Bioinformatic analysis and modeling of Influenza A H5/H7 Polymerase errors to predict high risk forms.

Résumé: Avian Influenza viruses AIV can be distinguished in two groups, Low Pathogenic Avian Influenza Viruses LPAV, and High Pathogenic Avian Influenza Viruses (HPAIV). While LPAIV cause only mild symptoms and a low lethality in poultry, HPAIV causes a systemic infection with high lethality rates and an extended tropism.

LPAIV can switch into HPAV by an insertion of several basic amino acids in the cleavage site of the Hemagglutinin protein HA, the presence of these novel amino acids creates a Multibasic Clevage Site MBCS that changes the tropism of the virus and allows systemic dissemination. Although this transition has been documented several times, the exact molecular mechanism behind remains unclear, being traceable to small duplication events (indels), substitutions and recombination events.

Our team centered in transitions linked to indel events, we found that some viral sequences are prone to having INDEL hotspots when modified with single nucleotide mutations, and that these hotspots are driven by the combination of adenine stretches and a neighboring sequence that induce polymerase errors.

Using these observations, we were able to create an algorithm capable of estimating the polymerase INDEL error potential of a complete HA sequence position by position, identify the insertion hotspots and, predict the frequency and identity of potential insertions. We expect to improve this algorithm to evaluate the potential of H5/H7 HA variants of acquiring a polybasic cleavage site via insertion accumulation and improve risk assessment of circulating avian influenza viruses.

KEYWORDS: HPAIV, LPAIV, MBCS, insertions, polymerase.