Mechanism-based prediction of insertion-driven high pathogenicity avian influenza virus emergence
Year: 2026
Type: preprint
Abstract: High pathogenicity avian influenza viruses (HPAIVs) emerge from H5 and H7 low-pathogenicity avian influenza virus progenitors through mutations that introduce a multibasic cleavage site in haemagglutinin. Although nucleotide insertions recurrently generate this motif, the molecular determinants of insertion and whether particular HA sequences are genetically predisposed to evolve toward HPAIV remain unknown. Combining experimental virology and thermodynamic modelling, we show that insertions arise through polymerase slippage controlled by local product–template duplex thermodynamics within the viral polymerase catalytic site. Predicted RNA secondary structures outside the polymerase are not required for high-frequency insertions and only modestly modulate insertion rates. We formalize this mechanism in HPAIVpredict, which predicts insertion profiles, recapitulates intermediates associated with documented HPAIV emergence events and identifies H5 and H7 sequence backgrounds predisposed to acquire functional multibasic cleavage sites.
Institutions: École Nationale Vétérinaire de Toulouse, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Interactions hôtes-agents pathogènes, Université de Toulouse, Mathématiques et Informatique Appliquées Toulouse, Genotoul coordination, Centre National de la Recherche Scientifique, Architecture et Réactivité de l'arN, Institut de Biologie Moléculaire et Cellulaire, Université de Strasbourg
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7204918125