Journal Article

Receptor binding by a ferret-transmissible H5 avian influenza virus

Kawaoka, Yoshihiro, Xiong, Xiaoli, Skehel, John J., Martin, Stephen R., Liu, Junfeng, Collins, Patrick J., Gamblin, Steven J., Xiao, Haixia, Locher, Kathrin, McCauley, John W., Walker, Philip A., Coombs, Peter J.

2013

Overview

Building on previous work that identified a mutant avian H5 virus that is transmissible between ferrets, the authors present an algorithm to predict virus avidity from the affinity of single haemagglutinin (HA)–receptor interactions; these studies predict that the mutant has a 200-fold preference for the human over the avian receptor, and crystal structures of the mutant HA in complex with human and avian receptors shed light on the molecular basis for these altered binding properties. Receptor binding of transmissible flu virus The recent identification of an avian H5 haemagglutinin (HA) that can mediate aerosol transmission in ferrets when incorporated into a human influenza virus backbone has provided a model in which the nature of transmission of this type of virus can be closely examined. This new study goes further in demonstrating that this same transmissible-mutant virus has acquired a small increase in affinity for the human receptor, but a marked decrease in affinity for the avian receptor, leading to a 200-fold preference for binding human over avian receptors. The authors provide a crystal structure of this mutant HA in complex with human and avian receptor analogues, revealing something of the molecular basis for the altered binding properties. Cell-surface-receptor binding by influenza viruses is a key determinant of their transmissibility, both from avian and animal species to humans as well as from human to human. Highly pathogenic avian H5N1 viruses that are a threat to public health have been observed to acquire affinity for human receptors, and transmissible-mutant-selection experiments have identified a virus that is transmissible in ferrets 1 , 2 , 3 , the generally accepted experimental model for influenza in humans. Here, our quantitative biophysical measurements of the receptor-binding properties of haemagglutinin (HA) from the transmissible mutant indicate a small increase in affinity for human receptor and a marked decrease in affinity for avian receptor. From analysis of virus and HA binding data we have derived an algorithm that predicts virus avidity from the affinity of individual HA–receptor interactions. It reveals that the transmissible-mutant virus has a 200-fold preference for binding human over avian receptors. The crystal structure of the transmissible-mutant HA in complex with receptor analogues shows that it has acquired the ability to bind human receptor in the same folded-back conformation as seen for HA from the 1918, 1957 (ref. 4 ), 1968 (ref. 5 ) and 2009 (ref. 6 ) pandemic viruses. This binding mode is substantially different from that by which non-transmissible wild-type H5 virus HA binds human receptor. The structure of the complex also explains how the change in preference from avian to human receptors arises from the Gln226Leu substitution, which facilitates binding to human receptor but restricts binding to avian receptor. Both features probably contribute to the acquisition of transmissibility by this mutant virus.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/535 / 692/308 / Agglutinins / Algorithms / Animal species / Animals / Avian influenza / Avian influenza viruses / Binding sites / Birds - metabolism / Birds - virology / Cell receptors / Chick Embryo / Crystal structure / Crystallography, X-Ray / Disease transmission / Distribution / Ferrets / Ferrets - virology / Health aspects / Hemagglutinin Glycoproteins, Influenza Virus - chemistry / Hemagglutinin Glycoproteins, Influenza Virus - genetics / Hemagglutinin Glycoproteins, Influenza Virus - metabolism / Host Specificity / Humanities and Social Sciences / Humans / Influenza A Virus, H5N1 Subtype - chemistry / Influenza A Virus, H5N1 Subtype - genetics / Influenza A Virus, H5N1 Subtype - metabolism / Influenza A Virus, H5N1 Subtype - pathogenicity / letter / Models, Biological / Models, Molecular / multidisciplinary / Mutation / Observations / Orthomyxoviridae Infections - transmission / Orthomyxoviridae Infections - virology / Pandemics / Physiological aspects / Properties / Protein Conformation / Public health / Receptors, Virus - metabolism / Science / Species Specificity / Testing / Viruses