title: Influenza A(H7N9) virus gains neuraminidase inhibitor resistance without loss of in vivo virulence or transmissibility.
abstract: Without baseline human immunity to the emergent avian influenza A(H7N9) virus, neuraminidase inhibitors are vital for controlling viral replication in severe infections. An amino acid change in the viral neuraminidase associated with drug resistance, NA-R292K (N2 numbering), has been found in some H7N9 clinical isolates. Here we assess the impact of the NA-R292K substitution on antiviral sensitivity and viral replication, pathogenicity and transmissibility of H7N9 viruses. Our data indicate that an H7N9 isolate encoding the NA-R292K substitution is highly resistant to oseltamivir and peramivir and partially resistant to zanamivir. Furthermore, H7N9 reassortants with and without the resistance mutation demonstrate comparable viral replication in primary human respiratory cells, virulence in mice and transmissibility in guinea pigs. Thus, in stark contrast to oseltamivir-resistant seasonal influenza A(H3N2) viruses, H7N9 virus replication and pathogenicity in these models are not substantially altered by the acquisition of high-level oseltamivir resistance due to the NA-R292K mutation.
authors: 1] Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1124, New York, New York 10029, USA [2].
authors: Rong
authors: R
authors: Hai
authors: Mirco
authors: M
authors: Schmolke
authors: Victor H
authors: VH
authors: Leyva-Grado
authors: Rajagowthamee R
authors: RR
authors: Thangavel
authors: Irina
authors: I
authors: Margine
authors: Eric L
authors: EL
authors: Jaffe
authors: Florian
authors: F
authors: Krammer
authors: Alicia
authors: A
authors: Solórzano
authors: Adolfo
authors: A
authors: García-Sastre
authors: Peter
authors: P
authors: Palese
authors: Nicole M
authors: NM
authors: Bouvier
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D064766:Influenza A Virus, H7N9 Subtype / Q000187:drug effects / Q000201:enzymology* / Q000472:pathogenicity* / Q000502:physiology; D007251:Influenza, Human / Q000635:transmission / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053139:Oseltamivir / Q000494:pharmacology; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014774:Virulence / Q000187:drug effects; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D014764:Viral Proteins; D053139:Oseltamivir; D009439:Neuraminidase