RT Journal Article SR Electronic T1 The polymerase complex genes contribute to the high virulence of the human H5N1 influenza virus isolate A/Vietnam/1203/04 JF The Journal of Experimental Medicine JO J Exp Med FD Rockefeller University Press SP 689 OP 697 DO 10.1084/jem.20051938 VO 203 IS 3 A1 Salomon, Rachelle A1 Franks, John A1 Govorkova, Elena A. A1 Ilyushina, Natalia A. A1 Yen, Hui-Ling A1 Hulse-Post, Diane J. A1 Humberd, Jennifer A1 Trichet, Michel A1 Rehg, Jerold E. A1 Webby, Richard J. A1 Webster, Robert G. A1 Hoffmann, Erich YR 2006 UL http://jem.rupress.org/content/203/3/689.abstract AB 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 α-(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.