Evolution of Oseltamivir Resistance Mutations in Influenza A(H1N1) and A(H3N2) Viruses during Selection in Experimentally Infected Mice

摘要: The evolution of oseltamivir resistance mutations during selection through serial passages in animals is still poorly described. Herein, we assessed the neuraminidase (NA) and hemagglutinin (HA) genes influenza A/WSN/33 (H1N1) A/Victoria/3/75 (H3N2) viruses recovered from lungs experimentally infected BALB/c mice receiving suboptimal doses (0.05 1 mg/kg body weight/day) over two generations. traditional phenotypic genotypic methods as well deep-sequencing analysis were used to characterize potential population dynamics oseltamivir-resistant variants. No NA or HA changes detected viruses. However, observed a positive I222T substitution viruses, with frequency increasing time an concentration 4% initial pretherapy inoculum up 28% after lung passages. Although presence mixed viral populations mouse only led minimal increase 50% enzyme-inhibitory concentrations (IC50s) (by mean 5.7-fold) compared that baseline virus, expressed recombinant protein displayed 16-fold IC50 level wild type (WT). In conclusion, combination vivo under inhibitor (NAI) pressure temporal enabled, for first time, identification mutation H3N2 virus. Additional experiments other antivirals drug combinations might provide important information on antiviral