title: Lethality to ferrets of H5N1 influenza viruses isolated from humans and poultry in 2004.
abstract: The 2004 outbreaks of H5N1 influenza viruses in Vietnam and Thailand were highly lethal to humans and to poultry; therefore, newly emerging avian influenza A viruses pose a continued threat, not only to avian species but also to humans. We studied the pathogenicity of four human and nine avian H5N1/04 influenza viruses in ferrets (an excellent model for influenza studies). All four human isolates were fatal to intranasally inoculated ferrets. The human isolate A/Vietnam/1203/04 (H5N1) was the most pathogenic isolate; the severity of disease was associated with a broad tissue tropism and high virus titers in multiple organs, including the brain. High fever, weight loss, anorexia, extreme lethargy, and diarrhea were observed. Two avian H5N1/04 isolates were as pathogenic as the human viruses, causing lethal systemic infections in ferrets. Seven of nine H5N1/04 viruses isolated from avian species caused mild infections, with virus replication restricted to the upper respiratory tract. All chicken isolates were nonlethal to ferrets. A sequence analysis revealed polybasic amino acids in the hemagglutinin connecting peptides of all H5N1/04 viruses, indicating that multiple molecular differences in other genes are important for a high level of virulence. Interestingly, the human A/Vietnam/1203/04 isolate had a lysine substitution at position 627 of PB2 and had one to eight amino acid changes in all gene products except that of the M1 gene, unlike the A/chicken/Vietnam/C58/04 and A/quail/Vietnam/36/04 viruses. Our results indicate that viruses that are lethal to mammals are circulating among birds in Asia and suggest that pathogenicity in ferrets, and perhaps humans, reflects a complex combination of different residues rather than a single amino acid difference.
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794, USA.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Govorkova
authors.forename: Jerold E
authors.initials: JE
authors.lastname: Rehg
authors.forename: Scott
authors.initials: S
authors.lastname: Krauss
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Yen
authors.forename: Yi
authors.initials: Y
authors.lastname: Guan
authors.forename: Malik
authors.initials: M
authors.lastname: Peiris
authors.forename: Tien D
authors.initials: TD
authors.lastname: Nguyen
authors.forename: Thi H
authors.initials: TH
authors.lastname: Hanh
authors.forename: Pilipan
authors.initials: P
authors.lastname: Puthavathana
authors.forename: Hoang T
authors.initials: HT
authors.lastname: Long
authors.forename: Chantanee
authors.initials: C
authors.lastname: Buranathai
authors.forename: Wilina
authors.initials: W
authors.lastname: Lim
authors.forename: Robert G
authors.initials: RG
authors.lastname: Webster
authors.forename: Erich
authors.initials: E
authors.lastname: Hoffmann
mesh_terms: D000818:Animals; D002645:Chickens; D005289:Ferrets; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry* / Q000235:genetics*; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype; D009980:Influenza A virus / Q000145:classification / Q000302:isolation & purification / Q000472:pathogenicity*; D007251:Influenza, Human / Q000401:mortality* / Q000473:pathology / Q000821:virology; D009975:Orthomyxoviridae / Q000472:pathogenicity*; D011201:Poultry Diseases / Q000453:epidemiology / Q000473:pathology / Q000821:virology*
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus