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Rescue experiments demonstrated that miRNA binding and 3' mutagenesis contribute to replication through mutually exclusive mechanisms. Altogether, our findings suggest that pestiviruses, although capable of miRNA-independent replication, took advantage of miRNAs as essential host factors, suggesting a favorable path during evolutionary adaptation. © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.The Omics Discovery Index is an open source platform that can be used to access, discover and di