A trapped polymerase hastens avian influenza virus evolution – Microbiology Research

Highly pathogenic avian influenza viruses emerge from H5 and H7 low-pathogenic variants following the acquisition of a multibasic cleavage site (MBCS) in the haemagglutinin protein, which enables cleavage by host proteases, leading to systemic viral spread and increased pathogenicity. However, the underlying molecular mechanisms of MBCS acquisition remained poorly understood. In this study, Funk and colleagues use a virus-free replication system, deep sequencing and structural analysis to reveal that MBCS acquisition in H5 haemagglutinin is the result of the combination of insertion-prone RNA sequences and the formation of transient RNA structures during replication by the viral RNA polymerase. Specifically, the authors showed that a transient RNA structure near the haemagglutinin cleavage site RNA sequence can be formed by base pairing between the entering and exiting template strands, temporarily trapping the viral polymerase and causing it to ‘stutter’ or ‘backtrack’ during replication. In addition, the authors showed that polymerase trapping at A/U-rich sequences, which are more insertion-prone, promotes duplication insertions and thus the acquisition of the MBCS. In sum, the authors provide a model for the emergence of H5 highly pathogenic avian influenza viruses from low-pathogenic strains and suggest that this RNA structure-driven mechanism could also occur in other RNA viruses.