Structure and Receptor binding properties of a pandemic H1N1 virus hemagglutinin

[tetano]

Plos Currents

Introduction
The first influenza pandemic of the new century emerged in April 2009, when a new H1N1 influenza virus (H1N1pdm), found in patients in Mexico and the United States, spread rapidly across the world by human-to-human transmission, resulting in the World Health Organization declaring a global pandemic on June 11th 2009 [1]. The pandemic H1N1 virus (2009 H1N1) was unique in that it had a gene constellation from both North American and Eurasian swine lineages that had not been isolated previously in either swine or human populations [2]. Phylogenetic and antigenic analysis of the hemagglutinin (HA) gene revealed it to be distinct from seasonal human H1N1 viruses but more similar to the classical North American swine lineage.
Ten months after the first viruses were isolated, the virus is still antigenically homogeneous [3]. However, as the HA continues to circulate in the human population, its HA antigenic sites will continue to be targeted by antibody-mediated selection pressure. Therefore it is important from a public health perspective to structurally characterize the hemagglutinin so that the research community has a template with which to visualize any changes affecting antigenicity or virulence that may emerge as this virus evolves. To this end, we have cloned, expressed and solved the structure of a pandemic H1 hemagglutinin by x-ray crystallography. The structure was used to analyze amino acid substitutions in the HA that have raised some concern during the last 11 months of global surveillance activities. The same protein was analyzed by glycan microarray and compared to seasonal and other pandemic variants. Results reveal a strict human-like receptor specificity.

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full article

http://knol.google.com/k/hua-yang/s...d=28qm4w0q65e4w.1&position=2#Acknowledgements

 

[mixin]

Re: Structure and Receptor binding properties of a pandemic H1N1 virus hemagglutinin

This has some interesting points:

In recent seasonal H1 HAs the Sa site (and possibly Sb) looks to be affected by the presence of two glycosylation sites at positions 125 and 159. Lack of these sites in the pandemic HA exposes the entire top of the HA1 for targeting by the immune system and this feature may explain why the antibody recall response to the pandemic vaccine in adults was so effective.

Other HA mutations have also been observed that affect antigenicity, but most have been sporadic throughout the year, geographically separated or results of egg growth. In particular, changes at positions 153-157 in the HA have been associated with reduced HI titers with ferret antisera to the A/California/7/09 vaccine virus. In most (if not all) cases, these changes have emerged after virus propagation in cell cultures.

The structure highlights this region to be a prominent loop on the top left of the receptor binding site and is a component of the Sa (H1) or Site B (H3) antigenic site. In the pandemic H1 HA, this region is exposed to the host immune system and not masked by vicinal glycosylation sites. Although this position is known to affect antigenicity, it does not appear to change receptor binding as shown by the glycan microarray results for A/Utah/20/2009 which has as Asn156Asp change compared to the other pandemic virus HAs analyzed. Its ability to change easily also highlights this region as a potential "hot spot" for future mutation as the human population gains immunity and the virus experiences increased pressure to evade the immune response.

Thus, on the current pandemic HA framework, the effect of these mutations at position 222 on receptor binding appears less dramatic when compared to the 1918 framework since the binding preference for a2-6 sialylglycans is still maintained. Analysis of the RBS of Darwin09 offers a possible reason. The galactose of a2-6-linked receptors can interact via its 3- and 2-hydroxyls through a hydrogen bond network using residues Lys219, Asp222 and Glu224. A loss of Asp222 through mutation might not compromise this network to the same extent as was seen in the 1918 HA framework when the Asp225Gly mutation was introduced.

Although a number of mutations have been reported in circulating pandemic H1N1 viruses, they have not affected virus antigenicity and pathogenicity.