NA) inhibitors (NAIs) are the only class of drugs available to treat influenza A and B virus infections, so development of NAI-resistant viruses with superior fitness is a public health concern. Fitness of NAI-resistant influenza B viruses is not widely studied. Here we examined the replicative capacity and relative fitness in normal human bronchial epithelial (NHBE) cells of recombinant (rg) influenza B/Yamanashi/166/1998 viruses containing a single amino acid substitution in NA that is associated with NAI-resistance. Replication in NHBE cells of viruses with reduced inhibition by oseltamivir (rg-E119A, rg-D198E, rg-I222T, rg-H274Y, rg-N294S, and rg-R371K, N2 numbering) or zanamivir (rg-E119A and rg-R371K) failed to be inhibited by the presence of the respective NAI. In a fluorescence-based assay, detection of rg-E119A was easily masked by the presence of NAI-susceptible virus. We co-infected NHBE cells with NAI-susceptible and -resistant viruses and used next-generation deep-sequencing to reveal the order of relative fitness -compared to that of wild-type (WT) virus: rg-H274Y > rg-WT > rg-I222T > rg-N294S > rg-D198E > rg-E119A >> rg-R371K. Based on the lack of attenuated replication of rg-E119A in NHBE cells in the presence of oseltamivir or zanamivir, and the fitness advantage of rg-H274Y over rg-WT, we emphasize the importance of these substitutions in the NA glycoprotein. Human infections with influenza B viruses carrying E119A or H274Y substitutions could limit therapeutic options for those infected; emergence of such viruses should be closely monitored.
[h=4]IMPORTANCE:[/h] Influenza B viruses are important human respiratory pathogens contributing to a significant portion of seasonal influenza infections worldwide. The development of resistance to a single class of available antivirals, the neuraminidase (NA) inhibitors (NAIs), is a public health concern. Amino acid substitutions in the NA glycoprotein of influenza B virus can not only confer antiviral resistance but also alter viral fitness. Here we use normal human bronchial epithelial (NHBE) cells, a model of the human upper respiratory tract, to examine replicative capacities and fitness of NAI-resistant influenza B viruses. We show that virus with an E119A NA substitution can replicate efficiently in NHBE cells in the presence of oseltamivir or zanamivir and that virus with the H274Y NA substitution has a relative fitness greater than that of the wild-type NAI-susceptible virus. This study is the first to use NHBE cells to determine the fitness of NAI-resistant influenza B viruses.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 25673705 [PubMed - as supplied by publisher]
[h=1]Competitive Fitness of Influenza B Viruses with Neuraminidase Inhibitor-Resistant Substitutions in a Co-infection Model of the Human Airway Epithelium.[/h] Burnham AJ[SUP]1[/SUP], Armstrong J[SUP]1[/SUP], Lowen AC[SUP]2[/SUP], Webster RG[SUP]1[/SUP], Govorkova EA[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Influenza A and B viruses are regarded almost equally as human pathogens with significant disease burden. Neuraminidase (NA) inhibitors (NAIs) are the only class of drugs available to treat influenza A and B virus infections, so development of NAI-resistant viruses with superior fitness is a public health concern. Fitness of NAI-resistant influenza B viruses is not widely studied. Here we examined the replicative capacity and relative fitness in normal human bronchial epithelial (NHBE) cells of recombinant (rg) influenza B/Yamanashi/166/1998 viruses containing a single amino acid substitution in NA that is associated with NAI-resistance. Replication in NHBE cells of viruses with reduced inhibition by oseltamivir (rg-E119A, rg-D198E, rg-I222T, rg-H274Y, rg-N294S, and rg-R371K, N2 numbering) or zanamivir (rg-E119A and rg-R371K) failed to be inhibited by the presence of the respective NAI. In a fluorescence-based assay, detection of rg-E119A was easily masked by the presence of NAI-susceptible virus. We co-infected NHBE cells with NAI-susceptible and -resistant viruses and used next-generation deep-sequencing to reveal the order of relative fitness -compared to that of wild-type (WT) virus: rg-H274Y > rg-WT > rg-I222T > rg-N294S > rg-D198E > rg-E119A >> rg-R371K. Based on the lack of attenuated replication of rg-E119A in NHBE cells in the presence of oseltamivir or zanamivir, and the fitness advantage of rg-H274Y over rg-WT, we emphasize the importance of these substitutions in the NA glycoprotein. Human infections with influenza B viruses carrying E119A or H274Y substitutions could limit therapeutic options for those infected; emergence of such viruses should be closely monitored.
[h=4]IMPORTANCE:[/h] Influenza B viruses are important human respiratory pathogens contributing to a significant portion of seasonal influenza infections worldwide. The development of resistance to a single class of available antivirals, the neuraminidase (NA) inhibitors (NAIs), is a public health concern. Amino acid substitutions in the NA glycoprotein of influenza B virus can not only confer antiviral resistance but also alter viral fitness. Here we use normal human bronchial epithelial (NHBE) cells, a model of the human upper respiratory tract, to examine replicative capacities and fitness of NAI-resistant influenza B viruses. We show that virus with an E119A NA substitution can replicate efficiently in NHBE cells in the presence of oseltamivir or zanamivir and that virus with the H274Y NA substitution has a relative fitness greater than that of the wild-type NAI-susceptible virus. This study is the first to use NHBE cells to determine the fitness of NAI-resistant influenza B viruses.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 25673705 [PubMed - as supplied by publisher]