Abstract
Neuraminidase inhibitors are the only licensed antiviral medications available to treat avian influenza A(H7N9) virus infections in humans. According to a neuraminidase inhibition assay, an R292K substitution reduced antiviral efficacy of inhibitors, especially oseltamivir, and decreased viral fitness in cell culture. Monitoring emergence of R292K-carrying viruses using a pH-modified neuraminidase inhibition assay should be considered.
Highlights
As with any emergent influenza virus, it is critical to assess the susceptibility of the influenza A(H7N9) outbreak virus to antiviral drugs, which are the first line of defense before an effective vaccine becomes available
When tested in the NA inhibition (NI) assay [6], the virus yielded subnanomolar IC50s with all 4 NAIs, similar to results for the drug-sensitive seasonal influenza A viruses used as controls (Table 1)
The inability to detect changes in oseltamivir IC50 despite the presence of R292K raised 2 questions: are conventional NI assays sufficiently sensitive to detect oseltamivir resistance caused by R292K, and is R292K truly a marker of oseltamivir resistance when it is present in these A(H7N9) outbreak viruses? We hypothesized that failure to detect the oseltamivir-resistant population by using the NI assay may stem from substantially reduced activity of the R292K variant NA
Summary
As with any emergent influenza virus, it is critical to assess the susceptibility of the influenza A(H7N9) outbreak virus to antiviral drugs, which are the first line of defense before an effective vaccine becomes available. Among the 4 NAIs, oseltamivir and zanamivir are approved in many countries; peramivir has been approved in Japan, South Korea, and China; and laninamivir is approved only in Japan In contrast to those for adamantanes, genetic markers of resistance to NAIs are often subtype specific and drug specific [5]. When tested in the NA inhibition (NI) assay [6], the virus yielded subnanomolar IC50s (concentration of neuraminidase inhibitor required to reduce enzyme activity by 50%) with all 4 NAIs, similar to results for the drug-sensitive seasonal influenza A viruses used as controls (Table 1). To clarify the effect of R292K on NAI susceptibility of influenza A(H7N9) viruses, the A/Shanghai/1/2013 egg-grown isolate (E1) was received and tested at the US Centers for Disease Control and Prevention by using the NI assay [6]. Pac bio RS sequencing library was constructed by using a 701-bp RT-PCR amplicon generated by RT-PCR
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