Defective Interfering Genomes and the Full-Length Viral Genome Trigger RIG-I After Infection With Vesicular Stomatitis Virus in a Replication Dependent Manner
Andreas Linder, Viktoria Bothe, Nicolas Linder, Paul Schwarzlmueller, Frank Dahlström, Christoph Bartenhagen, Martin Dugas, Dharmendra Pandey, Julia Thorn‐Seshold, Daniel F. R. Boehmer, Lars M. Koenig, Sebastian Kobold, Max Schnurr, Johannes Raedler, Giulia Spielmann, Hadi Karimzadeh, Andreas Schmidt, Stefan Endres, Simon Rothenfußer
Abstract
Replication competent vesicular stomatitis virus (VSV) is the basis of a vaccine against Ebola and VSV strains are developed as oncolytic viruses. Both functions depend on the ability of VSV to induce adequate amounts of interferon-α/β. It is therefore important to understand how VSV triggers interferon responses. VSV activates innate immunity via retinoic acid-inducible gene I (RIG-I), a sensor for viral RNA. Our results show that VSV needs to replicate for a robust interferon response. Analysis of RIG-I-associated RNA identified a copy-back defective-interfering (DI) genome and full-length viral genomes as main trigger of RIG-I. VSV stocks depleted of DI genomes lost most of their interferon-stimulating activity. The remaining full-length genome and leader-N-read-through sequences, however, still triggered RIG-I. Awareness for DI genomes as trigger of innate immune responses will help to standardize DI genome content and to purposefully deplete or use DI genomes as natural adjuvants in VSV-based therapeutics.