Quantitative biochemical rationale for differences in transmissibility of 1918 pandemic influenza A viruses

[Sally Furniss]

[SIZE=+2] Quantitative biochemical rationale for differences in transmissibility of 1918 pandemic influenza A viruses[/SIZE] <nobr>Aravind Srinivasan<sup>

</sup></nobr>, <nobr>Karthik Viswanathan<sup>

</sup></nobr>, <nobr>Rahul Raman<sup>

</sup></nobr>, <nobr>Aarthi Chandrasekaran<sup>

</sup></nobr>, <nobr>S. Raguram<sup>

</sup></nobr>, <nobr>Terrence M. Tumpey<sup>

</sup></nobr>, <nobr>V. Sasisekharan<sup>

</sup></nobr>, and <nobr>Ram Sasisekharan<sup>

</sup><sup>,

</sup>^,?^,||</nobr>
<sup>

</sup>Department of Biological Engineering, <sup>

</sup>Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, and ^?Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; and <sup>

</sup>Influenza Division, National Center for Immunization and Respiratory Diseases, Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Mailstop G-16, 1600 Clifton Road NE, Atlanta, GA 30333
Communicated by Robert Langer, Massachusetts Institute of Technology, Cambridge, MA, December 19, 2007 (received for review December 2, 2007)
[SIZE=+1]Abstract[/SIZE]
The human adaptation of influenza A viruses is critically governedby the binding specificity of the viral surface hemagglutinin(HA) to long (chain length)

2-6 sialylated glycan (

2-6) receptorson the human upper respiratory tissues. A recent study demonstratedthat whereas the 1918 H1N1 pandemic virus, A/South Carolina/1/1918(SC18), with

2-6 binding preference transmitted efficiently,a single amino acid mutation on HA resulted in a mixed

2-3 sialylatedglycan (

2-3)/

2-6 binding virus (NY18) that transmitted inefficiently.To define the biochemical basis for the observed differencesin virus transmission, in this study, we have developed an approachto quantify the multivalent HA?glycan interactions. Analysisof the molecular HA?glycan contacts showed subtle changesresulting from the single amino acid variations between SC18and NY18. The effect of these changes on glycan binding is amplifiedby multivalency, resulting in quantitative differences in theirlong

2-6 glycan binding affinities. Furthermore, these differencesare also reflected in the markedly distinct binding patternof SC18 and NY18 HA to the physiological glycans present inhuman upper respiratory tissues. Thus, the dramatic lower bindingaffinity of NY18 to long

2-6 glycans, as against a mixed

2-3/6binding, correlates with its inefficient transmission. In summary,this study establishes a quantitative biochemical correlatefor influenza A virus transmission.

http://www.pnas.org/cgi/content/abstract/0711963105v1?ct=ct