biostudies-literatureGraham RLNIAID NIH HHS1820-6https://www.ebi.ac.uk/biostudies/studies/S-EPMC3518599biostudies-literatureUnknown18(12)Live, attenuated RNA virus vaccines are efficacious but subject to reversion to virulence. Among RNA viruses, replication fidelity is recognized as a key determinant of virulence and escape from antiviral therapy; increased fidelity is attenuating for some viruses. Coronavirus (CoV) replication fidelity is approximately 20-fold greater than that of other RNA viruses and is mediated by a 3'→5' exonuclease (ExoN) activity that probably functions in RNA proofreading. In this study we demonstrate that engineered inactivation of severe acute respiratory syndrome (SARS)-CoV ExoN activity results in a stable mutator phenotype with profoundly decreased fidelity in vivo and attenuation of pathogenesis in young, aged and immunocompromised mice. The ExoN inactivation genotype and mutator phenotype are stable and do not revert to virulence, even after serial passage or long-term persistent infection in vivo. ExoN inactivation has potential for broad applications in the stable attenuation of CoVs and, perhaps, other RNA viruses.Nature medicineA live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease.PMC3518599F32 AI080148AI0752975F32AI080148U54-AI057157R01 AI075297HHSN272200900007CU54 AI057157Graham RLDenison MRBaric RSBecker MMBolles MEckerle LDfalseA live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease.Live, attenuated RNA virus vaccines are efficacious but subject to reversion to virulence. Among RNA viruses, replication fidelity is recognized as a key determinant of virulence and escape from antiviral therapy; increased fidelity is attenuating for some viruses. Coronavirus (CoV) replication fidelity is approximately 20-fold greater than that of other RNA viruses and is mediated by a 3'→5' exonuclease (ExoN) activity that probably functions in RNA proofreading. In this study we demonstrate that engineered inactivation of severe acute respiratory syndrome (SARS)-CoV ExoN activity results in a stable mutator phenotype with profoundly decreased fidelity in vivo and attenuation of pathogenesis in young, aged and immunocompromised mice. The ExoN inactivation genotype and mutator phenotype are stable and do not revert to virulence, even after serial passage or long-term persistent infection in vivo. ExoN inactivation has potential for broad applications in the stable attenuation of CoVs and, perhaps, other RNA viruses.2012-01-01T00:00:00Z2012 Dec2025-04-04T11:02:37.753Z2019-03-27T01:01:39ZS-EPMC35185992314282110.1038/nm.2972