title: Influenza viruses with B/Yamagata- and B/Victoria-like neuraminidases are differentially affected by mutations that alter antiviral susceptibility.
abstract: OBJECTIVE
  The burden of disease due to influenza B is often underestimated. Clinical studies have shown that oseltamivir, a widely used neuraminidase inhibitor (NAI) antiviral drug, may have reduced effectiveness against influenza B viruses. Therefore, it is important to study the effect of neuraminidase mutations in influenza B viruses that may further reduce NAI susceptibility, and to determine whether these mutations have the same effect in the two lineages of influenza B viruses that are currently circulating (B/Yamagata-like and B/Victoria-like).
  
  
  METHODS
  We characterized the effect of 16 amino acid substitutions across five framework residues and four monomeric interface residues on the susceptibility to four different NAIs (oseltamivir, zanamivir, peramivir and laninamivir).
  
  
  RESULTS
  Framework residue mutations E117A and E117G conferred highly reduced inhibition to three of the four NAIs, but substantially reduced neuraminidase activity, whereas other framework mutations retained a greater level of NA activity. Mutations E105K, P139S and G140R of the monomeric interface were also found to cause highly reduced inhibition, but, interestingly, their effect was substantially greater in a B/Victoria-like neuraminidase than in a B/Yamagata-like neuraminidase, with some susceptibility values being up to 1000-fold different between lineages.
  
  
  CONCLUSIONS
  The frequency and the effect of key neuraminidase mutations on neuraminidase activity and NAI susceptibility can differ substantially between the two influenza B lineages. Therefore, future surveillance, analysis and interpretation of influenza B virus NAI susceptibility should consider the B lineage of the neuraminidase in the same manner as already occurs for different influenza A neuraminidase subtypes.
authors: WHO Collaborating Centre for Reference and Research on Influenza, Melbourne, VIC, Australia Monash University, School of Applied Sciences and Engineering, Churchill, VIC, Australia.
authors: Rubaiyea
authors: R
authors: Farrukee
authors: WHO Collaborating Centre for Reference and Research on Influenza, Melbourne, VIC, Australia.
authors: Sook-Kwan
authors: SK
authors: Leang
authors: WHO Collaborating Centre for Reference and Research on Influenza, Melbourne, VIC, Australia.
authors: Jeff
authors: J
authors: Butler
authors: Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore.
authors: Raphael T C
authors: RT
authors: Lee
authors: Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore National Public Health Laboratory, Communicable Diseases Division Ministry of Health, Singapore School of Biological Sciences, Nanyang Technological University, Singapore.
authors: Sebastian
authors: S
authors: Maurer-Stroh
authors: WHO Collaborating Centre for Reference and Research on Influenza, Melbourne, VIC, Australia.
authors: Danielle
authors: D
authors: Tilmanis
authors: WHO Collaborating Centre for Reference and Research on Influenza, Melbourne, VIC, Australia.
authors: Sheena
authors: S
authors: Sullivan
authors: Monash University, School of Applied Sciences and Engineering, Churchill, VIC, Australia.
authors: Jennifer
authors: J
authors: Mosse
authors: WHO Collaborating Centre for Reference and Research on Influenza, Melbourne, VIC, Australia.
authors: Ian G
authors: IG
authors: Barr
authors: WHO Collaborating Centre for Reference and Research on Influenza, Melbourne, VIC, Australia Melbourne School of Population and Global Health, University of Melbourne, VIC, Australia aeron.hurt@influenzacentre.org.
authors: Aeron C
authors: AC
authors: Hurt
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000494:pharmacology; D009981:Influenza B virus / Q000187:drug effects* / Q000201:enzymology*; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics; D020125:Mutation, Missense; D009439:Neuraminidase / Q000737:chemistry / Q000235:genetics*; D011487:Protein Conformation
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D050505:Mutant Proteins; D009439:Neuraminidase
keywords: influenza B lineage; neuraminidase inhibitors; oseltamivir; resistance