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Drug Susceptibility Evaluation of an Influenza A(H7N9) Virus by Analyzing Recombinant Neuraminidase Proteins.
J Infect Dis. 2017 09 15; 216(suppl_4):S566-S574.JI

Abstract

Background

Neuraminidase (NA) inhibitors are the recommended antiviral medications for influenza treatment. However, their therapeutic efficacy can be compromised by NA changes that emerge naturally and/or following antiviral treatment. Knowledge of which molecular changes confer drug resistance of influenza A(H7N9) viruses (group 2NA) remains sparse.

Methods

Fourteen amino acid substitutions were introduced into the NA of A/Shanghai/2/2013(H7N9). Recombinant N9 (recN9) proteins were expressed in a baculovirus system in insect cells and tested using the Centers for Disease Control and Prevention standardized NA inhibition (NI) assay with oseltamivir, zanamivir, peramivir, and laninamivir. The wild-type N9 crystal structure was determined in complex with oseltamivir, zanamivir, or sialic acid, and structural analysis was performed.

Results

All substitutions conferred either reduced or highly reduced inhibition by at least 1 NA inhibitor; half of them caused reduced inhibition or highly reduced inhibition by all NA inhibitors. R292K conferred the highest increase in oseltamivir half-maximal inhibitory concentration (IC50), and E119D conferred the highest zanamivir IC50. Unlike N2 (another group 2NA), H274Y conferred highly reduced inhibition by oseltamivir. Additionally, R152K, a naturally occurring variation at the NA catalytic residue of A(H7N9) viruses, conferred reduced inhibition by laninamivir.

Conclusions

The recNA method is a valuable tool for assessing the effect of NA changes on drug susceptibility of emerging influenza viruses.

Authors+Show Affiliations

Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention.Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention.Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention.Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention.Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention. Carter Consulting, Atlanta, Georgia.Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention.Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention. Carter Consulting, Atlanta, Georgia.Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention.

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

28934455

Citation

Gubareva, Larisa V., et al. "Drug Susceptibility Evaluation of an Influenza A(H7N9) Virus By Analyzing Recombinant Neuraminidase Proteins." The Journal of Infectious Diseases, vol. 216, no. suppl_4, 2017, pp. S566-S574.
Gubareva LV, Sleeman K, Guo Z, et al. Drug Susceptibility Evaluation of an Influenza A(H7N9) Virus by Analyzing Recombinant Neuraminidase Proteins. J Infect Dis. 2017;216(suppl_4):S566-S574.
Gubareva, L. V., Sleeman, K., Guo, Z., Yang, H., Hodges, E., Davis, C. T., Baranovich, T., & Stevens, J. (2017). Drug Susceptibility Evaluation of an Influenza A(H7N9) Virus by Analyzing Recombinant Neuraminidase Proteins. The Journal of Infectious Diseases, 216(suppl_4), S566-S574. https://doi.org/10.1093/infdis/jiw625
Gubareva LV, et al. Drug Susceptibility Evaluation of an Influenza A(H7N9) Virus By Analyzing Recombinant Neuraminidase Proteins. J Infect Dis. 2017 09 15;216(suppl_4):S566-S574. PubMed PMID: 28934455.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Drug Susceptibility Evaluation of an Influenza A(H7N9) Virus by Analyzing Recombinant Neuraminidase Proteins. AU - Gubareva,Larisa V, AU - Sleeman,Katrina, AU - Guo,Zhu, AU - Yang,Hua, AU - Hodges,Erin, AU - Davis,Charles T, AU - Baranovich,Tatiana, AU - Stevens,James, PY - 2017/9/22/entrez PY - 2017/9/22/pubmed PY - 2017/9/30/medline KW - A(H7N9) KW - Neuraminidase KW - bird flu KW - drug resistance KW - recombinant protein SP - S566 EP - S574 JF - The Journal of infectious diseases JO - J. Infect. Dis. VL - 216 IS - suppl_4 N2 - Background: Neuraminidase (NA) inhibitors are the recommended antiviral medications for influenza treatment. However, their therapeutic efficacy can be compromised by NA changes that emerge naturally and/or following antiviral treatment. Knowledge of which molecular changes confer drug resistance of influenza A(H7N9) viruses (group 2NA) remains sparse. Methods: Fourteen amino acid substitutions were introduced into the NA of A/Shanghai/2/2013(H7N9). Recombinant N9 (recN9) proteins were expressed in a baculovirus system in insect cells and tested using the Centers for Disease Control and Prevention standardized NA inhibition (NI) assay with oseltamivir, zanamivir, peramivir, and laninamivir. The wild-type N9 crystal structure was determined in complex with oseltamivir, zanamivir, or sialic acid, and structural analysis was performed. Results: All substitutions conferred either reduced or highly reduced inhibition by at least 1 NA inhibitor; half of them caused reduced inhibition or highly reduced inhibition by all NA inhibitors. R292K conferred the highest increase in oseltamivir half-maximal inhibitory concentration (IC50), and E119D conferred the highest zanamivir IC50. Unlike N2 (another group 2NA), H274Y conferred highly reduced inhibition by oseltamivir. Additionally, R152K, a naturally occurring variation at the NA catalytic residue of A(H7N9) viruses, conferred reduced inhibition by laninamivir. Conclusions: The recNA method is a valuable tool for assessing the effect of NA changes on drug susceptibility of emerging influenza viruses. SN - 1537-6613 UR - https://www.unboundmedicine.com/medline/citation/28934455/Drug_Susceptibility_Evaluation_of_an_Influenza_A_H7N9__Virus_by_Analyzing_Recombinant_Neuraminidase_Proteins_ L2 - https://academic.oup.com/jid/article-lookup/doi/10.1093/infdis/jiw625 DB - PRIME DP - Unbound Medicine ER -