A speed–fidelity trade-off determines the mutation rate and virulence of an RNA virus

Abstract

Mutation rates can evolve through genetic drift, indirect selection due to genetic hitchhiking, or direct selection on the physicochemical cost of high fidelity. However, for many systems, it has been difficult to disentangle the relative impact of these forces empirically. In RNA viruses, an observed correlation between mutation rate and virulence has led many to argue that their extremely high mutation rates are advantageous because they may allow for increased adaptability. This argument has profound implications because it suggests that pathogenesis in many viral infections depends on rare or de novo mutations. Here, we present data for an alternative model whereby RNA viruses evolve high mutation rates as a byproduct of selection for increased replicative speed. We find that a poliovirus antimutator, 3DG64S, has a significant replication defect and that wild-type (WT) and 3DG64S populations have similar adaptability in 2 distinct cellular environments. Experimental evolution of 3DG64S under selection for replicative speed led to reversion and compensation of the fidelity phenotype. Mice infected with 3DG64S exhibited delayed morbidity at doses well above the lethal level, consistent with attenuation by slower growth as opposed to reduced mutational supply. Furthermore, compensation of the 3DG64S growth defect restored virulence, while compensation of the fidelity phenotype did not. Our data are consistent with the kinetic proofreading model for biosynthetic reactions and suggest that speed is more important than accuracy. In contrast with what has been suggested for many RNA viruses, we find that within-host spread is associated with viral replicative speed and not standing genetic diversity.

RNA-Dependent RNA Polymerase Speed and Fidelity are not the Only Determinants of the Mechanism or Efficiency of Recombination

“…Many years ago, our laboratory showed that the active site of all polymerases contain a general acid, Lys-359 in the case of PV RdRp, that protonated the pyrophosphate leaving group during nucleotidyl transfer, thereby increasing the catalytic efficiency of RdRp [25]. Substitutions of Lys-359 in PV RdRp give rise to changes in fidelity [7,18]. The arginine substitution of Lys-359 (K359R RdRp) and the histidine substitution (K359H RdRp) catalyze nucleotidyl transfer at a rate 10-fold lower than wild type [25].…”

“…The triple mutant replicated even faster but still exhibited a significant reduction in the rate of replication relative to WT ( Figure 1C). changes in fidelity [7,18]. The arginine substitution of Lys-359 (K359R RdRp) and the histidine substitution (K359H RdRp) catalyze nucleotidyl transfer at a rate 10-fold lower than wild type [25].…”

“…Changing RdRp fidelity decreases or increases the genetic variation of the viral population, which, in turn, decreases fitness and virulence of the viral population [11][12][13][14][15][16].Known RdRp variants exhibiting a high-fidelity phenotype can also exhibit a reduced speed of nucleotide incorporation, at least at the biochemical level [17]. Replication speed is also a determinant of viral fitness and virulence [18]. So, is it the increased fidelity or decreased speed of nucleotide addition that gives rise to the attenuated phenotype?…”

“…Known RdRp variants exhibiting a high-fidelity phenotype can also exhibit a reduced speed of nucleotide incorporation, at least at the biochemical level [17]. Replication speed is also a determinant of viral fitness and virulence [18]. So, is it the increased fidelity or decreased speed of nucleotide addition that gives rise to the attenuated phenotype?…”

Evolutionary Virology at 40

“…For example, the appearance of neurovirulent poliovirus infection in a mouse model system was associated with higher levels of virus genetic diversity (Vignuzzi et al 2006). A contrary view, which recently received strong support from another experimental study involving poliovirus, is that the evolution of mutation rates in fact reflects an evolutionary trade-off between replication speed and fidelity; that is, rapid replication is selectively advantageous for a virus but comes at the cost of lower replication fidelity (Fitzsimmons et al 2018).…”