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Lethal mutagenesis is an antiviral therapy that relies on increasing the viral mutation rate with mutagenic nucleoside or base analogues. Currently, the molecular mechanisms that lead to virus extinction through enhanced mutagenesis are not fully understood. Increasing experimental evidence supports the lethal defection model of lethal mutagenesis of RNA viruses, where replication-competent-defectors drive infective virus towards extinction. Here, we address lethal mutagenesis  in vivo  using 5-fluorouracil (5-FU) during the establishment of tobacco mosaic virus (TMV) systemic infections in  N. tabacum . The results show that 5-FU decreased the infectivity of TMV without affecting its viral load. Analysis of molecular clones spanning two genomic regions showed an increase of the FU-related base transitions A → G and U → C. Although the mutation frequency or the number of mutations per molecule did not increase, the complexity of the mutant spectra and the distribution of the mutations were altered. Overall, our results suggest that 5-FU antiviral effect on TMV is associated with the perturbation of the mutation-selection balance in the genomic region of the RNA-dependent RNA polymerase (RdRp). Our work supports the lethal defection model for lethal mutagenesis  in vivo  in a plant RNA virus and opens the way to study lethal mutagens in plant-virus systems.

Lethal mutagenesis of an RNA plant virus via lethal defection