The polymerase complex genes contribute to the high virulence of the human H5N1 influenza virus isolate A/Vietnam/1203/04.
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.
Salomon
Rachelle
R
Department of Infectious Diseases, St. Jude Children's Research Hospital, and Department of Pathology, University of Tennessee, Memphis, TN 38105, USA.
Franks
John
J
Govorkova
Elena A
EA
Ilyushina
Natalia A
NA
Yen
Hui-Ling
HL
Hulse-Post
Diane J
DJ
Humberd
Jennifer
J
Trichet
Michel
M
Rehg
Jerold E
JE
Webby
Richard J
RJ
Webster
Robert G
RG
Hoffmann
Erich
E
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D002645:Chickens / Q000821:virology; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005289:Ferrets / Q000821:virology; D014644:Genetic Variation; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics* / Q000472:pathogenicity; D005585:Influenza in Birds / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D007251:Influenza, Human / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009439:Neuraminidase / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors / Q000235:genetics*; D013045:Species Specificity; D037521:Virulence Factors / Q000235:genetics*
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D037521:Virulence Factors; D012324:RNA-Dependent RNA Polymerase; D009439:Neuraminidase