{"doi":"10.1128/jvi.76.17.8505-8517.2002","title":"Viral RNA Mutations Are Region Specific and Increased by Ribavirin in a Full-Length Hepatitis C Virus Replication System","abstract":"<jats:title>ABSTRACT</jats:title>\n          <jats:p>\n            High rates of genetic variation ensure the survival of RNA viruses. Although this variation is thought to result from error-prone replication, RNA viruses must also maintain highly conserved genomic segments. A balance between conserved and variable viral elements is especially important in order for viruses to avoid “error catastrophe.” Ribavirin has been shown to induce error catastrophe in other RNA viruses. We therefore used a novel hepatitis C virus (HCV) replication system to determine relative mutation frequencies in variable and conserved regions of the HCV genome, and we further evaluated these frequencies in response to ribavirin. We sequenced the 5′ untranslated region (5′ UTR) and the core, E2 HVR-1, NS5A, and NS5B regions of replicating HCV RNA isolated from cells transfected with a T7 polymerase-driven full-length HCV cDNA plasmid containing a\n            <jats:italic>cis</jats:italic>\n            -acting hepatitis delta virus ribozyme to control 3′ cleavage. We found quasispecies in the E2 HVR-1 and NS5B regions of untreated replicating viral RNAs but not in conserved 5′ UTR, core, or NS5A regions, demonstrating that important\n            <jats:italic>cis</jats:italic>\n            elements regulate mutation rates within specific viral segments. Neither T7-driven replication nor sequencing artifacts produced these nucleotide substitutions in control experiments. Ribavirin broadly increased error generation, especially in otherwise invariant regions, indicating that it acts as an HCV RNA mutagen in vivo. Similar results were obtained in hepatocyte-derived cell lines. These results demonstrate the potential utility of our system for the study of intrinsic factors regulating genetic variation in HCV. Our results further suggest that ribavirin acts clinically by promoting nonviable HCV RNA mutation rates. Finally, the latter result suggests that our replication model may be useful for identifying agents capable of driving replicating virus into error catastrophe.\n          </jats:p>","journal":"Journal of Virology","year":2002,"id":688697,"datarank":0.7886243058041673,"base_score":5.2574953720277815,"endowment":5.2574953720277815,"self_citation_contribution":0.7886243058041673,"citation_network_contribution":0.0,"self_endowment_contribution":0.7886243058041673,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":191,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1507822,"name":"Yoichi Hiasa","orcid":null,"position":1,"is_corresponding":false},{"id":1799206,"name":"Wenping He","orcid":null,"position":2,"is_corresponding":false},{"id":915804,"name":"Adam Terella","orcid":null,"position":3,"is_corresponding":false},{"id":268642,"name":"Emmett V. Schmidt","orcid":"0000-0003-4687-9367","position":4,"is_corresponding":false},{"id":50915,"name":"Raymond T. Chung","orcid":"0000-0003-1338-9564","position":5,"is_corresponding":false},{"id":1799205,"name":"Ana Maria Contreras","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Viral RNA Mutations Are Region Specific and Increased by Ribavirin in a Full-Length Hepatitis C Virus Replication System","abstract":"<jats:title>ABSTRACT</jats:title>\n          <jats:p>\n            High rates of genetic variation ensure the survival of RNA viruses. Although this variation is thought to result from error-prone replication, RNA viruses must also maintain highly conserved genomic segments. A balance between conserved and variable viral elements is especially important in order for viruses to avoid “error catastrophe.” Ribavirin has been shown to induce error catastrophe in other RNA viruses. We therefore used a novel hepatitis C virus (HCV) replication system to determine relative mutation frequencies in variable and conserved regions of the HCV genome, and we further evaluated these frequencies in response to ribavirin. We sequenced the 5′ untranslated region (5′ UTR) and the core, E2 HVR-1, NS5A, and NS5B regions of replicating HCV RNA isolated from cells transfected with a T7 polymerase-driven full-length HCV cDNA plasmid