Polymerase trapping as the mechanism of H5 highly pathogenic avian influenza virus genesis
Authors:
- Mathis FunkMathis Funk
- Monique I. SpronkenMSMonique I. Spronken
- Benoit ArragainBenoit Arragain
- Pauline JuyouxPJPauline Juyoux
- Anja C. M. de BruinAnja C. M. de Bruin
- Ron A. M. FouchierRon A. M. Fouchier
- Stephen CusackStephen Cusack
- Aartjan J. W. Te VelthuisAartjan J. W. Te Velthuis
- Mathilde RichardMathilde Richard
- 12 March 2026
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 391 (6790) , eadr6632
Abstract
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 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 an RNA structure–driven diversity-generating mechanism, which could also occur in other RNA viruses.Keywords
Funding Information
- Horizon 2020 Framework Programme (727922)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (OCENW.XS22.1.121)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (OCENW.M.21.150)
- ZonMw (04510012010056)
- National Institutes of Health National Institute of Allergy and Infectious Diseases AJWtV (DP2 AI75474)
- National Institutes of Health/National Institute of Allergy and Infectious Diseases (HHSN272201400008C)
- National Institutes of Health/National Institute of Allergy and Infectious Diseases (75N93021C00014)
- National Institutes of Health/National Institute of Allergy and Infectious Diseases (1R01AI177487)
- EMBL Grenoble
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