TY - JOUR
T1 - The HA and NS genes of human H5N1 influenza a virus contribute to high virulence in ferrets
AU - Imai, Hirotaka
AU - Shinya, Kyoko
AU - Takano, Ryo
AU - Kiso, Maki
AU - Muramoto, Yukiko
AU - Sakabe, Saori
AU - Murakami, Shin
AU - Ito, Mutsumi
AU - Yamada, Shinya
AU - thi Quynh Le, Mai
AU - Nidom, Chairul A.
AU - Sakai-Tagawa, Yuko
AU - Takahashi, Kei
AU - Omori, Yasuyuki
AU - Noda, Takeshi
AU - Shimojima, Masayuki
AU - Kakugawa, Satoshi
AU - Goto, Hideo
AU - Iwatsuki-Horimoto, Kiyoko
AU - Horimoto, Taisuke
AU - Kawaoka, Yoshihiro
N1 - Funding Information:
Our research protocol for the use of ferrets followed the University of Tokyo's Regulations for Animal Care and Use, which was approved by the Animal Experiment Committee of the Institute of Medical Science, the University of Tokyo (approval number: 19–29). The committee acknowledged and accepted both the legal and ethical responsibility for the animals, as specified in the Fundamental Guidelines for Proper Conduct of Animal Experiment and Related Activities in Academic Research Institutions under the jurisdiction of the Ministry of Education, Culture, Sports, Science and Technology, 2006.
PY - 2010/9
Y1 - 2010/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=78149286567&partnerID=8YFLogxK
U2 - 10.1371/journal.ppat.1001106
DO - 10.1371/journal.ppat.1001106
M3 - Article
C2 - 20862325
AN - SCOPUS:78149286567
SN - 1553-7366
VL - 6
JO - PLoS Pathogens
JF - PLoS Pathogens
IS - 9
M1 - e01106
ER -