Comparable fitness and transmissibility between oseltamivir-resistant pandemic 2009 and seasonal H1N1 influenza viruses with the H275Y neuraminidase mutation.

Diana D y Wong (1, 2) , Ka-Tim Choy (1, 2) , Renee W y Chan (1, 2, 3) , Sin Fun Sia (1, 2) , Hsin-Ping Chiu (1, 2) , Peter P H Cheung (1, 2) , Michael C W Chan (1, 2) , J S Malik Peiris (1, 2, 4) , Hui-Ling Yen (1, 2, 4)

1 Centre of Influenza Research
2 School of Public Health
3 Department of pathology [HKU]
4 Centre de recherche Université de Hong-Kong-Pasteur

Limited antiviral compounds are available for the control of influenza and the emergence of resistant variants would further narrow the options for defense. The H275Y neuraminidase (NA) mutation that confers resistance to oseltamivir carboxylate has been identified among the seasonal H1N1 and 2009 pandemic influenza viruses; however, their H275Y resistant variants demonstrate distinct epidemiological outcome in humans. Specifically, dominance of the H275Y variant over the oseltamivir-sensitive viruses was only reported for a seasonal H1N1 variant during 2008-2009. Here, we systematically analyze the effect of the H275Y NA mutation on viral fitness and transmissibility of A(H1N1)pdm09 and seasonal H1N1 influenza viruses. The NA gene from A(H1N1)pdm09 A/California/04/09 (CA04), seasonal H1N1 A/New Caledonia/20/1999 (NewCal), and A/Brisbane/59/2007 (Brisbane) was individually introduced into the genetic background of CA04. The H275Y mutation led to reduced NA enzyme activity, increased K(M) for 3' -sialylactose or 6' -sialylactose, and decreased infectivity in mucin-secreting human airway epithelial cells when compared to the oseltamivir-sensitive wild-type counterparts. Attenuated pathogenicity in both RG-CA04(NA-H275Y) and RG-CA04×Brisbane(NA-H275Y) viruses was observed in ferrets when compared to RG-CA04 virus, although their transmissibility was minimally affected. In parallel experiments using recombinant Brisbane viruses differing by HA and NA, comparable direct-contact and respiratory-droplet transmissibility was observed among RG-NewCal(HA,NA), RG-NewCal(HA,NA-H275Y), RG-Brisbane(HA,NA-H275Y), and RG-NewCal(HA)×Brisbane(NA-H275Y) viruses. Our results demonstrate that despite the H275Y mutation led to a minor reduction in viral fitness, the transmission potential of three different antigenic strains carrying this mutation was comparable using the naïve ferret model.

Mots clés: H1N1 influenza virus; neuraminidase inhibitors; H275Y; NA substrate specificity; transmissibility in ferrets

Domaines: Virologie

Diana D y Wong, Ka-Tim Choy, Renee W y Chan, Sin Fun Sia, Hsin-Ping Chiu, et al.. Comparable fitness and transmissibility between oseltamivir-resistant pandemic 2009 and seasonal H1N1 influenza viruses with the H275Y neuraminidase mutation.. Journal of Virology, 2012, epub ahead of print. ⟨10.1128/JVI.00985-12⟩. ⟨pasteur-00721356⟩