Regulation of the influenza A virus polymerase activity by the viral nuclear export protein (NEP)

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Influenza A viruses cause respiratory febrile illnesses in humans, resulting in significant morbidity and mortality in the population. Although the polymerase complex of these viruses generates all viral RNA species, we and others could provide evidence that NEP is required for efficient viral polymerase activity by stimulating vRNA and cRNA synthesis, suggesting that this protein acts as a co-factor supporting viral replication. We could further show that a single adaptive mutation in the NEP of a human H5N1 isolate increased the replication efficiency of the viral polymerase and the pathogenicity of this isolate in mice. Furthermore, we obtained preliminary evidence that NEP dimer formation is required for the polymerase co-factor activity of this protein. Using recombinant protein expression, biochemical characterization, reverse genetic approaches and in-vitro transcription/replication assays, we want to gain insights into the mechanisms by which NEP increases the activity of the viral polymerase and prove our hypothesis that NEP is a component of a viral „replicase“ complex. This project will not only provide new insights into the function of NEP in viral replication but also provide the basis for future antiviral interventions.