Atypical mutational spectrum of SARS-CoV-2 replicating in the presence of ribavirin. Deep sequencing analysis of the mutant spectrum of SARS-CoV-2 replicating in the absence or 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.