Quantification of H5N1 Receptor Binding Domain Changes
Recombinomics Commentary 15:17
January 7, 2008
The new knowledge may unlock strategies for tracking mutations in the avian flu virus that allow it to bind to long glycans, point to new therapeutic targets for both seasonal and pandemic flu, and expand our basic knowledge of glycans and their diversity.
Sasisekharan agreed questions about why H5N1 can infect some people and why clusters of cases occur among blood relatives may be answered through study of the concentration of cone-like alpha 2-6 receptors in infected people.
The above statements define the use of the newly described assay for determining receptor binding domain (RBD) affinities for human 2,6 receptors, followed by media’s attempts to use the assay to bolster the myth on H5N1 genetic predispositions. The new assay is described in the Nature Biotechnology paper, "Glycan topology determines human adaptation of avian H5N1 virus hemagglutinin."
The conceptual basis of RBD changes is straightforward, but muddied by an older assay that can identify differences in binding, but operates at the limits of the assay, so conflicting data is easily generated. The new assay uses a target that not only has the appropriate human 2,6 gal linkage, but also has a shape that more accurately represents human receptors, which is poorly recognized by most avian H5N1 receptor binding domains.
Earlier studies have shown that one or two amino acid changes could shift the specificity from avian to human, which would be of significant concern because H5N1 can already efficiently replicate in humans, with an associated high case fatality rate.
The line between inefficient H5N1 transmission, and efficient transmission to humans is thin, but such a jump can be partially achieved with many combinations of RBD changes.
This improvement in transmission efficiencies has been seen in larger clusters, especially when the genetic background of the H5N1 is clade 2.2 (Qinghai strain). Several different receptor binding domain changes have been associated with larger clusters, but to date the transmission chains have been relatively short, and frequently limited to family members or close contacts, such as friends or health care workers.
Thus, the more efficient transmission has been linked to RBD changes, but media reports ignore the viral sequences and focus on undefined genetic susceptibility genes in family members. The clusters are easily explained by increased risk due to increased contact.
The new assay can be used to screen H5N1 RBD changes that may nominally increase binding affinities, and find combinations of changes that will produce synergies.
The new assay should allow for straightforward quantification of such RBD changes on affinities, based on real sequence data instead of hypothetical genetic predispositions.
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