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E119D Neuraminidase Mutation Conferring Pan-Resistance to Neuraminidase Inhibitors in an A(H1N1)pdm09 Isolate From a Stem-Cell Transplant Recipient

L'Huillier, Arnaud G. ; Abed, Yacine ; Petty, Tom J. ; Cordey, Samuel ; Thomas, Yves ; Bouhy, Xavier ; Schibler, Manuel ; Simon, Audrey ; Chalandon, Yves ; van Delden, Christian ; Zdobnov, Evgeny ; Boquete-Suter, Patricia ; Boivin, Guy ; Kaiser, Laurent

In: The Journal of Infectious Diseases, 2015, vol. 212, no. 11, p. 1726-1734

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    Titre
    • E119D Neuraminidase Mutation Conferring Pan-Resistance to Neuraminidase Inhibitors in an A(H1N1)pdm09 Isolate From a Stem-Cell Transplant Recipient
    Auteur
    • L'Huillier, Arnaud G.. Laboratory of Virology, Divisions of Infectious Diseases and Laboratory Medicine
    • Abed, Yacine. Centre Hospitalier Universitaire de Québec and Université Laval, Quebec City, Canada
    • Petty, Tom J.. Department of Genetic Medicine and Development, University of Geneva Medical School
    • Cordey, Samuel. Laboratory of Virology, Divisions of Infectious Diseases and Laboratory Medicine
    • Thomas, Yves. Laboratory of Virology, Divisions of Infectious Diseases and Laboratory Medicine
    • Bouhy, Xavier. Centre Hospitalier Universitaire de Québec and Université Laval, Quebec City, Canada
    • Schibler, Manuel. Laboratory of Virology, Divisions of Infectious Diseases and Laboratory Medicine
    • Simon, Audrey. Division of Hematology, Department of Internal Medicine Specialties, University of Geneva Hospitals
    • Chalandon, Yves. Division of Hematology, Department of Internal Medicine Specialties, University of Geneva Hospitals
    • van Delden, Christian. Division of Infectious Diseases, Department of Internal Medicine Specialties, University of Geneva Hospitals
    • Zdobnov, Evgeny. Department of Genetic Medicine and Development, University of Geneva Medical School
    • Boquete-Suter, Patricia. Laboratory of Virology, Divisions of Infectious Diseases and Laboratory Medicine
    • Boivin, Guy. Centre Hospitalier Universitaire de Québec and Université Laval, Quebec City, Canada
    • Kaiser, Laurent. Laboratory of Virology, Divisions of Infectious Diseases and Laboratory Medicine
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • The Journal of Infectious Diseases, 2015, vol. 212, no. 11, p. 1726-1734. Oxford University Press
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:303995
    Summary
    Background. An influenza A(H1N1)pdm09 infection was diagnosed in a hematopoietic stem cell transplant recipient during conditioning regimen. He was treated with oral oseltamivir, later combined with intravenous zanamivir. The H275Y neuraminidase (NA) mutation was first detected, and an E119D NA mutation was identified during zanamivir therapy. Methods. Recombinant wild-type (WT) E119D and E119D/H275Y A(H1N1)pdm09 NA variants were generated by reverse genetics. Susceptibility to NA inhibitors (NAIs) was evaluated with a fluorometric assay using the 2′-(4-methylumbelliferyl)-α-d-N-acetylneuraminic acid (MUNANA) substrate. Susceptibility to favipiravir (T-705) was assessed using plaque reduction assays. The NA affinity and velocity values were determined with NA enzymatic studies. Results. We identified an influenza A(H1N1)pdm09 E119D mutant that exhibited a marked increase in the 50% inhibitory concentrations against all tested NAIs (827-, 25-, 286-, and 702-fold for zanamivir, oseltamivir, peramivir, and laninamivir, respectively). The double E119D/H275Y mutation further increased oseltamivir and peramivir 50% inhibitory concentrations by 790- and >5000-fold, respectively, compared with the WT. The mutant viruses remained susceptible to favipiravir. The NA affinity and velocity values of the E119D variant decreased by 8.1-fold and 4.5-fold, respectively, compared with the WT. Conclusions. The actual emergence of a single NA mutation conferring pan-NAI resistance in the clinical setting reinforces the pressing need to develop new anti-influenza strategies