Increased virulence of neuraminidase inhibitor-resistant pandemic H1N1 virus in mice: potential emergence of drug-resistant and virulent variants

Virulence. 2013 Aug 15;4(6):489-93. doi: 10.4161/viru.25952. Epub 2013 Aug 2.

Abstract

Pandemic H1N1 2009 (A[H1N1]pdm09) variants associated with oseltamivir resistance have emerged with a histidine-to-tyrosine substitution in the neuraminidase(NA) at position 274 (H274Y). To determine whether the H274Y variant has increased virulence potential, A(H1N1)pdm09 virus, with or without the H274Y mutation, was adapted by serial lung-to-lung passages in mice. The mouse-adapted H274Y (maCA04H274Y) variants showed increased growth properties and virulence in vitro and in vivo while maintaining high NA inhibitor resistance. Interestingly, most maCA04H274Y and maCA04 viruses acquired common mutations in HA (S183P and D222G) and NP (D101G), while only maCA04H274Y viruses had consensus additional K153E mutation in the HA gene, suggesting a potential association with the H274Y substitution. Collectively, our findings highlight the potential emergence of A(H1N1)pdm09 drug-resistant variants with increased virulence and the need for rapid development of novel antiviral drugs.

Keywords: drug resistance; mouse adaptation; neuraminidase; pandemic influenza; virulence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / therapeutic use*
  • Drug Resistance, Viral*
  • Enzyme Inhibitors / therapeutic use*
  • Humans
  • Influenza A Virus, H1N1 Subtype / drug effects
  • Influenza A Virus, H1N1 Subtype / enzymology
  • Influenza A Virus, H1N1 Subtype / genetics
  • Influenza A Virus, H1N1 Subtype / pathogenicity*
  • Influenza, Human / drug therapy
  • Influenza, Human / epidemiology
  • Influenza, Human / virology*
  • Mice
  • Mice, Inbred BALB C
  • Mutation, Missense
  • Neuraminidase / antagonists & inhibitors*
  • Neuraminidase / genetics*
  • Neuraminidase / metabolism
  • Oseltamivir / therapeutic use
  • Pandemics
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / genetics*
  • Viral Proteins / metabolism
  • Virulence / drug effects

Substances

  • Antiviral Agents
  • Enzyme Inhibitors
  • Viral Proteins
  • Oseltamivir
  • NA protein, influenza A virus
  • Neuraminidase