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Journal of Virology, September 2005, p. 11788-11800, Vol. 79, No. 18
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.18.11788-11800.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Avian Influenza (H5N1) Viruses Isolated from Humans in Asia in 2004 Exhibit Increased Virulence in Mammals

Taronna R. Maines,1 Xui Hua Lu,1 Steven M. Erb,1 Lindsay Edwards,1 Jeannette Guarner,2 Patricia W. Greer,2 Doan C. Nguyen,1 Kristy J. Szretter,1 Li-Mei Chen,1 Pranee Thawatsupha,3 Malinee Chittaganpitch,3 Sunthareeya Waicharoen,3 Diep T. Nguyen,4 Tung Nguyen,4 Hanh H. T. Nguyen,5 Jae-Hong Kim,6 Long T. Hoang,5 Chun Kang,7 Lien S. Phuong,4 Wilina Lim,8 Sherif Zaki,2 Ruben O. Donis,1 Nancy J. Cox,1 Jacqueline M. Katz,1 and Terrence M. Tumpey1*

Influenza Branch,1 Infectious Disease Pathology Activity, Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333,2 Thai National Influenza Center, National Institute of Health, Ministry of Public Health, Bangkok, Thailand 11000,3 National Center for Veterinary Diagnosis, Department of Animal Health, Ministry of Agriculture and Rural Development, Hanoi, Vietnam,4 National Institute of Hygiene and Epidemiology, Hanoi, Vietnam,5 National Veterinary Research and Quarantine Service, Anyang 430-824, Korea,6 Laboratory of Respiratory Viruses, Department of Viruses, Korean National Institute of Health, Seoul, Korea,7 Hong Kong National Influenza Center, Government Virus Unit, Kowloon, Hong Kong Special Administrative Region, China8

Received 9 April 2005/ Accepted 2 June 2005

The spread of highly pathogenic avian influenza H5N1 viruses across Asia in 2003 and 2004 devastated domestic poultry populations and resulted in the largest and most lethal H5N1 virus outbreak in humans to date. To better understand the potential of H5N1 viruses isolated during this epizootic event to cause disease in mammals, we used the mouse and ferret models to evaluate the relative virulence of selected 2003 and 2004 H5N1 viruses representing multiple genetic and geographical groups and compared them to earlier H5N1 strains isolated from humans. Four of five human isolates tested were highly lethal for both mice and ferrets and exhibited a substantially greater level of virulence in ferrets than other H5N1 viruses isolated from humans since 1997. One human isolate and all four avian isolates tested were found to be of low virulence in either animal. The highly virulent viruses replicated to high titers in the mouse and ferret respiratory tracts and spread to multiple organs, including the brain. Rapid disease progression and high lethality rates in ferrets distinguished the highly virulent 2004 H5N1 viruses from the 1997 H5N1 viruses. A pair of viruses isolated from the same patient differed by eight amino acids, including a Lys/Glu disparity at 627 of PB2, previously identified as an H5N1 virulence factor in mice. The virus possessing Glu at 627 of PB2 exhibited only a modest decrease in virulence in mice and was highly virulent in ferrets, indicating that for this virus pair, the K627E PB2 difference did not have a prevailing effect on virulence in mice or ferrets. Our results demonstrate the general equivalence of mouse and ferret models for assessment of the virulence of 2003 and 2004 H5N1 viruses. However, the apparent enhancement of virulence of these viruses in humans in 2004 was better reflected in the ferret.

* Corresponding author. Mailing address: Influenza Branch, Mail Stop G-16, DVRD, NCID, Centers for Disease Control and Prevention, 1600 Clifton Road, N.E., Atlanta, GA 30333. Phone: (404) 639-5444. Fax: (404) 639-2334. E-mail: tft9{at}cdc.gov.

Journal of Virology, September 2005, p. 11788-11800, Vol. 79, No. 18
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.18.11788-11800.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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