Atypical mutational spectrum of SARS-CoV-2 replicating in the presence of ribavirin

We report that ribavirin exerts an inhibitory and mutagenic activity on SARS-CoV-2 infecting Vero-E6 cells, with a therapeutic index higher than 11.9. Deep sequencing analysis of the mutant spectrum of SARS-CoV-2 replicating in the absence or presence of ribavirin indicated an increase of the number of mutations -but not of deletions-, and modification of diversity indices, expected from a mutagenic activity. Notably, the major mutation types induced by ribavirin were A?G and U?C transitions, a pattern which is opposite to the dominance of G?A and C?U transitions previously described for most RNA viruses. Implications of the inhibitory activity of ribavirin, and of the atypical mutational bias produced on SARS-CoV-2, for the search of synergistic anti-COVID-19 lethal mutagen combinations are discussed.