Abstract
RNA viruses replicate with low fidelity due to the error-prone nature of the RNA-dependent RNA polymerase, which generates approximately one mutation per round of genome replication. Due to the large population sizes produced by RNA viruses during replication, this results in a cloud of closely related virus variants during host infection, of which small increases or decreases in replication fidelity have been shown to result in virus attenuation in vivo, but not typically in vitro. Since the discovery of the first RNA virus fidelity mutants during the mid-aughts, the field has exploded with the identification of over 50 virus fidelity mutants distributed amongst 7 RNA virus families. This review summarizes the current RNA virus fidelity mutant literature, with a focus upon the definition of a fidelity mutant as well as methods to confirm any mutational changes associated with the fidelity mutant. Due to the complexity of such a definition, in addition to reports of unstable virus fidelity phenotypes, the future translational utility of these mutants and applications for basic science are examined.
Highlights
It is estimated that there are greater than 320,000 viruses that infect mammals, the vast majority of which are unknown [1]
When the first fidelity mutants were identified in the mid-aughts, they were hailed as major breakthroughs in our understanding of virus evolution and as tools for understanding the role of viral diversity in virus transmission and pathogenesis
It is becoming clearer that the phenotypes of these mutants are not always stable, and that there are some caveats to the production of fidelity variants that need to be explored more widely
Summary
It is estimated that there are greater than 320,000 viruses that infect mammals, the vast majority of which are unknown [1]. The virus consensus sequence forms the foundation of the fitness landscape, allowing the virus population to explore this landscape through genetic drift with the prospect of finding and climbing new fitness peaks [15] This landscape is not fixed but changes throughout the viral lifecycle, with the magnitude, location, and frequency of the peaks and valleys moving through both time and space [13,16]. RNA viruses are believed to exist on the edge of an error threshold, such that any increase in the mutational burden will cause the extinction of the virus population [15]. This error threshold is difficult to define, and likely dependent upon the environment, making the exact definition even more difficult, if not impossible [16]. We review the latest literature and current hypotheses on the nascent field of RNA virus fidelity, as well as questions to pursue in the future
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