{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:50:37Z","timestamp":1790776237473,"version":"4.1.0"},"reference-count":112,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2020,8,7]],"date-time":"2020-08-07T00:00:00Z","timestamp":1596758400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-2018-06335"],"award-info":[{"award-number":["RGPIN-2018-06335"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MOP-133458"],"award-info":[{"award-number":["MOP-133458"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008920","name":"University of Saskatchewan","doi-asserted-by":"publisher","award":["CoMBRIDGE"],"award-info":[{"award-number":["CoMBRIDGE"]}],"id":[{"id":"10.13039\/100008920","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hepatitis C virus (HCV) replication requires annealing of a liver specific microRNA, miR-122 to 2 sites on 5\u2032 untranslated region (UTR). While, microRNAs downregulate gene expression by binding to the 3\u2032 untranslated region of the target mRNA, in this case, the microRNA anneals to the 5\u2032UTR of the viral genomes and upregulates the viral lifecycle. In this review, we explore the current understandings of the mechanisms by which miR-122 promotes the HCV lifecycle, and its contributions to pathogenesis. Annealing of miR-122 has been reported to (a) stimulate virus translation by promoting the formation of translationally active internal ribosome entry site (IRES) RNA structure, (b) stabilize the genome, and (c) induce viral genomic RNA replication. MiR-122 modulates lipid metabolism and suppresses tumor formation, and sequestration by HCV may influence virus pathogenesis. We also discuss the possible use of miR-122 as a biomarker for chronic hepatitis and as a therapeutic target. Finally, we discuss roles for miR-122 and other microRNAs in promoting other viruses.<\/jats:p>","DOI":"10.3390\/ijms21165677","type":"journal-article","created":{"date-parts":[[2020,8,10]],"date-time":"2020-08-10T05:07:23Z","timestamp":1597036043000},"page":"5677","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["The Role of the Liver-Specific microRNA, miRNA-122 in the HCV Replication Cycle"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9933-9981","authenticated-orcid":false,"given":"Rasika D.","family":"Kunden","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK S7N5E5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juveriya Q.","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK S7N5E5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Ghezelbash","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK S7N5E5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5051-3088","authenticated-orcid":false,"given":"Joyce A.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK S7N5E5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"411","DOI":"10.3322\/caac.21403","article-title":"The oncologic burden of hepatitis C virus infection: A clinical perspective","volume":"67","author":"Torres","year":"2017","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.jhep.2006.05.013","article-title":"The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide","volume":"45","author":"Perz","year":"2006","journal-title":"J. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.jhep.2006.07.003","article-title":"Transmission of hepatitis C virus by blood transfusions and other medical procedures: A global review","volume":"45","author":"Prati","year":"2006","journal-title":"J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1002\/hep.21902","article-title":"Acute Hepatitis C Virus Infection: A Chronic Problem","volume":"47","author":"Blackard","year":"2008","journal-title":"Hepatol. Baltim. Md."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1089\/aid.2015.0236","article-title":"Interferon Stimulated Gene Expression in HIV\/HCV Coinfected Patients Treated with Nitazoxanide\/Peginterferon-Alfa-2a and Ribavirin","volume":"32","author":"Petersen","year":"2016","journal-title":"AIDS Res. Hum. Retrovir."},{"key":"ref_6","first-page":"w14560","article-title":"Excellent outcome of direct antiviral treatment for chronic hepatitis C in Switzerland","volume":"148","author":"Bachofner","year":"2018","journal-title":"Swiss Med. Wkly."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1159\/000501821","article-title":"Identifying Barriers to the Treatment of Chronic Hepatitis C Infection","volume":"38","author":"Patel","year":"2020","journal-title":"Dig. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.aohep.2018.06.001","article-title":"Barriers to treatment of chronic hepatitis C with direct acting antivirals in an urban clinic","volume":"18","author":"Malespin","year":"2019","journal-title":"Ann. