Identification, functional analysis, and clinical applications of defective viral genomes

Abstract

Defective viral genomes (DVGs) are fragments derived from defective interfering particles (DIPs) that form during viral replication. They play important roles by interfering with complete virus replication and regulating host immune responses. Advances in high-throughput sequencing (HTS) and bioinformatic technology have significantly improved the ability to identify DIPs and DVGs. Their heterogeneity and dynamic formation mechanisms have been analyzed using long-read sequencing technologies. Both DIPs and DVGs inhibit wild-type viral proliferation by competing for viral replication resources and activating innate immune pathways such as those of retinoic acid-inducible gene 1 and mitochondrial antiviral signaling protein. This might influence infection outcomes by regulating inflammatory cytokine storms. The clinical application of DIPs and DVGs in their natural attenuated virus forms has been investigated in terms of novel vaccine design and antiviral therapy. This report systematically reviews cutting-edge detection techniques, molecular mechanisms, and translational medicine advances of DIPs and DVGs and provides a theoretical basis for developing broad-spectrum antiviral strategies based on DIPs.

Keywords: application; defective viral genome; function; identification; interfering particle.

Figure 1

Scheme of standard viruses and DIPs cycling dynamics.

Figure 2

High concentrations of DVGs significantly enhance type I/III interferon signaling by detecting and activating RIG-I-like receptors and MAVS signaling pathways. DVGs-rich cells activate the cell survival pathway by up-regulating TNF/TNFR2/TRAF1, and combine with a small amount of standard viral genome to maintain a persistent infection state.

Figure 3

Schematic diagram of how DIPs activate host immune defense. DVGs are present in DIPs. Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA-5) recognize copyback DVGs and then trigger the creation of interferons (IFNs) and other cytokines, which supports the activation of the innate immune response. These factors contribute to the maturation of dendritic cells, thus contributing to the adaptive immune response. Subsequently, DVGs can enhance the recognition between naive T cells and mature dendritic cells, promoting the cell-mediated immune process mediated by type I IFN signaling. This, in turn, stimulates B cells to produce corresponding antibodies, thereby exerting the function of humoral immunity.