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

• 成果类型: Article
• 署名作者: Funk, Mathis; Spronken, Monique I.; Hutchinson, Roy M.; Arragain, Benoit; Juyoux, Pauline; Bestebroer, Theo M.; De Bruin, Anja C. M.; Gultyaev, Alexander P.; Fouchier, Ron A. M.; Cusack, Stephen; Te Velthuis, Aartjan J. W.; Richard, Mathilde
• 署名单位: Erasmus University Rotterdam; Erasmus University Rotterdam - Excl Erasmus MC; Erasmus MC; Centre National de la Recherche Scientifique (CNRS); European Molecular Biology Laboratory (EMBL); Communaute Universite Grenoble Alpes; CEA; Universite Grenoble Alpes (UGA); Leiden University - Excl LUMC; Leiden University; Princeton University; Institute of Science & Technology - Austria; Medical University of Innsbruck
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adr6632
• 发表日期: 2026-03-12
• 页码: eadr6632
• 关键词: HEMAGGLUTININ CLEAVAGE SITE; a virus; RNA RECOMBINATION; VIRAL-RNA; cryo-em; insertion; Visualization; replication; generation; phenotype

摘要

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.