Influenza A virus polymerase co-opts distinct sets of host proteins for RNA transcription or replication

The influenza A virus polymerase, consisting of a heterotrimer of three viral proteins, carries out both transcription and replication of the viral RNA genome. These distinct activities are regulated by viral proteins and various co-opted host cell proteins, which serve as targets for the development of novel antiviral interventions. However, little is known about which host proteins direct transcription versus replication. In this report, we performed a differential interactome screen to identify host proteins co-opted downstream or upstream of primary transcription, some of which may be transcription- or replication-specific factors. We found that distinct sets of host proteins interact with the influenza polymerase as it carries out the different activities. We functionally characterized HMGB2 and RUVBL2 as replication cofactors and RPAP2 as a transcription cofactor. Our data demonstrate that comparative proteomics can be used as a targeted approach to uncover virus-host interactions that regulate specific stages of the viral life cycle.