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Journal of Virology, September 2005, p. 12058-12064, Vol. 79, No. 18
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.18.12058-12064.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Molecular Basis of Replication of Duck H5N1 Influenza Viruses in a Mammalian Mouse Model

Zejun Li,1 Hualan Chen,1* Peirong Jiao,1 Guohua Deng,1 Guobin Tian,1 Yanbing Li,1 Erich Hoffmann,2 Robert G. Webster,2 Yumiko Matsuoka,3 and Kangzhen Yu1*

Animal Influenza Laboratory, Ministry of Agriculture, and National Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150001, People's Republic of China,1 Division of Virology, Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105,2 Influenza Branch, Centers for Disease Control, 1600 Clifton Road, Atlanta, Georgia 303333

Received 27 January 2005/ Accepted 10 June 2005

We recently analyzed a series of H5N1 viruses isolated from healthy ducks in southern China since 1999 and found that these viruses had progressively acquired the ability to replicate and cause disease in mice. In the present study, we explored the genetic basis of this change in host range by comparing two of the viruses that are genetically similar but differ in their ability to infect mice and have different pathogenicity in mice. A/duck/Guangxi/22/2001 (DKGX/22) is nonpathogenic in mice, whereas A/duck/Guangxi/35/2001 (DKGX/35) is highly pathogenic. We used reverse genetics to create a series of single-gene recombinants that contained one gene from DKGX/22 and the remaining seven gene segments from DKGX/35. We find that the PA, NA, and NS genes of DKGX/22 could attenuate DKGX/35 virus to some extent, but PB2 of DKGX/22 virus attenuated the DKGX/35 virus dramatically, and an Asn-to-Asp substitution at position 701 of PB2 plays a key role in this function. Conversely, of the recombinant viruses in the DKGX/22 background, only the one that contains the PB2 gene of DKGX/35 was able to replicate in mice. A single amino acid substitution (Asp to Asn) at position 701 of PB2 enabled DKGX/22 to infect and become lethal for mice. These results demonstrate that amino acid Asn 701 of PB2 is one of the important determinants for this avian influenza virus to cross the host species barrier and infect mice, though the replication and lethality of H5N1 influenza viruses involve multiple genes and may result from a constellation of genes. Our findings may help to explain the expansion of the host range and lethality of the H5N1 influenza viruses to humans.

* Corresponding author. Mailing address for Hualan Chen: Harbin Veterinary Research Institute, CAAS, 427 Maduan Street, Harbin 150001, People's Republic of China. Phone: 86-451-82761925. Fax: 86-451-82733132. E-mail: hlchen1{at}yahoo.com. Present address for Kangzhen Yu: National Animal Husbandry and Veterinary Service of the Ministry of Agriculture, 20 Maizidian Street, Beijing 100026, People's Republic of China. Phone: 86-10-64194613. Fax: 86-10-64194611. E-mail: yukangzhen{at}agri.gov.cn.

Journal of Virology, September 2005, p. 12058-12064, Vol. 79, No. 18
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.18.12058-12064.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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