Increased virulence of neuraminidase inhibitor-resistant pandemic H1N1 virus in mice: potential emergence of drug-resistant and virulent variants.
Pandemic H1N1 2009 (A[H1N1]pdm09) variants associated with oseltamivir resistance have emerged with a histidine-to-tyrosine substitution in the neuraminidase(NA) at position 274 (H274Y). To determine whether the H274Y variant has increased virulence potential, A(H1N1)pdm09 virus, with or without the H274Y mutation, was adapted by serial lung-to-lung passages in mice. The mouse-adapted H274Y (maCA04H274Y) variants showed increased growth properties and virulence in vitro and in vivo while maintaining high NA inhibitor resistance. Interestingly, most maCA04H274Y and maCA04 viruses acquired common mutations in HA (S183P and D222G) and NP (D101G), while only maCA04H274Y viruses had consensus additional K153E mutation in the HA gene, suggesting a potential association with the H274Y substitution. Collectively, our findings highlight the potential emergence of A(H1N1)pdm09 drug-resistant variants with increased virulence and the need for rapid development of novel antiviral drugs.
Chungbuk National University, Cheongju, Republic of Korea.
Min-Suk
MS
Song
Yun
Y
Hee Baek
Eun-Ha
EH
Kim
Su-Jin
SJ
Park
Semi
S
Kim
Gyo-Jin
GJ
Lim
Hyeok-Il
HI
Kwon
Philippe Noriel Q
PN
Pascua
Arun G
AG
Decano
Byeong-Jae
BJ
Lee
Young-Il
YI
Kim
Richard J
RJ
Webby
Young-Ki
YK
Choi
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000472:pathogenicity*; D007251:Influenza, Human / Q000188:drug therapy / Q000453:epidemiology / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D020125:Mutation, Missense; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D053139:Oseltamivir / Q000627:therapeutic use; D058873:Pandemics; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D014774:Virulence / Q000187:drug effects
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D014764:Viral Proteins; D053139:Oseltamivir; C487630:NA protein, influenza A virus; D009439:Neuraminidase
drug resistance; mouse adaptation; neuraminidase; pandemic influenza; virulence