Topological Glycan Changes and H5N1 Transmission
Recombinomics Commentary 21:21
January 6, 2008
The two representative H5N1 viruses showed binding signals for long 2-6 at the highest viral concentrations. However, the binding affinity for long 2-6 is minimal compared to the high affinity for 2-3 over the entire viral concentration range (Fig. 4b). Interpretation of the glycan binding data at the highest concentration alone would have led to an erroneous conclusion that these viruses have acquired binding to human-like receptors.
The above comments describe the key finding in the Nature Biotechnology paper, "Glycan topology determines human adaptation of avian H5N1 virus hemagglutinin". The paper uses an assay that is more three dimensional for the measurement of the ability of various HA receptor binding domain sequences to distinguish human (2,6 gal) and avian (2,3 gal) receptors. Prior assays required a relatively high concentration of receptor binding doman, which limited the concentration range and therefore was not as useful for distinguishing intermediate differences.
This more precise assay should help define changes associated with intermediate differences between various receptor binding domains. A year ago there was some progress in this area with the identification of several receptor binding domain changes that increased affinity for 2,6 gal linkages. These included S227N linked to clusters in the outbreak in Turkey as well as N186K in Azerbaijan clusters, N186S and Q196R in an Iraq cluster, and V223I and M230I in an Egyptian cluster. The only significant Qinghai cluster not associated with changes was the recent sustaned transmission in Pakistan, but that sequence has not been released, and the samples were plagued by a long string of technical issues.
The new paper indicates the human target is not just 2,6 gal linkages, but those in a specific conformation that produce optimal binding for seasonal flu viruses (H1 and H3). The new assay will allow for screening of various combinations of changes that produce more efficient binding that may be of an intermediate level between 2,3 and 2,6 binding affinities generated in the past.
Many of the changes noted a year ago were found in clade 2.2 isolates associated with human clusters. These changes can be acquire via recombination, and placed onto different genetic backgrounds. The new assay will allow detection of more subtle changes in binding affinities, which would help explain the genetic basis for the larger clusters, and measure which combinations would most approximate the affinities of seasonal flu.
Sequences from past clade 2.2 isolates have shown a strong correlation between receptor binding domain changes and reports of clusters. However, the more efficient transmission fell short of the efficiency seen for seasonal flu, and the transmission chains were limited.
H5N1 can already grow efficient in humans, and create case fatality rates that are ten fold higher than those seen in the 1918 pandemic. Thus, the ability of H5N1 to transmit at efficiencies approximating seasonal flu would generate a catastrophic pandemic.
This new assay should help determine changes that create increased efficiencies as well as specific changes that would more closely approximate the efficiencies seen in seasonal flu. The earlier assays indocated changes in just two positions could dramatically increase transmission efficiencies, The new assays should identify combinations that will produce intermediate efficiencies.
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