Polymerase trapping as mechanism of H5 highly pathogenic avian influenza virus genesis

Highly pathogenic avian influenza viruses (HPAIVs) derive from H5 and H7 low pathogenic avian influenza viruses (LPAIVs). Although insertion of a furin-cleavable multibasic cleavage site (MBCS) in the hemagglutinin gene was identified decades ago as the genetic basis for the LPAIV-to-HPAIV transition, the mechanisms underlying the occurrence of insertion are unknown. Here, we show that transient H5 RNA structures predicted to trap the influenza virus polymerase on purine-rich sequences drive nucleotide insertions, providing the first strong empirical evidence of RNA structure involvement in MBCS acquisition. Introduction of H5-like sequences and structures into an H6 hemagglutinin resulted in MBCS-yielding insertions. Our results show that nucleotide insertions that underlie H5 HPAIV emergence result from a previously unknown RNA-structure-driven diversity-generating mechanism, which could be shared with other RNA viruses.
, , , # Polymerase trapping as mechanism of H5 highly pathogenic avian influenza virus genesis

Authors: Mathis Funk, Monique I. Spronken, Roy M. Hutchinson, Benoit Arragain, Pauline Juyoux, Theo M. Bestebroer, Anja C.M. de Bruin, Alexander P. Gultyaev, Ron A.M. Fouchier, Stephen Cusack, Aartjan J.W. te Velthuis, Mathilde Richard

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#### Context of the study

Highly pathogenic avian influenza viruses (HPAIVs) cause severe disease and high fatality in poultry. HPAIVs spontaneously emerge from low pathogenic avian influenza viruses (LPAIV). Although insertion of a furin-cleavable multibasic cleavage site in the hemagglutinin (HA) gene was identified decades ago as the genetic basis for LPAIV-to-HPAIV transition, the exact mechanisms underlying said insertion have remained unknown.

We have suggested previously that these insertions are driven by transient RNA template structures forming around the influenza polymeras...,