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

^†Department of Biological Engineering,
^§Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, and
^¶Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; and
^‡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)

Abstract

The human adaptation of influenza A viruses is critically governed by the binding specificity of the viral surface hemagglutinin (HA) to long (chain length) α2-6 sialylated glycan (α2-6) receptors on the human upper respiratory tissues. A recent study demonstrated that whereas the 1918 H1N1 pandemic virus, A/South Carolina/1/1918 (SC18), with α2-6 binding preference transmitted efficiently, a single amino acid mutation on HA resulted in a mixed α2-3 sialylated glycan (α2-3)/α2-6 binding virus (NY18) that transmitted inefficiently. To define the biochemical basis for the observed differences in virus transmission, in this study, we have developed an approach to quantify the multivalent HA–glycan interactions. Analysis of the molecular HA–glycan contacts showed subtle changes resulting from the single amino acid variations between SC18 and NY18. The effect of these changes on glycan binding is amplified by multivalency, resulting in quantitative differences in their long α2-6 glycan binding affinities. Furthermore, these differences are also reflected in the markedly distinct binding pattern of SC18 and NY18 HA to the physiological glycans present in human upper respiratory tissues. Thus, the dramatic lower binding affinity of NY18 to long α2-6 glycans, as against a mixed α2-3/6 binding, correlates with its inefficient transmission. In summary, this study establishes a quantitative biochemical correlate for influenza A virus transmission.

Footnotes

^‖To whom correspondence should be addressed. E-mail: rams{at}mit.edu
Author contributions: A.S., K.V., R.R., and A.C. contributed equally to this work; V.S., R.R., and R.S. designed research; A.S., K.V., R.R., A.C., and S.R. performed research; A.S., A.C., and T.M.T. contributed new reagents/analytic tools; A.S., K.V., R.R., A.C., S.R., T.M.T., and R.S. analyzed data; and R.R., V.S., and R.S. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0711963105/DC1.
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