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Of the 132 people known to have been infected with H7N9 influenza viruses in China, 37 died, and many were severely ill. Infection seems to have involved contact with infected poultry. We have examined the receptor-binding properties of this H7N9 virus and compared them with those of an avian H7N3 virus. We find that the human H7 virus has significantly higher affinity for α-2,6-linked sialic acid analogues ('human receptor') than avian H7 while retaining the strong binding to α-2,3-linked sialic acid analogues ('avian receptor') characteristic of avian viruses. The human H7 virus does not, therefore, have the preference for human versus avian receptors characteristic of pandemic viruses. X-ray crystallography of the receptor-binding protein, haemagglutinin (HA), in complex with receptor analogues indicates that both human and avian receptors adopt different conformations when bound to human H7 HA than they do when bound to avian H7 HA. Human receptor bound to human H7 HA exits the binding site in a different direction to that seen in complexes formed by HAs from pandemic viruses and from an aerosol-transmissible H5 mutant. The human-receptor-binding properties of human H7 probably arise from the introduction of two bulky hydrophobic residues by the substitutions Gln226Leu and Gly186Val. The former is shared with the 1957 H2 and 1968 H3 pandemic viruses and with the aerosol-transmissible H5 mutant. We conclude that the human H7 virus has acquired some of the receptor-binding characteristics that are typical of pandemic viruses, but its retained preference for avian receptor may restrict its further evolution towards a virus that could transmit efficiently between humans, perhaps by binding to avian-receptor-rich mucins in the human respiratory tract rather than to cellular receptors.

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.

The structure and receptor-binding characteristics are presented of the haemagglutinin (HA) from an avian H10N2 virus that closely resembles an isolate from recent human fatalities; although avian H10 has a marked preference for the avian receptor, it is already able to bind to the human receptor, and its structure in complex with the human receptor shows similarities to HA from pandemic H1 and H7 viruses. Influenza virus H10N8 is the most recent example of an avian influenza virus that has infected and killed humans. Steven Gamblin and colleagues investigate the structure and receptor-binding characteristics of the haemagglutinin of an avian H10 virus, which is closely related to the human isolate. They show that H10 virus can already bind to the human receptor, although it has a marked preference for avian receptors. The structure of the H10 haemagglutinin bound to its human receptor also shows similarities with the characteristics of haemagglutinin from pandemic H1N1 viruses and H7N9 viruses. The authors suggest that mutations in the receptor-binding site of the H10 haemagglutinin that decrease its avidity for avian receptor could enable it to be more readily transmitted between humans, so should be the focus of surveillance efforts. H10N8 follows H7N9 and H5N1 as the latest in a line of avian influenza viruses that cause serious disease in humans and have become a threat to public health1. Since December 2013, three human cases of H10N8 infection have been reported, two of whom are known to have died. To gather evidence relating to the epidemic potential of H10 we have determined the structure of the haemagglutinin of a previously isolated avian H10 virus and we present here results relating especially to its receptor-binding properties, as these are likely to be major determinants of virus transmissibility. Our results show, first, that the H10 virus possesses high avidity for human receptors and second, from the crystal structure of the complex formed by avian H10 haemagglutinin with human receptor, it is clear that the conformation of the bound receptor has characteristics of both the 1918 H1N1 pandemic virus2 and the human H7 viruses isolated from patients in 2013 (ref. 3). We conclude that avian H10N8 virus has sufficient avidity for human receptors to account for its infection of humans but that its preference for avian receptors should make avian-receptor-rich human airway mucins4 an effective block to widespread infection. In terms of surveillance, particular attention will be paid to the detection of mutations in the receptor-binding site of the H10 haemagglutinin that decrease its avidity for avian receptor, and could enable it to be more readily transmitted between humans.

The oligonucleotides pppA2'p5'A2'p5'A and related oligomers (2-5A) are synthesized by an enzyme that is widely distributed in a variety of cells, the activity of which varies with interferon treatment, growth and hormone status. Because significant amounts of 2-5A have recently been detected in interferon-treated cells, it has been suggested that the oligonucleotides may be involved in interferon action and in the control of cell metabolism. In both intact cells and cell-free systems 2-5A has been shown to activate a ribonuclease. We report here investigations of the sequence specificities of the 2-5A-dependent ribonucleases in extracts of rabbit reticulocytes, mouse ascites tumour cells and human lymphoblastoid cells in conditions of partial digestion using terminally labelled RNA substrates. The enzymes cleaved on the 3'-side of UN sequences to yield UpNp terminated products. Cleavage was observed predominantly at UA and UU sequences.