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Evolutionary selection of pestivirus variants with altered or no miRNA dependency

ABSTRACT: Host microRNA (miRNA) dependency is a hallmark of the human pathogen hepatitis C virus (HCV) and was recently also described for the related pestiviruses, which are important livestock pathogens. HCV critically depends on the liver-specific miR-122, whereas the broadly expressed let-7 and miR-17 families bind two sites (S1 and S2) in the pestiviral 3’ untranslated region (UTR). Here, we elucidated the miRNA dependency of bovine viral diarrhea virus (BVDV) and confirmed its critical dependence on miR-17 and Argonaute 2 (AGO2). Let-7 binding to S1 had only minor effect on virus production but was required for full translational efficiency. Evolutionary selection experiments using seed site randomized genomes revealed that tropism could be re-directed to different miRNAs. AGO cross-linking and immunoprecipitation (AGO-CLIP) and miRNA antagonism demonstrated that these alternative variants bound and depended on the corresponding miRNAs. Furthermore, we identified variants with miRNA independent replication through acquisition of compensatory mutations near the genomic 3’ terminus. Rescue experiments using miRNA mimics demonstrated that miRNA binding and 3’ mutagenesis contribute to replication through mutually exclusive mechanisms. Our findings illustrate that pestiviruses, although capable of miRNA independent replication, took advantage of miRNAs as essential host factors, suggesting a favorable path during evolutionary adaptation.

ORGANISM(S): Bos taurus

PROVIDER: GSE146910 | GEO | 2020/03/13

REPOSITORIES: GEO

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