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JAC Advance Access originally published online on August 5, 2006
Journal of Antimicrobial Chemotherapy 2006 58(4):723-732; doi:10.1093/jac/dkl321
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
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Mutations conferring zanamivir resistance in human influenza virus N2 neuraminidases compromise virus fitness and are not stably maintained in vitro

Thomas Zürcher1, Phillip J. Yates1, Janet Daly1,{dagger}, Anjali Sahasrabudhe2, Matthew Walters1,{ddagger}, Laura Dash1, Margaret Tisdale1 and Jennifer L. McKimm-Breschkin2,*

1 Medicine Research Centre, GlaxoSmithKline Stevenage, SG1 2NY, UK 2 Biomolecular Research Institute Parkville 3052, Australia

Received 11 May 2006; returned 16 June 2006; revised 11 July 2006; accepted 12 July 2006

*Correspondence address. CSIRO Molecular and Health Technologies, 343 Royal Parade, Parkville 3052, Australia. Tel: +61-3-9662-7257; Fax: +61-3-9662-7101; E-mail: jennifer.mckimm-breschkin{at}csiro.au

Background: Viruses resistant to zanamivir have been generated in vitro, but no resistant virus has yet been isolated from a zanamivir-treated immunocompetent patient. In contrast most resistant viruses isolated from oseltamivir-treated patients correspond to those selected in vitro. However, despite mutations being in conserved residues in the neuraminidase (NA) they do not confer resistance in all NA subtypes.

Objectives and methods: We have used reverse genetics and the recombinant baculovirus expression system for investigating reasons for the lack of isolation of zanamivir-resistant H3N2 viruses and for further exploring subtype-specific oseltamivir resistance.

Results: H3N2 viruses generated by reverse genetics with H274Y, R292K E119V and E119D mutations were rescued. Those with E119G, E119A or R152K mutations could only be rescued in the presence of exogenous NA and after passage in the absence of exogenous NA only isolates that had reverted to the wild-type NA or, surprisingly, E119G/A to E119V NA were isolated. Mutations conferring zanamivir resistance significantly affected enzyme activity, virus replication or NA thermal stability. E119V viruses were stable and grew to similar titres as wild-type virus, consistent with their isolation from oseltamivir-treated patients. Mutations conferring oseltamivir resistance in N1 (H274Y) and B (R152K) NAs also conferred resistance in recombinant G70C N9 NA expressed in insect cells.

Conclusions: These data suggest that zanamivir-resistant H3N2 viruses may not readily arise in vivo due to their poor viability. The G70C N9 NA may also provide a useful model for understanding the structural basis of subtype-specific drug resistance.

Keywords: drug resistance , oseltamivir , reverse genetics , baculovirus


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