Mechanism-based prediction of insertion-driven high pathogenicity avian influenza virus emergence
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.
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BibTeX
@misc{dupre2026mechanismbased,
title = {{Mechanism-based prediction of insertion-driven high pathogenicity avian influenza virus emergence}},
author = {Gabriel Dupré and Bertille Pouget and Aldair Martinez-Pineda and Charlotte Foret-Lucas and Pierre Bessière and Delphine Chrétien and Mariette Ducatez and Nathalie Vialaneix and Claire Hoede and Roland Marquet and Christine Gaspin and Romain Volmer},
howpublished = {HAL},
year = {2026},
month = aug,
doi = {10.64898/2026.08.27.747464},
url = {https://hal.science/hal-05799116v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Mechanism-based prediction of insertion-driven high pathogenicity avian influenza virus emergence
AU - Gabriel Dupré
AU - Bertille Pouget
AU - Aldair Martinez-Pineda
AU - Charlotte Foret-Lucas
AU - Pierre Bessière
AU - Delphine Chrétien
AU - Mariette Ducatez
AU - Nathalie Vialaneix
AU - Claire Hoede
AU - Roland Marquet
AU - Christine Gaspin
AU - Romain Volmer
PY - 2026
DA - 2026/08/27
PB - HAL
DO - 10.64898/2026.08.27.747464
UR - https://hal.science/hal-05799116v1
AB - 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.
ER -