Mutated influenza A virus exhibiting reduced susceptibility to baloxavir marboxil from an experimentally infected horse

J Gen Virol. 2019 Nov;100(11):1471-1477. doi: 10.1099/jgv.0.001325.

Abstract

Baloxavir marboxil (BXM), an inhibitor of the cap-dependent endonuclease of the influenza virus polymerase acidic protein (PA), exerts an antiviral effect against influenza A virus. It has been available in Japan since March 2018. This study evaluated the antiviral efficacy of BXM against equine influenza A virus (EIV) by an experimental challenge study using horses. Six horses were experimentally inoculated with EIV, and BXM was administered to the three horses at 2 days post inoculation. Horses treated with BXM showed milder clinical signs than horses without treatment and shed less virus. These results suggest that BXM is effective against EIV. The PA gene of viruses present in the nasopharyngeal swabs collected from horses treated with BXM was sequenced. Two mutations have been detected in viruses recovered from horses treated with BXM. These mutations were the substitution of isoleucine with threonine at position 38 (PA-I38T) and that of asparagine with aspartic acid at position 675 in PA (PA-N675D). A mutated virus with PA-I38T was less susceptible to BXM than viruses with PA-N675D or without mutation. A PA-I38T mutation has also been detected in viruses recovered from humans treated with BXM and is responsible for the reduction in susceptibility to BXM. This suggests that we should not unthinkingly use BXM for the treatment of EI. BXM is likely to easily induce resistance in influenza A viruses, not only in humans but also in horses.

Keywords: PA-I38T; baloxavir marboxil; equine influenza virus; influenza A virus; mutation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use*
  • Dibenzothiepins
  • Drug Resistance, Viral*
  • Horse Diseases / drug therapy
  • Horse Diseases / pathology
  • Horse Diseases / virology*
  • Horses
  • Influenza A Virus, H3N8 Subtype / drug effects*
  • Influenza A Virus, H3N8 Subtype / isolation & purification
  • Japan
  • Morpholines
  • Mutation, Missense
  • Nasopharynx / virology
  • Orthomyxoviridae Infections / drug therapy
  • Orthomyxoviridae Infections / pathology
  • Orthomyxoviridae Infections / veterinary*
  • Orthomyxoviridae Infections / virology
  • Oxazines / pharmacology
  • Oxazines / therapeutic use*
  • Pyridines / pharmacology
  • Pyridines / therapeutic use*
  • Pyridones
  • RNA-Dependent RNA Polymerase / genetics
  • Sequence Analysis, DNA
  • Thiepins / pharmacology
  • Thiepins / therapeutic use*
  • Treatment Outcome
  • Triazines / pharmacology
  • Triazines / therapeutic use*
  • Viral Proteins / genetics

Substances

  • Antiviral Agents
  • Dibenzothiepins
  • Morpholines
  • Oxazines
  • PA protein, influenza viruses
  • Pyridines
  • Pyridones
  • Thiepins
  • Triazines
  • Viral Proteins
  • baloxavir
  • RNA-Dependent RNA Polymerase