containing a\n            <jats:italic>cis</jats:italic>\n            -acting hepatitis delta virus ribozyme to control 3′ cleavage. We found quasispecies in the E2 HVR-1 and NS5B regions of untreated replicating viral RNAs but not in conserved 5′ UTR, core, or NS5A regions, demonstrating that important\n            <jats:italic>cis</jats:italic>\n            elements regulate mutation rates within specific viral segments. Neither T7-driven replication nor sequencing artifacts produced these nucleotide substitutions in control experiments. Ribavirin broadly increased error generation, especially in otherwise invariant regions, indicating that it acts as an HCV RNA mutagen in vivo. Similar results were obtained in hepatocyte-derived cell lines. These results demonstrate the potential utility of our system for the study of intrinsic factors regulating genetic variation in HCV. Our results further suggest that ribavirin acts clinically by promoting nonviable HCV RNA mutation rates. Finally, the latter result suggests that our replication model may be useful for identifying agents capable of driving replicating virus into error catastrophe.\n          </jats:p>","is_dataset_classified":null,"base_score":5.2574953720277815,"endowment":5.2574953720277815,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"12163570","pmcid":"PMC136407","openalex_id":"https://openalex.org/W2039884199","authors":[],"funders":[{"funder_name":"NIAID NIH HHS","grant_id":"R01 AI43478","title":null},{"funder_name":"NIA NIH HHS","grant_id":"R01 AG043478","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"R01 DK 57857","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"R01 DK057857","title":null},{"funder_name":"National Institutes of Health","grant_id":"5R01DK057857-03","title":"NOVEL ANIMAL MODELS OF HCV-RELATED HEPATOCARCINOGENESIS"},{"funder_name":"National Institutes of Health","grant_id":"1R01AI043478-01","title":"HEPATITIS C TRANSGENIC MICE AS MODEL OF LIVER INJURY"}],"total_grants":6,"fwci":8.1373,"citation_percentile":0.98184282,"influential_citations":0,"citation_trend":[{"year":2012,"count":15},{"year":2013,"count":7},{"year":2014,"count":10},{"year":2015,"count":6},{"year":2016,"count":2},{"year":2017,"count":2},{"year":2018,"count":4},{"year":2019,"count":4},{"year":2020,"count":4},{"year":2021,"count":3},{"year":2022,"count":2},{"year":2023,"count":2},{"year":2024,"count":2},{"year":2025,"count":1}],"oa_status":"green","license":"ASM Journals Non-Commercial TDM","oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/136407","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/136407","host_type":"repository"},{"url":"https://journals.asm.org/doi/pdf/10.1128/JVI.76.17.8505-8517.2002","host_type":"publisher"},{"url":"https://doi.org/10.1128/jvi.76.17.8505-8517.2002","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/12163570","host_type":"repository"},{"url":"http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.327.3647","host_type":""},{"url":"https://jvi.asm.org/content/76/17/8505.full.pdf","host_type":""},{"url":"https://dx.doi.org/10.1128/jvi.76.17.8505-8517.2002","host_type":""}],"fields_of_study":["Hepatitis C virus research","Hepatitis B Virus Studies","HIV Research and Treatment","0301 basic medicine","0303 health sciences","03 medical and health sciences","Amino Acid Sequence","Antiviral Agents","Base Sequence","Cell Line","Gene Expression Regulation, Viral","Genetic Variation","Hepacivirus","Humans","Interferon-alpha","Mutation","RNA, Viral","Ribavirin","Virus Replication"],"mesh_terms":["Amino Acid Sequence","Antiviral Agents","Base Sequence","Cell Line","Humans","Mutation","Ribavirin","RNA, Viral","Genetic Variation","Virus Replication","Gene Expression Regulation, Viral","Hepacivirus","Interferon-alpha"],"keywords":["Biology","NS5B","Virology","NS5A","Viral quasispecies","Viral replication","RNA","RNA-dependent RNA polymerase","Genetics","Hepatitis C virus","Ribavirin","Untranslated region","Virus","Gene","Hepacivirus","Gene Expression Regulation, Viral","Base Sequence","Genetic Variation","Interferon-alpha","Virus Replication","Antiviral Agents","Cell Line","Mutation","Humans","RNA, Viral","Amino Acid Sequence"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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