1. Division of Virology, Department of Microbiology and Immunology, and,
2. International Research Centre for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
3. Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
4. College of Life and Health Sciences, Chubu University, Kasugai, Aichi 487-8501, Japan
5. Department of Biochemistry, University of Shizuoka, School of Pharmaceutical Sciences and COE Program in the 21st Century, Yada, Shizuoka 422-8526, Japan
6. National Institute of Hygiene and Epidemiology, Hanoi, Vietnam
7. Avian Influenza Laboratory, Tropical Disease Centre, Airlangga University, Surabaya, Indonesia
8. The Avian Zoonosis Research Centre, Tottori University, Tottori 680-8553, Japan
9. Department of Applied Bioorganic Chemistry, The United Graduate School of Agricultural Science, Gifu University, Yanagido, Gifu 501-1193, Japan
10. Department of Applied Biological Chemistry, Shizuoka University, Shizuoka 422-8529, Japan
11. MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK
12. Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA
13. Present address: Centre for Biomolecular Sciences, University of St Andrews, St Andrews KY16 9ST, UK.

Correspondence to: Yoshihiro Kawaoka^1,2,3,12 Correspondence and requests for materials should be addressed to Y.K. (Email: kawaoka@ims.u-tokyo.ac.jp). Coordinates for the H5 structure have been deposited in the Protein Data Bank under accession code 2IBX.

Abstract

H5N1 influenza A viruses have spread to numerous countries in Asia, Europe and Africa, infecting not only large numbers of poultry, but also an increasing number of humans, often with lethal effects^{1, 2}. Human and avian influenza A viruses differ in their recognition of host cell receptors: the former preferentially recognize receptors with saccharides terminating in sialic acid-2,6-galactose (SA2,6Gal), whereas the latter prefer those ending in SA2,3Gal (refs 3–6). A conversion from SA2,3Gal to SA2,6Gal recognition is thought to be one of the changes that must occur before avian influenza viruses can replicate efficiently in humans and acquire the potential to cause a pandemic. By identifying mutations in the receptor-binding haemagglutinin (HA) molecule that would enable avian H5N1 viruses to recognize human-type host cell receptors, it may be possible to predict (and thus to increase preparedness for) the emergence of pandemic viruses. Here we show that some H5N1 viruses isolated from humans can bind to both human and avian receptors, in contrast to those isolated from chickens and ducks, which recognize the avian receptors exclusively. Mutations at positions 182 and 192 independently convert the HAs of H5N1 viruses known to recognize the avian receptor to ones that recognize the human receptor. Analysis of the crystal structure of the HA from an H5N1 virus used in our genetic experiments shows that the locations of these amino acids in the HA molecule are compatible with an effect on receptor binding. The amino acid changes that we identify might serve as molecular markers for assessing the pandemic potential of H5N1 field isolates.

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