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e000181","DOI":"10.1136\/bmjgast-2017-000181","article-title":"Barriers to care for chronic hepatitis C in the direct-acting antiviral era: A single-centre experience","volume":"4","author":"Nguyen","year":"2017","journal-title":"BMJ Open Gastroenterol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.3389\/fimmu.2018.01480","article-title":"Hepatitis C Vaccines, Antibodies, and T Cells","volume":"9","author":"Shoukry","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Fauquet, C.M., Mayo, M.A., Maniloff, J., Desselberger, U., and Ball, L.A. (2005). Virus Taxonomy: VIIIth Report of the International Committee on Taxonomy of Viruses, Academic Press.","DOI":"10.1016\/B978-0-12-249951-7.50004-3"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e00280-17","DOI":"10.1128\/JVI.00280-17","article-title":"Attachment and Postattachment Receptors Important for Hepatitis C Virus Infection and Cell-to-Cell Transmission","volume":"91","author":"Fan","year":"2017","journal-title":"J. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8374","DOI":"10.1128\/JVI.00690-07","article-title":"Hepatitis C Virus p7 and NS2 Proteins Are Essential for Production of Infectious Virus","volume":"81","author":"Jones","year":"2007","journal-title":"J. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Steinmann, E., Penin, F., Kallis, S., Patel, A.H., Bartenschlager, R., and Pietschmann, T. (2007). Hepatitis C Virus p7 Protein Is Crucial for Assembly and Release of Infectious Virions. PLOS Pathog., 3.","DOI":"10.1371\/journal.ppat.0030103"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1038\/ncb1631","article-title":"The lipid droplet is an important organelle for hepatitis C virus production","volume":"9","author":"Miyanari","year":"2007","journal-title":"Nat. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.jhep.2010.04.015","article-title":"Hepatitis C virus replication cycle","volume":"53","author":"Bartenschlager","year":"2010","journal-title":"J. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/j.cell.2015.02.025","article-title":"Hepatitis C virus RNA functionally sequesters miR-122","volume":"160","author":"Luna","year":"2015","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1002\/wrna.1186","article-title":"miR-122 Promotion of the hepatitis C virus life cycle: Sound in the silence","volume":"4","author":"Wilson","year":"2013","journal-title":"WIREs RNA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.jhep.2014.10.004","article-title":"miR-122\u2014A key factor and therapeutic target in liver disease","volume":"62","author":"Bandiera","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1128\/AAC.04220-14","article-title":"In Vitro Antiviral Activity and Preclinical and Clinical Resistance Profile of Miravirsen, a Novel Anti-Hepatitis C Virus Therapeutic Targeting the Human Factor miR-122","volume":"59","author":"Ottosen","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kunden, R.D., Ghezelbash, S., Khan, J.Q., and Wilson, J.A. (2020). Location specific annealing of miR-122 and other small RNAs defines an Hepatitis C Virus 5\u2032 UTR regulatory element with distinct impacts on virus translation and genome stability. Nucleic Acids Res.","DOI":"10.1093\/nar\/gkaa664"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4230","DOI":"10.1093\/nar\/gkt075","article-title":"Unconventional miR-122 binding stabilizes the HCV genome by forming a trimolecular RNA structure","volume":"41","author":"Mortimer","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5307","DOI":"10.1093\/nar\/gkz194","article-title":"miR-122 and Ago interactions with the HCV genome alter the structure of the viral 5\u2032 terminus","volume":"47","author":"Chahal","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/j.csbj.2020.02.019","article-title":"Prediction of the miRNA interactome\u2014Established methods and upcoming perspectives","volume":"18","author":"Ciaudo","year":"2020","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"402","DOI":"10.3389\/fendo.2018.00402","article-title":"Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation","volume":"9","author":"Hayder","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.molcel.2016.09.004","article-title":"Pairing beyond the Seed Supports MicroRNA Targeting Specificity","volume":"64","author":"Broughton","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1172\/JCI63539","article-title":"Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver","volume":"122","author":"Hsu","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5321","DOI":"10.1038\/s41467-018-07786-7","article-title":"miR-122 removal in the liver activates imprinted microRNAs and enables more effective microRNA-mediated gene repression","volume":"9","author":"Valdmanis","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"106","DOI":"10.4161\/rna.1.2.1066","article-title":"miR-122, a mammalian liver-specific microRNA, is processed from hcr mRNA and may downregulate the high affinity cationic amino acid transporter