Turning defects into defenses: the potential and challenges of defective viral genome-based antiviral strategies

SUMMARYViral defective interfering particles (DIPs) are produced during replication by many RNA viruses, acting as non-infectious particles containing defective viral genomes (DVGs). DVGs are most clearly defined and mechanistically understood in positive- and negative-strand RNA viruses, and this review focuses on these RNA viruses in which DVGs and DIPs are best characterized. DVGs function as molecular parasites that rely on co-infection with a standard virus to obtain essential viral proteins needed for their replication. This parasitic relationship interferes with wild-type virus replication, making DIPs attractive antiviral candidates because they resist viral escape through mutation. Beyond replication interference, DVGs have emerged as potent stimulators of innate immunity, capable of inhibiting diverse, unrelated viruses by triggering robust antiviral responses. These dual mechanisms, direct interference and immune activation, highlight the value of DIPs/DVGs as a versatile antiviral strategy. Advances in understanding DIP/DVG formation, immune modulation, and therapeutic engineering underscore their promise for broad-spectrum antiviral applications. This review explores recent breakthroughs and addresses the critical remaining challenges for DIPs/DVGs to progress from promising preclinical agents to effective clinical antivirals.