Characterization of 2 influenza A(H3N2) clinical isolates with reduced susceptibility to neuraminidase inhibitors due to mutations in the hemagglutinin gene

J Infect Dis. 2002 Oct 15;186(8):1074-80. doi: 10.1086/344237. Epub 2002 Sep 30.


Previous studies have shown that amino acid changes in the hemagglutinin (HA) gene of influenza viruses may result in decreased susceptibility to neuraminidase inhibitors (NAIs) in vitro. However, the emergence and characteristics of such HA variants in the clinical setting remain poorly studied. Herein, we report 2 influenza A(H3N2) isolates, from untreated patients, harboring an Arg229-->Ile substitution in the HA1 gene. The Ile229 variants were as sensitive as the Arg229 viruses to zanamivir and oseltamivir in neuroaminidase inhibition assays but were significantly less susceptible (by 60-140-fold) in cell-based assays. Although the Ile229 variants adsorbed less efficiently to Madin-Darby canine kidney (MDCK) cells in kinetic binding assays, they remained very sensitive to zanamivir in ferrets. Our study shows the importance of the HA1 229 residue in virus binding to MDCK cells and confirms the unreliability of cell-based assays in predicting the in vivo susceptibility of HA variants to NAIs.

MeSH terms

  • Amino Acid Substitution / genetics
  • Animals
  • Antiviral Agents / pharmacology*
  • Cells, Cultured
  • Dogs
  • Drug Resistance, Viral / genetics*
  • Ferrets
  • Genetic Variation / genetics
  • Hemagglutinin Glycoproteins, Influenza Virus / genetics*
  • Hemagglutinin Glycoproteins, Influenza Virus / metabolism
  • Humans
  • Influenza A Virus, H3N2 Subtype*
  • Influenza A virus / drug effects*
  • Influenza A virus / enzymology
  • Influenza A virus / genetics*
  • Influenza, Human / drug therapy
  • Influenza, Human / virology
  • Kidney / cytology
  • Microbial Sensitivity Tests
  • Mutation / genetics*
  • Neuraminidase / antagonists & inhibitors*
  • Viral Plaque Assay


  • Antiviral Agents
  • Hemagglutinin Glycoproteins, Influenza Virus
  • Neuraminidase