CAT-1","volume":"1","author":"Chang","year":"2004","journal-title":"RNA Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.cmet.2006.01.005","article-title":"miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting","volume":"3","author":"Esau","year":"2006","journal-title":"Cell Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1093\/nar\/gkm1113","article-title":"Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver","volume":"36","author":"Lindow","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1172\/JCI44883","article-title":"The liver-specific microRNA miR-122 controls systemic iron homeostasis in mice","volume":"121","author":"Castoldi","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3526","DOI":"10.1038\/onc.2009.211","article-title":"Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties","volume":"28","author":"Coulouarn","year":"2009","journal-title":"Oncogene"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2884","DOI":"10.1172\/JCI63455","article-title":"MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis","volume":"122","author":"Tsai","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.aohep.2019.07.005","article-title":"Over-expression of MiR-122 promotes apoptosis of hepatocellular carcinoma via targeting TLR4","volume":"18","author":"Wei","year":"2019","journal-title":"Ann. Hepatol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Pan, C., Wang, X., Shi, K., Zheng, Y., Li, J., Chen, Y., Jin, L., and Pan, Z. (2016). MiR-122 Reverses the Doxorubicin-Resistance in Hepatocellular Carcinoma Cells through Regulating the Tumor Metabolism. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0152090"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"577","DOI":"10.21037\/atm.2019.09.142","article-title":"The role of microRNA in the resistance to treatment of hepatocellular carcinoma","volume":"7","author":"Pratama","year":"2019","journal-title":"Ann. Transl. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6092","DOI":"10.1158\/0008-5472.CAN-06-4607","article-title":"Cyclin G1 Is a Target of miR-122a, a MicroRNA Frequently Down-regulated in Human Hepatocellular Carcinoma","volume":"67","author":"Gramantieri","year":"2007","journal-title":"Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1007\/s00535-014-0932-4","article-title":"Antitumor function of microRNA-122 against hepatocellular carcinoma","volume":"49","author":"Nakao","year":"2014","journal-title":"J. Gastroenterol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"32015","DOI":"10.1074\/jbc.M109.016774","article-title":"MicroRNA-122 inhibits tumorigenic properties of hepatocellular carcinoma cells and sensitizes these cells to sorafenib","volume":"284","author":"Bai","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.jhep.2010.12.023","article-title":"Positive regulation of hepatic miR-122 expression by HNF4\u03b1","volume":"55","author":"Li","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1126\/science.1113329","article-title":"Modulation of Hepatitis C Virus RNA Abundance by a Liver-Specific MicroRNA","volume":"309","author":"Jopling","year":"2005","journal-title":"Science"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.chom.2008.05.013","article-title":"Position-Dependent Function for a Tandem MicroRNA miR-122-Binding Site Located in the Hepatitis C Virus RNA Genome","volume":"4","author":"Jopling","year":"2008","journal-title":"Cell Host Microbe"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1042\/BST0361220","article-title":"Regulation of hepatitis C virus by microRNA-122","volume":"36","author":"Jopling","year":"2008","journal-title":"Biochem. Soc. Trans."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"9776","DOI":"10.1093\/nar\/gky662","article-title":"miR-122, small RNA annealing and sequence mutations alter the predicted structure of the Hepatitis C virus 5\u2032 UTR RNA to stabilize and promote viral RNA accumulation","volume":"46","author":"Panigrahi","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2613","DOI":"10.1038\/s41467-018-05053-3","article-title":"microRNA-122 amplifies hepatitis C virus translation by shaping the structure of the internal ribosomal entry site","volume":"9","author":"Schult","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3193","DOI":"10.1073\/pnas.1012464108","article-title":"Masking the 5\u2032 terminal nucleotides of the hepatitis C virus genome by an unconventional microRNA-target RNA complex","volume":"108","author":"Machlin","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"6615","DOI":"10.1128\/JVI.00417-10","article-title":"Regulation of Hepatitis C Virus Translation and Infectious Virus Production by the MicroRNA miR-122","volume":"84","author":"Jangra","year":"2010","journal-title":"J. Virol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"7372","DOI":"10.1128\/JVI.00513-12","article-title":"Base Pairing between Hepatitis C Virus RNA and MicroRNA 122 3\u2032 of Its Seed Sequence Is Essential for Genome Stabilization and Production of Infectious Virus","volume":"86","author":"Shimakami","year":"2012","journal-title":"J. Virol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4991","DOI":"10.1073\/pnas.1016606108","article-title":"MicroRNA-122 antagonism against