Seasonal influenza epidemics affect three to five million people annually and can cause up to 500 000 deaths globally. In addition, recurrent pandemics can lead to the emergence of novel viruses to which the population has no pre-existing immunity. Existing vaccines are rendered inadequate and a new vaccine against the novel viral strain would require months to produce. Furthermore, the number of available antivirals to treat influenza virus infections is limited and the development of resistance against these is an increasing problem. Interfering with the viral RNA polymerase has emerged as a promising approach for blocking viral transcription and replication. Accumulating evidence indicates that it interacts with cellular RNA polymerase II (Pol II), but many aspects of this interaction remain unclear and its biological role is not known. The primary objective of the EU-funded FLU-POLII (Association between influenza virus RNA polymerase and the transcriptional machinery of the host cell) project was to understand how interactions of the influenza virus polymerase with cellular factors regulate its function at the molecular level. For this purpose, they developed an in vitro assay for the binding of the viral RNA polymerase to the host Poll II. Results showed that fully assembled viral ribonucleoproteins, responsible for viral transcription, bound directly to the C terminal domain of Pol II. This binding was mediated by the viral polymerase and was conserved among evolutionarily distant influenza A and C viruses. This observation underscored the importance of this interaction for influenza biology. Future mapping of the binding domain of the viral polymerase to Pol II is expected to unveil targets for the development of novel antivirals. Furthermore, scientists performed genome-wide analysis to show the global effects of influenza infection on cellular transcription. Specific genes were identified, which shed light on gene expression regulation upon influenza virus infection. Given that current measures to combat influenza are limited, the findings of the FLU-POLII study have profound socioeconomic consequences. Viral RNA polymerase constitutes a ubiquitous target for antivirals that could complement existing antivirals against which resistance is emerging.
Influenza virus, antivirals RNA polymerase II, FLU-POLII, genome