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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.
J Infect Dis. 2015 Dec 01; 212(11):1726-34.JI

Abstract

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.

Authors+Show Affiliations

Laboratory of Virology, Divisions of Infectious Diseases and Laboratory Medicine.Centre Hospitalier Universitaire de Québec and Université Laval, Quebec City, Canada.Department of Genetic Medicine and Development, University of Geneva Medical School Swiss Institute of Bioinformatics, University of Geneva, Switzerland.Laboratory of Virology, Divisions of Infectious Diseases and Laboratory Medicine.Laboratory of Virology, Divisions of Infectious Diseases and Laboratory Medicine.Centre Hospitalier Universitaire de Québec and Université Laval, Quebec City, Canada.Laboratory of Virology, Divisions of Infectious Diseases and Laboratory Medicine.Division of Hematology, Department of Internal Medicine Specialties, University of Geneva Hospitals.Division of Hematology, Department of Internal Medicine Specialties, University of Geneva Hospitals.Division of Infectious Diseases, Department of Internal Medicine Specialties, University of Geneva Hospitals.Department of Genetic Medicine and Development, University of Geneva Medical School Swiss Institute of Bioinformatics, University of Geneva, Switzerland.Laboratory of Virology, Divisions of Infectious Diseases and Laboratory Medicine.Centre Hospitalier Universitaire de Québec and Université Laval, Quebec City, Canada.Laboratory of Virology, Divisions of Infectious Diseases and Laboratory Medicine University of Geneva Medical School, University of Geneva, Switzerland.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25985905

Citation

L'Huillier, Arnaud G., et al. "E119D Neuraminidase Mutation Conferring Pan-Resistance to Neuraminidase Inhibitors in an A(H1N1)pdm09 Isolate From a Stem-Cell Transplant Recipient." The Journal of Infectious Diseases, vol. 212, no. 11, 2015, pp. 1726-34.
L'Huillier AG, Abed Y, Petty TJ, et al. E119D Neuraminidase Mutation Conferring Pan-Resistance to Neuraminidase Inhibitors in an A(H1N1)pdm09 Isolate From a Stem-Cell Transplant Recipient. J Infect Dis. 2015;212(11):1726-34.
L'Huillier, A. G., Abed, Y., Petty, T. J., Cordey, S., Thomas, Y., Bouhy, X., Schibler, M., Simon, A., Chalandon, Y., van Delden, C., Zdobnov, E., Boquete-Suter, P., Boivin, G., & Kaiser, L. (2015). E119D Neuraminidase Mutation Conferring Pan-Resistance to Neuraminidase Inhibitors in an A(H1N1)pdm09 Isolate From a Stem-Cell Transplant Recipient. The Journal of Infectious Diseases, 212(11), 1726-34. https://doi.org/10.1093/infdis/jiv288
L'Huillier AG, et al. E119D Neuraminidase Mutation Conferring Pan-Resistance to Neuraminidase Inhibitors in an A(H1N1)pdm09 Isolate From a Stem-Cell Transplant Recipient. J Infect Dis. 2015 Dec 1;212(11):1726-34. PubMed PMID: 25985905.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - E119D Neuraminidase Mutation Conferring Pan-Resistance to Neuraminidase Inhibitors in an A(H1N1)pdm09 Isolate From a Stem-Cell Transplant Recipient. AU - L'Huillier,Arnaud G, AU - Abed,Yacine, AU - Petty,Tom J, AU - Cordey,Samuel, AU - Thomas,Yves, AU - Bouhy,Xavier, AU - Schibler,Manuel, AU - Simon,Audrey, AU - Chalandon,Yves, AU - van Delden,Christian, AU - Zdobnov,Evgeny, AU - Boquete-Suter,Patricia, AU - Boivin,Guy, AU - Kaiser,Laurent, Y1 - 2015/05/17/ PY - 2015/03/12/received PY - 2015/05/08/accepted PY - 2015/5/20/entrez PY - 2015/5/20/pubmed PY - 2016/2/18/medline KW - H1N1 influenza KW - immunosuppression KW - oseltamivir KW - resistance KW - zanamivir SP - 1726 EP - 34 JF - The Journal of infectious diseases JO - J Infect Dis VL - 212 IS - 11 N2 - 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. SN - 1537-6613 UR - https://www.unboundmedicine.com/medline/citation/25985905/E119D_Neuraminidase_Mutation_Conferring_Pan_Resistance_to_Neuraminidase_Inhibitors_in_an_A_H1N1_pdm09_Isolate_From_a_Stem_Cell_Transplant_Recipient_ L2 - https://academic.oup.com/jid/article-lookup/doi/10.1093/infdis/jiv288 DB - PRIME DP - Unbound Medicine ER -