tetano
Editor, Senior Moderator
J Virol. 2010 Aug 25. [Epub ahead of print]
Oseltamivir-resistant variants of the 2009 pandemic H1N1 influenza A virus are not attenuated in the guinea pig and ferret transmission models.
Seibert CW, Kaminski M, Philipp J, Rubbenstroth D, Albrecht RA, Schwalm F, Stertz S, Medina RA, Kochs G, Garc?a-Sastre A, Staeheli P, Palese P.
Dept. of Microbiology, Institute of Global Health and Emerging Pathogens, Dept. of Medicine, Mount Sinai School of Medicine, New York, New York, USA; Dept. of Virology, University of Freiburg, Freiburg, Germany; Dept. of Virology, University of Marburg, Marburg, Germany.
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 defence 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 the viral neuraminidase 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 the 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 were not impaired detectably and both wild-type and mutant viruses were transmitted equally well from animals that were initially inoculated with 1:1 virus mixtures to na?ve 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.
PMID: 20739532 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/20739532
Oseltamivir-resistant variants of the 2009 pandemic H1N1 influenza A virus are not attenuated in the guinea pig and ferret transmission models.
Seibert CW, Kaminski M, Philipp J, Rubbenstroth D, Albrecht RA, Schwalm F, Stertz S, Medina RA, Kochs G, Garc?a-Sastre A, Staeheli P, Palese P.
Dept. of Microbiology, Institute of Global Health and Emerging Pathogens, Dept. of Medicine, Mount Sinai School of Medicine, New York, New York, USA; Dept. of Virology, University of Freiburg, Freiburg, Germany; Dept. of Virology, University of Marburg, Marburg, Germany.
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 defence 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 the viral neuraminidase 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 the 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 were not impaired detectably and both wild-type and mutant viruses were transmitted equally well from animals that were initially inoculated with 1:1 virus mixtures to na?ve 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.
PMID: 20739532 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/20739532