Characterization of Oseltamivir-Resistant 2009 H1N1 Pandemic Influenza A Viruses

PLoS Pathogens

Makoto Yamashita¹  Yoshihiro Kawaoka²  Hiroaki Katsura³  Ryo Takano³  Kei Takahashi³  Masayuki Shimojima³  Satoshi Kakugawa³  Maki Kiso³  Kyoko Shinya⁴  Makoto Ozawa⁵  Mai thi Quynh Le⁶  Yousuke Furuta⁷ 

[1] Daiichi Sankyo Co Ltd, Shinagawa, Tokyo, Japan;Department of Pathobiological Sciences, University of Wisconsin, Madison, Wisconsin, United States of America;Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan;Division of Zoonosis, Department of Microbiology and Infectious Diseases, Graduate School of Medicine, Kobe University, Hyogo, Japan;International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan;National Institute of Hygiene and Epidemiology, Hanoi, Vietnam;Toyama Chemical Co., Ltd., Toyama, Japan

关键词: Viral pathogens;    Ferrets;    H1N1;    Viral transmission;    infection;    Viral replication;    Influenza viruses;    Influenza A virus;    Influenza;   

DOI  :  10.1371/journal.ppat.1001079

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Influenza viruses resistant to antiviral drugs emerge frequently. Not surprisingly, the widespread treatment in many countries of patients infected with 2009 pandemic influenza A (H1N1) viruses with the neuraminidase (NA) inhibitors oseltamivir and zanamivir has led to the emergence of pandemic strains resistant to these drugs. Sporadic cases of pandemic influenza have been associated with mutant viruses possessing a histidine-to-tyrosine substitution at position 274 (H274Y) in the NA, a mutation known to be responsible for oseltamivir resistance. Here, we characterized in vitro and in vivo properties of two pairs of oseltaimivir-sensitive and -resistant (possessing the NA H274Y substitution) 2009 H1N1 pandemic viruses isolated in different parts of the world. An in vitro NA inhibition assay confirmed that the NA H274Y substitution confers oseltamivir resistance to 2009 H1N1 pandemic viruses. In mouse lungs, we found no significant difference in replication between oseltamivir-sensitive and -resistant viruses. In the lungs of mice treated with oseltamivir or even zanamivir, 2009 H1N1 pandemic viruses with the NA H274Y substitution replicated efficiently. Pathological analysis revealed that the pathogenicities of the oseltamivir-resistant viruses were comparable to those of their oseltamivir-sensitive counterparts in ferrets. Further, the oseltamivir-resistant viruses transmitted between ferrets as efficiently as their oseltamivir-sensitive counterparts. Collectively, these data indicate that oseltamivir-resistant 2009 H1N1 pandemic viruses with the NA H274Y substitution were comparable to their oseltamivir-sensitive counterparts in their pathogenicity and transmissibility in animal models. Our findings highlight the possibility that NA H274Y-possessing oseltamivir-resistant 2009 H1N1 pandemic viruses could supersede oseltamivir-sensitive viruses, as occurred with seasonal H1N1 viruses.

【 授权许可】

CC BY