title: Characterization of oseltamivir-resistant 2009 H1N1 pandemic influenza A viruses.
abstract: Influenza viruses resistant to antiviral drugs emerge frequently. Not surprisingly, the widespread treatment in many countries of patients infected with 2009 pandemic influenza A (H1N1) viruses with the neuraminidase (NA) inhibitors oseltamivir and zanamivir has led to the emergence of pandemic strains resistant to these drugs. Sporadic cases of pandemic influenza have been associated with mutant viruses possessing a histidine-to-tyrosine substitution at position 274 (H274Y) in the NA, a mutation known to be responsible for oseltamivir resistance. Here, we characterized in vitro and in vivo properties of two pairs of oseltaimivir-sensitive and -resistant (possessing the NA H274Y substitution) 2009 H1N1 pandemic viruses isolated in different parts of the world. An in vitro NA inhibition assay confirmed that the NA H274Y substitution confers oseltamivir resistance to 2009 H1N1 pandemic viruses. In mouse lungs, we found no significant difference in replication between oseltamivir-sensitive and -resistant viruses. In the lungs of mice treated with oseltamivir or even zanamivir, 2009 H1N1 pandemic viruses with the NA H274Y substitution replicated efficiently. Pathological analysis revealed that the pathogenicities of the oseltamivir-resistant viruses were comparable to those of their oseltamivir-sensitive counterparts in ferrets. Further, the oseltamivir-resistant viruses transmitted between ferrets as efficiently as their oseltamivir-sensitive counterparts. Collectively, these data indicate that oseltamivir-resistant 2009 H1N1 pandemic viruses with the NA H274Y substitution were comparable to their oseltamivir-sensitive counterparts in their pathogenicity and transmissibility in animal models. Our findings highlight the possibility that NA H274Y-possessing oseltamivir-resistant 2009 H1N1 pandemic viruses could supersede oseltamivir-sensitive viruses, as occurred with seasonal H1N1 viruses.
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Kiso
authors.forename: Kyoko
authors.initials: K
authors.lastname: Shinya
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shimojima
authors.forename: Ryo
authors.initials: R
authors.lastname: Takano
authors.forename: Kei
authors.initials: K
authors.lastname: Takahashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Katsura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kakugawa
authors.forename: Mai Thi Quynh
authors.initials: MT
authors.lastname: Le
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamashita
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Furuta
authors.forename: Makoto
authors.initials: M
authors.lastname: Ozawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D005289:Ferrets; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics* / Q000472:pathogenicity*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009439:Neuraminidase / Q000235:genetics; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000635:transmission; D053139:Oseltamivir / Q000494:pharmacology*; D058873:Pandemics; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D053139:Oseltamivir; D009439:Neuraminidase