Oseltamivir-resistant variants of the 2009 pandemic H1N1 influenza A virus are not attenuated in the guinea pig and ferret transmission models.
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.
Seibert
Christopher W
CW
Department of Microbiology, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029-6574, USA.
Kaminski
Michael
M
Philipp
Jennifer
J
Rubbenstroth
Dennis
D
Albrecht
Randy A
RA
Schwalm
Folker
F
Stertz
Silke
S
Medina
Rafael A
RA
Kochs
Georg
G
García-Sastre
Adolfo
A
Staeheli
Peter
P
Palese
Peter
P
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
D053139:Oseltamivir; D053243:Zanamivir