title: The HA and NS genes of human H5N1 influenza A virus contribute to high virulence in ferrets.
abstract: Highly pathogenic H5N1 influenza A viruses have spread across Asia, Europe, and Africa. More than 500 cases of H5N1 virus infection in humans, with a high lethality rate, have been reported. To understand the molecular basis for the high virulence of H5N1 viruses in mammals, we tested the virulence in ferrets of several H5N1 viruses isolated from humans and found A/Vietnam/UT3062/04 (UT3062) to be the most virulent and A/Vietnam/UT3028/03 (UT3028) to be avirulent in this animal model. We then generated a series of reassortant viruses between the two viruses and assessed their virulence in ferrets. All of the viruses that possessed both the UT3062 hemagglutinin (HA) and nonstructural protein (NS) genes were highly virulent. By contrast, all those possessing the UT3028 HA or NS genes were attenuated in ferrets. These results demonstrate that the HA and NS genes are responsible for the difference in virulence in ferrets between the two viruses. Amino acid differences were identified at position 134 of HA, at positions 200 and 205 of NS1, and at positions 47 and 51 of NS2. We found that the residue at position 134 of HA alters the receptor-binding property of the virus, as measured by viral elution from erythrocytes. Further, both of the residues at positions 200 and 205 of NS1 contributed to enhanced type I interferon (IFN) antagonistic activity. These findings further our understanding of the determinants of pathogenicity of H5N1 viruses in mammals.
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Imai
authors.forename: Kyoko
authors.initials: K
authors.lastname: Shinya
authors.forename: Ryo
authors.initials: R
authors.lastname: Takano
authors.forename: Maki
authors.initials: M
authors.lastname: Kiso
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Muramoto
authors.forename: Saori
authors.initials: S
authors.lastname: Sakabe
authors.forename: Shin
authors.initials: S
authors.lastname: Murakami
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Ito
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamada
authors.forename: Mai Thi Quynh
authors.initials: MT
authors.lastname: Le
authors.forename: Chairul A
authors.initials: CA
authors.lastname: Nidom
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sakai-Tagawa
authors.forename: Kei
authors.initials: K
authors.lastname: Takahashi
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Omori
authors.forename: Takeshi
authors.initials: T
authors.lastname: Noda
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shimojima
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kakugawa
authors.forename: Hideo
authors.initials: H
authors.lastname: Goto
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Iwatsuki-Horimoto
authors.forename: Taisuke
authors.initials: T
authors.lastname: Horimoto
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004285:Dogs; D005289:Ferrets; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000302:isolation & purification / Q000472:pathogenicity*; D007251:Influenza, Human / Q000235:genetics / Q000473:pathology / Q000821:virology*; D007372:Interferons / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000378:metabolism / Q000821:virology; D008168:Lung / Q000166:cytology / Q000378:metabolism / Q000821:virology; D008297:Male; D008907:Mink; D009154:Mutation / Q000235:genetics; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000473:pathology / Q000821:virology*; D017361:Viral Nonstructural Proteins / Q000235:genetics* / Q000378:metabolism; D014774:Virulence / Q000502:physiology*
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; C085820:INS1 protein, influenza virus; D017361:Viral Nonstructural Proteins; D007372:Interferons