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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, termed quasispecies1,2,3,4. Quasispecies arise from rapid genomic evolution powered by the high mutation rate of RNA viral replication5,6,7,8. Although a high mutation rate is dangerous for a virus because 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 infection4,9,10,11. Mathematical models predict that viral quasispecies are not simply a collection of diverse mutants but a group of interactive variants, which together contribute to the characteristics of the population4,12. According to this view, viral populations, rather than individual variants, are the target of evolutionary selection4,12. Here we test this hypothesis by examining the consequences of limiting genomic diversity on viral populations. We find that poliovirus carrying a high-fidelity polymerase replicates at wild-type levels but generates less genomic diversity and is unable to adapt to adverse growth conditions. In infected animals, the reduced viral diversity leads to loss of neurotropism and an attenuated pathogenic phenotype. Notably, using chemical mutagenesis to expand quasispecies diversity of the high-fidelity virus before infection restores neurotropism and pathogenesis. Analysis of viruses isolated from brain provides direct evidence for complementation between members in the quasispecies, indicating that selection indeed occurs at the population level rather than on individual variants. Our study provides direct evidence for a fundamental prediction of the quasispecies theory and establishes a link between mutation rate, population dynamics and pathogenesis.

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Figure 1: A restricted quasispecies of poliovirus is less neuropathogenic.
Figure 2: Genomic diversity in quasispecies is critical in viral tissue tropism and pathogenesis.
Figure 3: Cooperative interactions among members of the virus population link quasispecies diversity with pathogenesis.

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Acknowledgements

We are grateful to J. Frydman, D. Ganem, A. Frankel and members of the Andino laboratory for critical reading of the manuscript. This work was supported by NIH-NIAID grants to R.A and C.E.C and a predoctoral NIH fellowship to J.K.S.

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Correspondence to Raul Andino.

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Supplementary information

Supplementary Methods

Additional details of the methods used in this study. (RTF 17 kb)

Supplementary Figure Legends

Text to accompany the below Supplementary Figures. (RTF 9 kb)

Supplementary Table 1

Titres and proportion of G64SSac in brain homogenates. (RTF 24 kb)

Supplementary Data

This file contains additional details of experimental results and discussion from the study. (RTF 41 kb)

Supplementary Figure 1

Isolation of ribavirin resistant poliovirus and growth characteristics of ribavirin resistant virus. (PDF 32 kb)

Supplementary Figure 2

The G64S mutation confers enhanced fidelity without significantly altering replication kinetics. (PDF 64 kb)

Supplementary Figure 3

The G64S quasispecies has compromised evolution, adaptability and viral fitness in tissue culture. (PDF 38 kb)

Supplementary Figure 4

Schematic representation of the mutation distribution in wildtype and G64S populations and the predicted effect of treatment with mutagens (ribavirin). (PDF 38 kb)

Supplementary Figure 5

Neuropathogenicity of viruses re-isolated from brain. (PDF 36 kb)

Supplementary Figure 6

Analysis of bar-coded G64SSac virus. (PDF 105 kb)

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Vignuzzi, M., Stone, J., Arnold, J. et al. Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population. Nature 439, 344–348 (2006). https://doi.org/10.1038/nature04388

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