Focusing on the generation and function of SARS-CoV-2 DVGs, these studies identify new hotspots for non-homologous recombination and strongly suggest that the secondary structures within viral genomes mediate the recombination. SARS-CoV-2 DVGs are generated through the recombination of two discontinuous genomic fragments by viral polymerase complex and the recombination is also one of the major mechanisms for the emergence of new coronaviruses. Their interference activity to full-length viruses and IFN stimulation provide them the potential for novel antiviral therapies and vaccine development. Importance Defective viral genomes (DVGs) are ubiquitously generated in many RNA viruses, including SARS-CoV-2. Together, our findings strongly suggest a critical role of DVGs in modulating host IFN responses and symptom development, calling for further inquiry into the mechanisms of DVG generation and how DVGs modulate host responses and infection outcome during SARS-CoV-2 infection. Finally, we observed unusually high DVG frequency in one immunosuppressive patient up to 140 days after admitted to hospital due to COVID-19, first-time suggesting an association between DVGs and persistent viral infections in SARS-CoV-2. We further applied our criteria to the NGS dataset from a published cohort study and observed significantly higher DVG amount and frequency in symptomatic patients than that in asymptomatic patients. Functionally, bulk and single cell RNA-seq analysis indicated the IFN stimulation of SARS-CoV-2 DVGs. Four genomic hotspots were identified for DVG recombination and RNA secondary structures were suggested to mediate DVG formation. We observed DVGs ubiquitously from RNA-seq datasets of in vitro infections and autopsy lung tissues of COVID-19 patients. In this study, we elucidated DVG generation in SARS-CoV-2 and its relationship with host antiviral immune response. However, the generation and function of DVGs in SARS-CoV-2 infection are less known. Defective viral genomes (DVGs) have been identified in many RNA viruses as a major factor influencing antiviral immune response and viral pathogenesis.
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June 2023
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