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Enhanced Human-Type Receptor Binding by Ferret-Transmissible H5N1 with a K193T Mutation.
J Virol. 2018 05 15; 92(10)JV

Abstract

All human influenza pandemics have originated from avian influenza viruses. Although multiple changes are needed for an avian virus to be able to transmit between humans, binding to human-type receptors is essential. Several research groups have reported mutations in H5N1 viruses that exhibit specificity for human-type receptors and promote respiratory droplet transmission between ferrets. Upon detailed analysis, we have found that these mutants exhibit significant differences in fine receptor specificity compared to human H1N1 and H3N2 and retain avian-type receptor binding. We have recently shown that human influenza viruses preferentially bind to α2-6-sialylated branched N-linked glycans, where the sialic acids on each branch can bind to receptor sites on two protomers of the same hemagglutinin (HA) trimer. In this binding mode, the glycan projects over the 190 helix at the top of the receptor-binding pocket, which in H5N1 would create a stearic clash with lysine at position 193. Thus, we hypothesized that a K193T mutation would improve binding to branched N-linked receptors. Indeed, the addition of the K193T mutation to the H5 HA of a respiratory-droplet-transmissible virus dramatically improves both binding to human trachea epithelial cells and specificity for extended α2-6-sialylated N-linked glycans recognized by human influenza viruses.IMPORTANCE Infections by avian H5N1 viruses are associated with a high mortality rate in several species, including humans. Fortunately, H5N1 viruses do not transmit between humans because they do not bind to human-type receptors. In 2012, three seminal papers have shown how these viruses can be engineered to transmit between ferrets, the human model for influenza virus infection. Receptor binding, among others, was changed, and the viruses now bind to human-type receptors. Receptor specificity was still markedly different compared to that of human influenza viruses. Here we report an additional mutation in ferret-transmissible H5N1 that increases human-type receptor binding. K193T seems to be a common receptor specificity determinant, as it increases human-type receptor binding in multiple subtypes. The K193T mutation can now be used as a marker during surveillance of emerging viruses to assess potential pandemic risk.

Authors+Show Affiliations

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA.Pathology Division, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA.Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, USA.Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, USA.Pathology Division, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA.Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA r.vries@uu.nl. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA. Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

29491160

Citation

Peng, Wenjie, et al. "Enhanced Human-Type Receptor Binding By Ferret-Transmissible H5N1 With a K193T Mutation." Journal of Virology, vol. 92, no. 10, 2018.
Peng W, Bouwman KM, McBride R, et al. Enhanced Human-Type Receptor Binding by Ferret-Transmissible H5N1 with a K193T Mutation. J Virol. 2018;92(10).
Peng, W., Bouwman, K. M., McBride, R., Grant, O. C., Woods, R. J., Verheije, M. H., Paulson, J. C., & de Vries, R. P. (2018). Enhanced Human-Type Receptor Binding by Ferret-Transmissible H5N1 with a K193T Mutation. Journal of Virology, 92(10). https://doi.org/10.1128/JVI.02016-17
Peng W, et al. Enhanced Human-Type Receptor Binding By Ferret-Transmissible H5N1 With a K193T Mutation. J Virol. 2018 05 15;92(10) PubMed PMID: 29491160.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enhanced Human-Type Receptor Binding by Ferret-Transmissible H5N1 with a K193T Mutation. AU - Peng,Wenjie, AU - Bouwman,Kim M, AU - McBride,Ryan, AU - Grant,Oliver C, AU - Woods,Robert J, AU - Verheije,Monique H, AU - Paulson,James C, AU - de Vries,Robert P, Y1 - 2018/04/27/ PY - 2017/11/24/received PY - 2018/02/12/accepted PY - 2018/3/2/pubmed PY - 2018/5/18/medline PY - 2018/3/2/entrez KW - H5N1 KW - N-linked glycan KW - glycan array KW - influenza KW - receptor binding KW - sialic acid JF - Journal of virology JO - J. Virol. VL - 92 IS - 10 N2 - All human influenza pandemics have originated from avian influenza viruses. Although multiple changes are needed for an avian virus to be able to transmit between humans, binding to human-type receptors is essential. Several research groups have reported mutations in H5N1 viruses that exhibit specificity for human-type receptors and promote respiratory droplet transmission between ferrets. Upon detailed analysis, we have found that these mutants exhibit significant differences in fine receptor specificity compared to human H1N1 and H3N2 and retain avian-type receptor binding. We have recently shown that human influenza viruses preferentially bind to α2-6-sialylated branched N-linked glycans, where the sialic acids on each branch can bind to receptor sites on two protomers of the same hemagglutinin (HA) trimer. In this binding mode, the glycan projects over the 190 helix at the top of the receptor-binding pocket, which in H5N1 would create a stearic clash with lysine at position 193. Thus, we hypothesized that a K193T mutation would improve binding to branched N-linked receptors. Indeed, the addition of the K193T mutation to the H5 HA of a respiratory-droplet-transmissible virus dramatically improves both binding to human trachea epithelial cells and specificity for extended α2-6-sialylated N-linked glycans recognized by human influenza viruses.IMPORTANCE Infections by avian H5N1 viruses are associated with a high mortality rate in several species, including humans. Fortunately, H5N1 viruses do not transmit between humans because they do not bind to human-type receptors. In 2012, three seminal papers have shown how these viruses can be engineered to transmit between ferrets, the human model for influenza virus infection. Receptor binding, among others, was changed, and the viruses now bind to human-type receptors. Receptor specificity was still markedly different compared to that of human influenza viruses. Here we report an additional mutation in ferret-transmissible H5N1 that increases human-type receptor binding. K193T seems to be a common receptor specificity determinant, as it increases human-type receptor binding in multiple subtypes. The K193T mutation can now be used as a marker during surveillance of emerging viruses to assess potential pandemic risk. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/29491160/Enhanced_Human_Type_Receptor_Binding_by_Ferret_Transmissible_H5N1_with_a_K193T_Mutation_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/29491160/ DB - PRIME DP - Unbound Medicine ER -