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Steve Gamblin group project:

Influenza hemagglutinin

The influenza virus surface glycoprotein hemagglutinin (HA) mediates receptor binding and membrane fusion in influenza infections. HA binds to sialic acids that are found in α2,3 or α2,6 linkages to galactose on cell surface glycoproteins and glycolipids. Avian influenza viruses preferentially bind α2,3-linked sialic acids, which predominate in the enteric tract of birds where the viruses replicate. Human influenza viruses preferentially bind to α2,6-linked sialic acids, which are the predominant form found in the human upper respiratory tract.

The viruses that caused the three influenza pandemics of the twentieth century in 1918, 1957, and 1968 had distinct hemagglutinin receptor binding glycoproteins that had evolved the capacity to recognize human cell receptors. We have recently determined the structure of the H2 hemagglutinin from the second pandemic, the “Asian Influenza” of 1957 (Figure 1). We can compare it with the 1918 “Spanish Influenza” hemagglutinin, H1, and the 1968 “Hong Kong Influenza” hemagglutinin, H3, and show that despite its close overall structural similarity to H1, and its more distant relationship to H3, the H2 receptor binding site is closely related to that of H3 hemagglutinin.

By analyzing hemagglutinins of potential H2 avian precursors of the pandemic virus, we show that the human receptor can be bound by avian hemagglutinins that lack the human–specific mutations of H2 and H3 pandemic viruses, Gln-226Leu, and Gly-228Ser. We show how Gln-226 in the avian H2 receptor binding site, together with Asn-186, form hydrogen bond networks through bound water molecules to mediate binding to human receptor. We show that the human receptor adopts a very similar conformation in both human and avian hemagglutinin-receptor complexes. We also show that Leu-226 in the receptor binding site of human virus hemagglutinins creates a hydrophobic environment near the Sia-1-Gal-2 glycosidic linkage that favours binding of the human receptor and is unfavourable for avian receptor binding.

We have also been developing a quantitative assay to measure the binding of influenza viruses to immobilized sialic acids. Using instrumentation from Biacore and Fortebio, we are able to measure virus binding in real time to determine the specificity for different sugars. Analysis of different human, avian and swine influenza strains, as well as analysis of certain mutations in specific strains, reveals which viruses are able to bind well to human receptors. With consideration of the structural and binding information, we consider the significance of hemagglutinin specificity for the development of pandemics and of the existence of avian viruses that can bind to both avian and human receptors.