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Journal of Virology, February 2005, p. 2191-2198, Vol. 79, No. 4
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.4.2191-2198.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Lethality to Ferrets of H5N1 Influenza Viruses Isolated from Humans and Poultry in 2004

Elena A. Govorkova,1 Jerold E. Rehg,2 Scott Krauss,1 Hui-Ling Yen,1 Yi Guan,3 Malik Peiris,3 Tien D. Nguyen,4 Thi H. Hanh,5 Pilipan Puthavathana,6 Hoang T. Long,5 Chantanee Buranathai,7 Wilina Lim,8 Robert G. Webster,1,9* and Erich Hoffmann1

Departments of Infectious Diseases,1 Pathology, St. Jude Children's Research Hospital,2 Department of Pathology, University of Tennessee, Memphis, Tennessee,9 Joint Influenza Research Center (Shantou University Medical College and Hong Kong University), Shantou University Medical College, Shantou, Guangdong,3 Government Virus Unit, Department of Health, Hong Kong, Special Administrative Region, People's Republic of China,8 Department of Virology, National Institute of Veterinary Research, Ministry of Agriculture and Rural Development,4 Virology Department, National Institute of Hygiene and Epidemiology, Hanoi, Vietnam,5 Department of Microbiology, Sriraj Hospital,6 Department of Livestock Development, National Institute of Animal Health, Bangkok, Thailand7

Received 15 July 2004/ Accepted 23 September 2004

The 2004 outbreaks of H5N1 influenza viruses in Vietnam and Thailand were highly lethal to humans and to poultry; therefore, newly emerging avian influenza A viruses pose a continued threat, not only to avian species but also to humans. We studied the pathogenicity of four human and nine avian H5N1/04 influenza viruses in ferrets (an excellent model for influenza studies). All four human isolates were fatal to intranasally inoculated ferrets. The human isolate A/Vietnam/1203/04 (H5N1) was the most pathogenic isolate; the severity of disease was associated with a broad tissue tropism and high virus titers in multiple organs, including the brain. High fever, weight loss, anorexia, extreme lethargy, and diarrhea were observed. Two avian H5N1/04 isolates were as pathogenic as the human viruses, causing lethal systemic infections in ferrets. Seven of nine H5N1/04 viruses isolated from avian species caused mild infections, with virus replication restricted to the upper respiratory tract. All chicken isolates were nonlethal to ferrets. A sequence analysis revealed polybasic amino acids in the hemagglutinin connecting peptides of all H5N1/04 viruses, indicating that multiple molecular differences in other genes are important for a high level of virulence. Interestingly, the human A/Vietnam/1203/04 isolate had a lysine substitution at position 627 of PB2 and had one to eight amino acid changes in all gene products except that of the M1 gene, unlike the A/chicken/Vietnam/C58/04 and A/quail/Vietnam/36/04 viruses. Our results indicate that viruses that are lethal to mammals are circulating among birds in Asia and suggest that pathogenicity in ferrets, and perhaps humans, reflects a complex combination of different residues rather than a single amino acid difference.

* Corresponding author. Mailing address: Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794. Phone: (901) 495-3400. Fax: (901) 523-2622. E-mail: robert.webster{at}stjude.org.

Journal of Virology, February 2005, p. 2191-2198, Vol. 79, No. 4
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.4.2191-2198.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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