1. Substitution of I222L-E119V in neuraminidase from highly pathogenic avian influenza H7N9 virus exhibited synergistic resistance effect to oseltamivir in mice.
- Author
-
Tang J, Gao R, Liu L, Zhang S, Liu J, Li X, Fang Q, Feng Z, Xu C, Huang W, and Wang D
- Subjects
- Amino Acid Substitution drug effects, Animals, Antiviral Agents pharmacology, Birds virology, Cell Line, Dogs, Enzyme Inhibitors pharmacology, Female, HEK293 Cells, Humans, Influenza in Birds drug therapy, Influenza in Birds virology, Influenza, Human drug therapy, Influenza, Human virology, Madin Darby Canine Kidney Cells, Mice, Mice, Inbred C57BL, Mutation genetics, Orthomyxoviridae Infections drug therapy, Orthomyxoviridae Infections virology, Viral Proteins genetics, Virus Replication drug effects, Virus Replication genetics, Amino Acid Substitution genetics, Drug Resistance, Viral genetics, Influenza A Virus, H7N9 Subtype drug effects, Influenza A Virus, H7N9 Subtype genetics, Neuraminidase genetics, Oseltamivir pharmacology
- Abstract
That the high frequency and good replication capacity of strains with reduced susceptibility to neuraminidase inhibitors (NAIs) in highly pathogenic avian influenza H7N9 (HPAI H7N9) virus made it a significance to further study its drug resistance. HPAI H7N9 viruses bearing NA I222L or E119V substitution and two mutations of I222L-E119V as well as their NAIs-sensitive counterpart were generated by reverse genetics for NA inhibition test and replication capability evaluation in vitro. The attenuated H7N9/PR8 recombinant viruses were developed to study the pathogenicity and drug resistance brought by the above substitutions to mice. The IC
50 fold change of oseltamivir to HPAI H7N9 with NA222L-119V is 306.34 times than that of its susceptible strain, and 3.5 times than the E119V mutant virus. HPAI H7N9 bearing NA222L-119V had good replication ability with peak value of more than 6log10 TCID50 /ml in MDCK cells. H7N9/PR8 virus bearing NA222L-119V substitutions leaded to diffuse pneumonia, significant weight loss and fatality in mice. NA E119V made H7N9/PR8 virus resistant to oseltamivir, and I222L-E119V had synergistic resistance to oseltamivir in mice. Due to the good fitness of drug resistant strains of HPAI H7N9 virus, it is necessary to strengthen drug resistance surveillance and new drug research., (© 2021. The Author(s).)- Published
- 2021
- Full Text
- View/download PDF