title: Oseltamivir-resistant variants of the 2009 pandemic H1N1 influenza A virus are not attenuated in the guinea pig and ferret transmission models.
abstract: Oseltamivir is routinely used worldwide for the treatment of severe influenza A virus infection, and should drug-resistant pandemic 2009 H1N1 viruses become widespread, this potent defense strategy might fail. Oseltamivir-resistant variants of the pandemic 2009 H1N1 influenza A virus have been detected in a substantial number of patients, but to date, the mutant viruses have not moved into circulation in the general population. It is not known whether the resistance mutations in viral neuraminidase (NA) reduce viral fitness. We addressed this question by studying transmission of oseltamivir-resistant mutants derived from two different isolates of the pandemic H1N1 virus in both the guinea pig and ferret transmission models. In vitro, the virus readily acquired a single histidine-to-tyrosine mutation at position 275 (H275Y) in viral neuraminidase when serially passaged in cell culture with increasing concentrations of oseltamivir. This mutation conferred a high degree of resistance to oseltamivir but not zanamivir. Unexpectedly, in guinea pigs and ferrets, the fitness of viruses with the H275Y point mutation was not detectably impaired, and both wild-type and mutant viruses were transmitted equally well from animals that were initially inoculated with 1:1 virus mixtures to naïve contacts. In contrast, a reassortant virus containing an oseltamivir-resistant seasonal NA in the pandemic H1N1 background showed decreased transmission efficiency and fitness in the guinea pig model. Our data suggest that the currently circulating pandemic 2009 H1N1 virus has a high potential to acquire drug resistance without losing fitness.
authors.affiliation: Department of Microbiology, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029-6574, USA.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Seibert
authors.forename: Michael
authors.initials: M
authors.lastname: Kaminski
authors.forename: Jennifer
authors.initials: J
authors.lastname: Philipp
authors.forename: Dennis
authors.initials: D
authors.lastname: Rubbenstroth
authors.forename: Randy A
authors.initials: RA
authors.lastname: Albrecht
authors.forename: Folker
authors.initials: F
authors.lastname: Schwalm
authors.forename: Silke
authors.initials: S
authors.lastname: Stertz
authors.forename: Rafael A
authors.initials: RA
authors.lastname: Medina
authors.forename: Georg
authors.initials: G
authors.lastname: Kochs
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.forename: Peter
authors.initials: P
authors.lastname: Staeheli
authors.forename: Peter
authors.initials: P
authors.lastname: Palese
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D024882:Drug Resistance, Viral / Q000235:genetics*; D005289:Ferrets; D006168:Guinea Pigs; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics* / Q000472:pathogenicity; D007251:Influenza, Human; D020125:Mutation, Missense; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000635:transmission*; D053139:Oseltamivir / Q000494:pharmacology*; D053243:Zanamivir / Q000494:pharmacology
chemical_list: D053139:Oseltamivir; D053243:Zanamivir