Imposed mutational meltdown as an antiviral strategy

Abstract

Following widespread infections of the most recent coronavirus known to infect humans, SARS-CoV-2, attention has turned to potential therapeutic options. With no drug or vaccine yet approved, one focal point of research is to evaluate the potential value of repurposing existing antiviral treatments, with the logical strategy being to identify at least a short-term intervention to prevent within-patient progression, while long-term vaccine strategies unfold. Here, we offer an evolutionary/population-genetic perspective on one approach that may overwhelm the capacity for pathogen defense (i.e., adaptation) - induced mutational meltdown - providing an overview of key concepts, review of previous theoretical and experimental work of relevance, and guidance for future research. Applied with appropriate care, including target specificity, induced mutational meltdown may provide a general, rapidly implemented approach for the within-patient eradication of a wide range of pathogens or other undesirable microorganisms.

Keywords: Antivirals; SARS-CoV-2; lethal mutagenesis; mutational meltdown; population genetics.

Figure 1

An idealized schematic of mutational meltdown. Starting with a genetically homogeneous base population, deleterious mutations accumulate relatively rapidly for a short period (phase 1, dashed line), until a point is reached at which the rate of input of mutations is balanced by the rate of selective removal. In this second steady‐state phase (solid black line), although mutation and selection pressures remain relatively balanced, there is a progressive increase in the average mutation load owing to the stochastic processes outlined in Figure 2. The final and rapid meltdown phase (solid red line) is initiated once the mean mutation load is high enough that the population is incapable of numerical replacement. The blue line represents the viral population size, which remains constant until the mutation load reaches the survival threshold, at which point there is a rapid decline toward extinction.

Figure 2

(A) At approximate selection‐mutation‐drift balance, an asexual population has an approximately constant steady‐state distribution close to Poisson in form, but with the mean number of deleterious mutations progressively increasing, as the least‐loaded class (typically containing a very small number of individuals) is stochastically lost (and not recovered). For reference, the red line denotes the mean number of deleterious mutations per individual at time 0. (B) The progressive buildup of deleterious mutations (indicated with an x) over time, shown with a sample of seven genomes. In the earliest episode, the population has progressed to the point that no individual carries less than one deleterious mutation (the ratchet has clicked once). In the next episode, all individuals carry at least two deleterious mutations, but one has acquired a beneficial mutation (red dot) conferring a net selective advantage that sweeps this chromosomal type to fixation, dragging along three deleterious mutations and transiently removing all variation from the population. Finally, more deleterious mutations accumulate on this previously beneficial background, obliterating the prior selective advantage. Should one of the previously fixed deleterious mutation have increased the mutation rate, this final episode will have also incurred a higher rate of accumulation of mutations.

Figure 3

An idealized schematic of mutation accumulation among viral genomes within an individual host cell. On the left are four viral genome templates (e.g., negative‐strand RNAs), two of which carry novel mutations (marked by an x) that have arisen within the host cell. In the center, the shapes represent nonmutant (grey) and mutant (red) replication complexes residing within the host cell; the latter may have arisen from transcriptional errors or be results of prior genomic mutations within the original host‐cell colonists. To the right is a subset of viral progeny genomes, with the variant replicase generating an elevated number of mutations. Although a number of details are omitted, the figure illustrates the molecular population‐genetic aspects of RNA virus replication that need to be evaluated in future applications of mutational‐meltdown theory.