Thinking Outside the Triangle: Replication Fidelity of the Largest RNA Viruses

When judged by ubiquity, adaptation, and emergence of new diseases, RNA viruses are arguably the most successful biological organisms. This success has been attributed to a defect of sorts: high mutation rates (low fidelity) resulting in mutant swarms that allow rapid selection for fitness in new environments. Studies of viruses with small RNA genomes have identified fidelity determinants in viral RNA-dependent RNA polymerases and have shown that RNA viruses likely replicate within a limited fidelity range to maintain fitness. In this review we compare the fidelity of small RNA viruses with that of the largest RNA viruses, the coronaviruses. Coronaviruses encode the first known viral RNA proofreading exoribonuclease, a function that likely allowed expansion of the coronavirus genome and that dramatically increases replication fidelity and the range of tolerated variation. We propose models for regulation of coronavirus fidelity and discuss the implications of altered fidelity for RNA virus replication, pathogenesis, and evolution.