Role of Defective Interfering Particles in Complement-Mediated Lysis of Parainfluenza Virus-Infected Cells

RNA viruses pose a significant global public health burden due to their high mutation rates, zoonotic potential, and ability to evade immune responses. A common aspect of their replication is the generation of defective interfering particles (DIPs), which contain truncated defective viral genomes (DVGs) that depend on full-length standard (STD) virus for replication. DVGs have gained recognition as they are increasingly detected in clinical samples from natural infections. While their role in modulating type I interferon (IFN-I) responses is well established, their impact on the complement (C') system is not understood. In this study, we examined how DVGs influence C'-mediated lysis during parainfluenza virus 5 (PIV5) infection using real-time in vitro cell viability assays. Our results demonstrated that C' effectively killed human lung epithelial cells infected with STD PIV5, whereas co-infection with DIP-enriched stocks significantly suppressed C'-mediated killing through mechanisms that were dependent on DVG replication but independent of IFN-I production. The titration of DI units in co-infection with STD PIV5 showed a strong linear relationship between DIP-mediated decreases in surface viral glycoprotein expression and the inhibition of C'-mediated lysis. Our findings reveal a previously unrecognized function of DVGs in modulating C' pathways, shedding light on their potential role in viral persistence and immune evasion.