The polymerase complex genes contribute to the high virulence of the human H5N1 influenza virus isolate A/Vietnam/1203/04

被引:299
作者
Salomon, R
Franks, J
Govorkova, EA
Ilyushina, NA
Yen, HL
Hulse-Post, DJ
Humberd, J
Trichet, M
Rehg, JE
Webby, RJ
Webster, RG
Mann, EH
机构
[1] St Jude Childrens Res Hosp, Dept Infect Dis, Memphis, TN 38105 USA
[2] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA
[3] Univ Tennessee, Dept Pathol, Memphis, TN 38105 USA
关键词
D O I
10.1084/jem.20051938
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
H5N1 influenza viruses transmitted from poultry to humans in Asia cause high mortality and pose a pandemic threat. Viral genes important for cell tropism and replication efficiency must be identified to elucidate and target virulence factors. We applied reverse genetics to generate H5N1 reassortants combining genes of lethal A/Vietnam/1203/04 (VN1203), a fatal human case isolate, and nonlethal A/chicken/Vietnam/C58/04 (CH58) and tested their pathogenicity in ferrets and mice. The viruses' hemagglutinins have six amino acids differences, identical cleavage sites, and avian- like alpha-(2,3)-linked receptor specificity. Surprisingly, exchanging hemagglutinin and neuraminidase genes did not alter pathogenicity, but substituting CH58 polymerase genes completely attenuated VN1203 virulence and reduced viral polymerase activity. CH58's NS gene partially attenuated VN1203 in ferrets but not in mice. Our findings suggest that for high virulence in mammalian species an avian H5N1 virus with a cleavable hemagglutinin requires adaptive changes in polymerase genes to overcome the species barrier. Thus, novel antivirals targeting polymerase proteins should be developed.
引用
收藏
页码:689 / 697
页数:9
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