A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease
| Autor: | Meagan Bolles, Michelle M. Becker, Lance D. Eckerle, Mark R. Denison, Ralph S. Baric, Rachel L. Graham |
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| Rok vydání: | 2012 |
| Předmět: |
viruses
Molecular Sequence Data Virulence Real-Time Polymerase Chain Reaction Severe Acute Respiratory Syndrome Virus Replication medicine.disease_cause Article Statistics Nonparametric General Biochemistry Genetics and Molecular Biology Immunocompromised Host Mice 03 medical and health sciences Exon chemistry.chemical_compound Serial passage medicine Animals DNA Primers 030304 developmental biology Coronavirus Mice Inbred BALB C 0303 health sciences Base Sequence biology 030306 microbiology Age Factors RNA Viral Vaccines RNA virus Sequence Analysis DNA General Medicine biology.organism_classification Virology 3. Good health Severe acute respiratory syndrome-related coronavirus Viral replication chemistry Drug Design Exoribonucleases Female DNA Plasmids |
| Zdroj: | Nature medicine Nature Medicine |
| ISSN: | 1546-170X 1078-8956 |
| DOI: | 10.1038/nm.2972 |
| Popis: | 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 replication fidelity is approximately 20-fold greater than that of other RNA viruses and is mediated by a 3′-5′ exonuclease activity (ExoN) that likely functions in RNA proofreading. In this study, we demonstrate that engineered inactivation of 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 mouse models of human SARS. 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. Our approach represents a strategy with potential for broad applications for the stable attenuation of coronaviruses and possibly other RNA viruses. |
| Databáze: | OpenAIRE |
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