The recent outbreak of avian influenza has led to renewed interest in how avian viruses cross the species barrier and become adapted to humans. But how do avian viruses bind to human receptors, and what made the 1918 influenza virus so infectious? Now, reporting in Science, two groups propose answers to these questions.

The first steps of an influenza infection — receptor binding and membrane fusion — are mediated by influenza virus haemagglutinins (HAs), which recognize sialic acids of cell-surface glycoproteins. Sialic acids are present as either α2,3- or α2,6-linkages — the HAs of avian viruses bind to α2,3-linked sialic acids, whereas those of human viruses bind to α2,6-linked sialic acids. So, HA receptor-binding specificity is important for the virus to infect and spread through the human population.

Reporting in Science, Gamblin et al. and Stevens et al. present X-ray crystal structures of the HA from the 1918 influenza virus (1918HA) — an influenza virus of H1 subtype that killed more than 20 million people worldwide — which reveal several structural surprises. First, the presence of two features that could contribute to the high infectivity of the 1918 virus. The cleavage loop of 1918HA is in a concealed conformation relative to other viral HAs, which could prevent premature cleavage by intracellular proteases, and there are two basic histidine patches that are not observed in other HA structures, which could facilitate membrane fusion in a manner similar to that of vesicular stomatitis virus. Stevens et al. speculate that these could enhance virus infectivity. Second, despite infecting humans, the 1918HA receptor-binding site is characteristic of avian viruses. It is narrower than other human HAs and, although in H2 and H3 virus HAs mutation of Gln226 and Gly228 to Leu and Ser, respectively, have been shown to be associated with changes in binding specificity, the 1918HA has avian residues, similar to other H1 virus HAs.

So how can this 'avian-type' HA bind to human receptors? Gamblin and co-workers obtained crystal structures of human and avian H1 and H3 HA–receptor complexes, using α2,3- and α2,6-linked sialopentasaccharides as avian and human receptor analogues, respectively. Structural analyses identified four residues within the binding site as important for forming interactions with human receptors — 190, 193, 222 and 225. The presence of lysine and aspartic acid residues at positions 222 and 225, respectively, positions the α2,6-linked sialic acid of a human receptor lower in the HA receptor-binding site then the α2,3-linked sialic acid of an avian receptor. This, in turn, allows Asp190 and Lys222 to form interactions with the receptor, forming a network of interactions between 1918HA residues and human receptors.

These analyses provide important insights into the interactions between HAs and human receptors, and reveal the residues that enable 1918HA to interact with human receptors. All human influenza viruses responsible for major epidemics — including the virus responsible for the 1918 influenza pandemic — are believed to be of avian origin. Although based on a now extinct influenza virus, these analyses could be used to design anti-influenza agents and vaccines to help prevent outbreaks of viral diseases such as avian influenza in humans.