Influenza Virus Exploits an Interferon-Independent lncRNA to Preserve Viral RNA Synthesis through Stabilizing Viral RNA Polymerase PB1

Summary Long noncoding RNAs (lncRNAs) participate in host antiviral defense by modulating immune responses. However, it remains largely unexplored how viruses exploit interferon (IFN)-independent host lncRNAs to facilitate viral replication. Here, we have identified a group of human lncRNAs that modulate influenza A virus (IAV) replication in a loss-of-function screen and found that an IFN-independent lncRNA, called IPAN, is hijacked by IAV to assist IAV replication. IPAN is specifically induced by IAV infection independently of IFN and associates with and stabilizes viral RNA-dependent RNA polymerase PB1, enabling efficient viral RNA synthesis. Silencing IPAN results in PB1 degradation and severely impairs viral infection. Therefore, our data unveil an important role of host lncRNAs in promoting viral replication by modulating viral protein stability. Our findings may open avenues to the development of antiviral therapeutics.