Receptor binding by a ferret-transmissible H5 avian influenza virus

Abstract

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, 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.

Structure and receptor-binding properties of an airborne transmissible avian influenza A virus hemagglutinin H5 (VN1203mut)

“…This particular H5 mutant hemagglutinin binds the human α2,6-linked receptor in the same binding pattern (cis conformation) as seen for the HAs of previously reported 1957 and 1968 pandemic infl uenza viruses, which warrants further assessment in the future in order to prevent any possible pandemic caused by H5N1 subtype of avain infl uenza virus. During the preparation of this manuscript, two similar results have been reported in top journals (Xiong et al, 2013;Zhang et al, 2013), indicating this research is really a hot area.…”

Structural basis for preferential avian receptor binding by the human-infecting H10N8 avian influenza virus

“…23). The different outcomes could be due to the different receptor-binding properties of the H5N1 and H7N9 viruses 15,[24][25][26][27][28][29][30][31][32] . The H5N1 viruses display strong binding to avian receptors and weak binding to human receptors, and sporadically infect humans.…”

Vaccine-elicited antibody that neutralizes H5N1 influenza and variants binds the receptor site and polymorphic sites

“…1). We also determined the structures of H5.3 in complex with H5hd containing the rdt mutations from the Kawaoka (H5hd_rdt_Vn, PDB ID code 4XNQ) and Fouchier (H5hd_rdt_In, PDB ID code 4XRC) laboratory strains to 2.15 Å and 2.74 Å, respectively (18,23). Refinement and data quality statistics are given in Table S1.…”

“…Receptor specificity is critically influenced by position 226 on HA; Gln226-containing H3 strains are specific for α2,3 sialic acid linkages, and Leu226-containing H3 strains are specific for α2,6 sialic acid linkages (5, 16). In H5 strains, Leu226 enhances binding to α2,6-linked sialic acid receptors, but H5 viruses isolated from humans contain mutations at other sites that also promote use of α2,6-linked sialic acid receptors (11,17,18). Recent influenza pandemics have been caused by the acquisition of mutations that change the receptor preference to α2,6 sialic acid linkages, and recent studies with multiply passaged laboratory strains indicated that only a small number of mutations are necessary to introduce preference for α2,6 linkages into H5 strains (1, 6-9, 18-23).…”

“…In H5 strains, Leu226 enhances binding to α2,6-linked sialic acid receptors, but H5 viruses isolated from humans contain mutations at other sites that also promote use of α2,6-linked sialic acid receptors (11,17,18). Recent influenza pandemics have been caused by the acquisition of mutations that change the receptor preference to α2,6 sialic acid linkages, and recent studies with multiply passaged laboratory strains indicated that only a small number of mutations are necessary to introduce preference for α2,6 linkages into H5 strains (1,(6)(7)(8)(9)(18)(19)(20)(21)(22)(23). These viruses, termed respiratory droplet transmissible (rdt), typically have three mutations in or near the receptor binding site on HA (21,22).…”