Faculty Opinions recommendation of Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population.

Abstract

An RNA virus population does not consist of a single genotype; rather, it is an ensemble of related sequences, named quasispecies 1-4. Quasispecies arise from rapid genomic evolution powered by the high mutation rate of RNA viral replication 5-8. While a high mutation rate is dangerous for a virus as it results in nonviable individuals, it has been hypothesized that high mutation rates create a "cloud" of potentially beneficial mutations at the population level, which afford the viral quasispecies a greater probability to evolve and adapt to new environments and challenges during infection 4,9-11. Importantly, mathematical modelling predicts that the viral quasispecies is not simply a collection of diverse mutants but a group of interactive variants, which together contribute to the characteristics of the population 4,12. In this view, viral populations, rather than individuals, are the target of evolutionary selection 4,12. To test this hypothesis we examined whether limiting genomic diversity affects viral pathogenesis. We find that poliovirus carrying a high fidelity polymerase replicates at wildtype levels but generates less genomic diversity and is unable to adapt to adverse growth conditions. In infected animals, the reduced viral diversity led to loss of neurotropism and an attenuated pathogenic phenotype. Strikingly, expanding quasispecies diversity of the high fidelity virus by chemical mutagenesis prior to infection restored neurotropism and pathogenesis. Analysis of viruses isolated from brain provides direct evidence for complementation between members within the quasispecies, indicating that selection indeed occurred at the population level rather than on individual mutants. Our study provides direct evidence for a fundamental prediction of the quasispecies theory and establishes a compelling link between mutation rate, population dynamics and pathogenesis.

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