A highly pathogenic avian influenza virus, H5N1, caused disease outbreaks in poultry in China and seven other east Asian countries between late 2003 and early 2004; the same virus was fatal to humans in Thailand and Vietnam1. Here we demonstrate a series of genetic reassortment events traceable to the precursor of the H5N1 viruses that caused the initial human outbreak in Hong Kong in 1997 (refs 2–4) and subsequent avian outbreaks in 2001 and 2002 (refs 5, 6). These events gave rise to a dominant H5N1 genotype (Z) in chickens and ducks that was responsible for the regional outbreak in 2003–04. Our findings indicate that domestic ducks in southern China had a central role in the generation and maintenance of this virus, and that wild birds may have contributed to the increasingly wide spread of the virus in Asia. Our results suggest that H5N1 viruses with pandemic potential have become endemic in the region and are not easily eradicable. These developments pose a threat to public and veterinary health in the region and potentially the world, and suggest that long-term control measures are required.
Subscribe to Journal
Get full journal access for 1 year
only $3.83 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
World Health Organization, Avian influenza A (H5N1). Weekly Epidemiol. Rev. 79, 65–70 (2004)
Xu, X., Subbarao, K., Cox, N. J. & Guo, Y. Genetic characterization of the pathogenic influenza A/Goose/Guangdong/1/96 (H5N1) virus: similarity of its hemagglutinin gene to those of H5N1 viruses from the 1997 outbreaks in Hong Kong. Virology 261, 15–19 (1999)
Claas, E. C. J. et al. Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus. Lancet 351, 472–477 (1998)
Guan, Y., Shortridge, K. F., Krauss, S. & Webster, R. G. Molecular characterization of H9N2 influenza viruses: were they the donors of the “internal” genes of H5N1 viruses in Hong Kong? Proc. Natl Acad. Sci. USA 96, 9363–9367 (1999)
Guan, Y. et al. Emergence of multiple genotypes of H5N1 avian influenza viruses in Hong Kong SAR. Proc. Natl Acad. Sci. USA 99, 8950–8955 (2002)
Guan, Y. et al. H5N1 Influenza: A protean pandemic threat. Proc. Natl Acad. Sci. USA 101, 8156–8161 (2004)
Shortridge, K. F. et al. Characterization of avian H5N1 influenza viruses from poultry in Hong Kong. Virology 252, 331–342 (1998)
Matrosovich, M., Zhou, N. N., Kawaoka, Y. & Webster, R. G. The surface glycoproteins of H5 influenza viruses isolated from humans, chickens, and wild aquatic birds have distinguishable properties. J. Virol. 73, 1146–1155 (1999)
Hien, T. T. et al. Avian influenza A (H5N1) in 10 patients in Vietnam. N. Engl. J. Med. 350, 1179–1188 (2004)
Li, K. S. et al. Characterization of H9 subtype influenza viruses from the ducks of southern China: a candidate for the next influenza pandemic in humans? J. Virol. 77, 6988–6994 (2003)
Presgraves, D. C., Balagopalan, L., Abmayr, S. M. & Orr, H. A. Adaptive evolution drives divergence of a hybrid inviability gene between two species of Drosophila. Nature 423, 715–719 (2003)
Webster, R. G., Bean, W. J., Gorman, O. T., Chambers, T. M. & Kawaoka, Y. Evolution and ecology of influenza A viruses. Microbiol. Rev. 56, 152–179 (1992)
Scholtissek, C., Quack, G., Klenk, H. D. & Webster, R. G. How to overcome resistance of influenza A viruses against adamantane derivatives. Antiviral Res. 37, 83–95 (1998)
Holsinger, L. J., Shaughnessy, M. A., Micko, A., Pinto, L. H. & Lamb, R. A. Analysis of the posttranslational modifications of the influenza virus M2 protein. J. Virol. 69, 1219–1225 (1995)
Thomas, J. M., Stevens, M. P., Percy, N. & Barclay, W. S. Phosphorylation of the M2 protein of influenza A virus is not essential for virus viability. Virology 252, 54–64 (1998)
