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bioRxiv · 10.1101/2024.06.18.599480

Increase of permissive secondary antiviral mutations in the evolution of A(H1N1)pdm09 influenza virus neuraminidases

Duwe, S. C.·Milde, J.·Heider, A.·Wedde, M.·Schweiger, B.·Duerrwald, R.
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Abstract

BackgroundThe unexpected emergence of oseltamivir-resistant A(H1N1) viruses in 2008 was facilitated in part by the establishment of permissive secondary neuraminidase (NA) substitutions that compensated for the fitness loss due to the NA-H275Y resistance substitution. These viruses were replaced in 2009 by oseltamivir-susceptible A(H1N1)pdm09 influenza viruses. MethodsGenetic analysis and screening A(H1N1)pdm09 viruses circulating in Germany between 2009 and 2024 were conducted to identify any potentially permissive or resistance-associated NA substitutions. Selected viruses were then subjected to further characterization in vitro. ResultsIn the NA gene of circulating A(H1N1)pdm09 viruses, two secondary permissive substitutions, NA-V241I and NA-N369K, were identified. These substitutions demonstrated a stable lineage in phylogenetic analysis since the 2010-2011 influenza season. The data indicates a slight increase in viral NA bearing two additional potentially permissive substitutions, NA-I223V and NA-S247N, in the 2023-2024 season, that both result in a slight reduction in susceptibility to NA inhibitors. ConclusionsThe accumulation of secondary permissive substitutions in the NA of A(H1N1)pdm09 viruses increases the probability of the emergence of antiviral-resistant viruses. Therefore, it is crucial to closely monitor the evolution of circulating influenza viruses and to develop additional antiviral drugs against different target proteins.

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Duwe, S. C., Milde, J., Heider, A., Wedde, M., Schweiger, B., Duerrwald, R.. 2024-06-18. Increase of permissive secondary antiviral mutations in the evolution of A(H1N1)pdm09 influenza virus neuraminidases. https://doi.org/10.1101/2024.06.18.599480

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