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Foot-and-mouth disease virus low-fidelity polymerase mutants are attenuated

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Abstract

Previous studies have shown that RNA viruses can be attenuated by either increased or decreased viral polymerase replication fidelity. Although foot-and-mouth disease virus (FMDV) high-fidelity RNA-dependent RNA polymerase (RdRp) variants with an attenuated phenotype have been isolated using mutagens, no FMDV mutant with a low-fidelity polymerase has been documented to date. Here, we describe the generation of several FMDV RdRp mutants using site-directed mutagenesis via a reverse genetic system. Mutation frequency assays confirmed that five rescued FMDV RdRp mutant populations had lower replication fidelity than the wild-type virus population, which allowed us to assess the effects of the change in replication fidelity on the virus phenotype. These low-fidelity FMDV RdRp mutants showed increased sensitivity to ribavirin or 5-fluorouracil (5-FU) treatment without a loss of growth capacity in cell cultures. In addition, decreased fitness and attenuated virulence were observed for the RdRp mutants with lower fidelity. Importantly, based on a quantitative analysis for fidelity and virulence, we concluded that lower replication fidelity is associated with a more attenuated virus phenotype. These results further contribute to our understanding of the replication fidelity of polymerases of RNA viruses and its relationship to virulence attenuation.

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Acknowledgments

This work was supported by grants from the Key Project of Heilongjiang Provincial Science and Technology Programme (No. GA06B202).

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Authors and Affiliations

  1. Division of Livestock Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, No. 427 Maduan Street, Harbin, 150001, P. R. China

    Xiaochun Xie, Haiwei Wang, Jianxiong Zeng, Chen Li, Guohui Zhou, Decheng Yang & Li Yu

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  1. Xiaochun Xie
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  2. Haiwei Wang
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  4. Chen Li
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  7. Li Yu
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Correspondence to Li Yu.

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X. Xie and H. Wang contributed equally to this work.

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Xie, X., Wang, H., Zeng, J. et al. Foot-and-mouth disease virus low-fidelity polymerase mutants are attenuated. Arch Virol 159, 2641–2650 (2014). https://doi.org/10.1007/s00705-014-2126-z

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  • DOI: https://doi.org/10.1007/s00705-014-2126-z

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