Mechanism-based prediction of insertion-driven high pathogenicity avian influenza virus emergence

High pathogenicity avian influenza viruses (HPAIVs) emerge from low-pathogenicity H5 and H7 progenitors through mutations that introduce a multibasic cleavage site in the haemagglutinin. Researchers have discovered that RNA insertions leading to this motif frequently occur due to polymerase slippage, a process governed by the thermodynamics of the product-template duplex within the viral polymerase catalytic site.

These insertions do not rely on secondary structures outside the polymerase, and only slightly affect the frequency of insertions. To model this mechanism, scientists have developed HPAIVpredict, a tool that forecasts insertion profiles, reproduces intermediates linked to documented HPAIV emergence events, and identifies H5 and H7 sequence backgrounds that are more likely to develop functional multibasic cleavage sites.