Ha, Y., Stevens, D. J., Skehel, J. J. & Wiley, D. C. X-ray structures of H5 avian and H9 swine influenza virus hemagglutinins bound to avian and human receptor analogs. Proc. Natl Acad. Sci. USA 98, 11181–11186 (2001)
Kaverin, N. V. et al. Structure of antigenic sites on the haemagglutinin molecule of H5 avian influenza virus and phenotypic variation of escape mutants. J. Gen. Virol. 83, 2497–2505 (2002)
Iwatsuki-Horimoto, K., Kanazawa, R., Sugii, S., Kawaoka, Y. & Horimoto, T. The index influenza A virus subtype H5N1 isolated from a human in 1997 differs in its receptor-binding properties from a virulent avian influenza virus. J. Gen. Virol. 85, 1001–1005 (2004)
Hatta, M., Gao, P., Halfmann, P. & Kawaoka, Y. Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 293, 1773–1775 (2001)
Fouchier, R. A. M. et al. Avian influenza A virus (H7N7) associated with conjunctivitis and a fatal case of acute respiratory distress syndrome. Proc. Natl Acad. Sci. USA 101, 1356–1361 (2004)
Seo, S. H., Hoffmann, E. & Webster, R. G. Lethal H5N1 influenza viruses escape host anti-viral cytokine responses. Nature Med. 8, 950–954 (2002)
Peiris, J. S. M. et al. Co-circulation of avian H9N2 and contemporary “human” H3N2 influenza viruses in pigs in southeastern China: potential for genetic reassortment? J. Virol. 75, 9679–9686 (2001)
Sims, L. D. et al. Avian influenza in Hong Kong 1977–2002. Avian Dis. 47, 832–838 (2003)
Guan, Y. et al. H9N2 influenza viruses possessing H5N1-like internal genomes continue to circulate in poultry in southeastern China. J. Virol. 74, 9372–9380 (2000)
Swofford, D. L. PAUP*: Phylogenetic Analysis Using Parsimony (and Other Methods) 4.0 Beta (Sinauer Associates, Sunderland, USA, 2001)
Kumar, S., Tamura, K., Jakobsen, I. B. & Nei, M. MEGA2: molecular evolutionary genetics analysis software. Bioinformatics 17, 1244–1245 (2001)
We acknowledge K. Stöhr and the World Health Organization for facilitating the study; L. J. Zhang, C. L. Cheung and Y. H. C. Leung for technical assistance; N. Ng and colleagues for provision of computing facilities; and T. M. Ellis, K. Dyrting, W. Wong, P. Li and C. Li of the Department of Agriculture, Fisheries and Conservation of Hong Kong for their support of field work and W. Lim, for virus isolates. We also thank S. Naron for editorial assistance. These studies were supported by a grant from the National Institutes of Health, a grant from The Wellcome Trust, the Ellison Foundation, the Li Ka Shing Foundation, and grants from the Research Grants Council of Hong Kong.
The authors declare that they have no competing financial interests.
Phylogenetic relationships of the NA, NP, PA, PB1 and PB2 genes. (PDF 87 kb)
Phylogenetic tree of the NS gene. (PDF 80 kb)
Location of a potential additional glycosylation site superimposed on the 3D structure of the hemagluttinin molecule. (PDF 73 kb)
Results of the Ka/Ks rates of substitution analysis for genotype Z viruses. (DOC 52 kb)
About this article
Cite this article
Li, K., Guan, Y., Wang, J. et al. Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia. Nature 430, 209–213 (2004). https://doi.org/10.1038/nature02746
Design, synthesis and in vitro biological evaluation of isoxazol-4-carboxa piperidyl derivatives as new anti-influenza A agents targeting virus nucleoprotein
RSC Advances (2020)
Contribution of Fc-dependent cell-mediated activity of a vestigial esterase-targeting antibody against H5N6 virus infection
Emerging Microbes & Infections (2020)
HopPER: an adaptive model for probability estimation of influenza reassortment through host prediction
BMC Medical Genomics (2020)
A Broad and Potent H1-Specific Human Monoclonal Antibody Produced in Plants Prevents Influenza Virus Infection and Transmission in Guinea Pigs
Translational Research (2020)