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Identification of a six adenine stretch in the hemagglutinin of H5 subtype avian influenza viruses as the critical determinant of the acquisition of a furin-cleavage site
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International audience. Influenza viruses are a major problem for animal and human health because of their high variability, their potential to evolve into highly pathogenic forms and their zoonotic nature. Some subtypes have a greater potential to evolve into highly pathogenic avian influenza viruses (HPAIV), such as the low pathogenic avian influenza viruses (LPAIV) of subtype H5. This evolution is characterized by the acquisition of a multi-basic cleavage site (MBCS) in hemagglutinin (HA). The genetic mechanism leading to the appearance of this multibasic site is poorly characterized. We wondered whether all H5 subtype LPAIV have the same evolutionary potential. Are there specific characteristics of the HA genomic segment that could influence evolution towards HPAIV? To address this question, we developed a reverse genetics system that generates influenza viruses containing complete HA sequences as a transgene at the end of the PA coding segment. In this model, the HA transgene cannot be translated into protein, so that no selection pressure is exerted on protein function. The accumulation of mutations can therefore be studied as a function of the template nucleotide sequence alone. We successfully rescued and characterized infectious viruses containing the HA transgene. We tested how different nucleotide environments could influence viral polymerase errors using this system and deep sequencing. We identified a minimal nucleotide motif consisting of a stretch of six consecutive adenines that could favor nucleotide insertion events, a critical step in MBCS acquisition and HPAIV emergence. These findings provide novel insights into the mechanisms involved in the LPAIV to HPAIV switch.
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