hepatitis C virus genotypes 1\u20136 and reduced efficacy by host RNA insertion or mutations in the HCV 5\u2032 UTR","volume":"108","author":"Li","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"6294","DOI":"10.1128\/JVI.03631-14","article-title":"Regulation of Hepatitis C Virus Genome Replication by Xrn1 and MicroRNA-122 Binding to Individual Sites in the 5\u2032 Untranslated Region","volume":"89","author":"Thibault","year":"2015","journal-title":"J. Virol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.virol.2010.11.015","article-title":"Competing roles of microRNA-122 recognition elements in hepatitis C virus RNA","volume":"410","author":"Nasheri","year":"2011","journal-title":"Virology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1007\/s00018-016-2377-9","article-title":"microRNA-122 target sites in the hepatitis C virus RNA NS5B coding region and 3\u2032 untranslated region: Function in replication and influence of RNA secondary structure","volume":"74","author":"Gerresheim","year":"2017","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1099\/jgv.0.001217","article-title":"Beyond sites 1 and 2, miR-122 target sites in the HCV genome have negligible contributions to HCV RNA accumulation in cell culture","volume":"100","author":"Bernier","year":"2019","journal-title":"J. Gen. Virol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3300","DOI":"10.1038\/emboj.2008.244","article-title":"microRNA-122 stimulates translation of hepatitis C virus RNA","volume":"27","author":"Henke","year":"2008","journal-title":"EMBO J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"7716","DOI":"10.1093\/nar\/gkr426","article-title":"miR-122 activates hepatitis C virus translation by a specialized mechanism requiring particular RNA components","volume":"39","author":"Roberts","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"20160177","DOI":"10.1098\/rstb.2016.0177","article-title":"Dynamics of IRES-mediated translation","volume":"372","author":"Johnson","year":"2017","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/nrmicro1558","article-title":"Structural and mechanistic insights into hepatitis C viral translation initiation","volume":"5","author":"Fraser","year":"2007","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1126\/science.1058409","article-title":"Hepatitis C Virus IRES RNA-Induced Changes in the Conformation of the 40S Ribosomal Subunit","volume":"291","author":"Spahn","year":"2001","journal-title":"Science"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1038\/nsb1004","article-title":"Structure of HCV IRES domain II determined by NMR","volume":"10","author":"Lukavsky","year":"2003","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"7263","DOI":"10.1073\/pnas.0911896107","article-title":"Inhibitor-induced structural change in the HCV IRES domain IIa RNA","volume":"107","author":"Paulsen","year":"2010","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"11989","DOI":"10.1128\/JVI.01508-09","article-title":"Role of RNA Structures in Genome Terminal Sequences of the Hepatitis C Virus for Replication and Assembly","volume":"83","author":"Friebe","year":"2009","journal-title":"J. Virol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.virol.2012.11.007","article-title":"MicroRNA-122-dependent and -independent replication of Hepatitis C Virus in Hep3B human hepatoma cells","volume":"436","author":"Thibault","year":"2013","journal-title":"Virology"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e00009-15","DOI":"10.1128\/mSphere.00009-15","article-title":"Viral Determinants of miR-122-Independent Hepatitis C Virus Replication","volume":"1","author":"Hopcraft","year":"2015","journal-title":"mSphere"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Ono, C., Fukuhara, T., Motooka, D., Nakamura, S., Okuzaki, D., Yamamoto, S., Tamura, T., Mori, H., Sato, A., and Uemura, K. (2017). Characterization of miR-122-independent propagation of HCV. PLOS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006374"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Yu, Y., Scheel, T.K.H., Luna, J.M., Chung, H., Nishiuchi, E., Scull, M.A., Echeverr\u00eda, N., Ricardo-Lax, I., Kapoor, A., and Lipkin, I.W. (2017). miRNA independent hepacivirus variants suggest a strong evolutionary pressure to maintain miR-122 dependence. PLOS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006694"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"4857","DOI":"10.1128\/JVI.03692-14","article-title":"Dissecting the Roles of the 5\u2032 Exoribonucleases Xrn1 and Xrn2 in Restricting Hepatitis C Virus Replication","volume":"89","author":"Li","year":"2015","journal-title":"J. Virol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.chom.2014.07.006","article-title":"Hepatitis C Virus Subverts Liver-Specific miR-122 to Protect the Viral Genome from Exoribonuclease Xrn2","volume":"16","author":"Sedano","year":"2014","journal-title":"Cell Host Microbe"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"5139","DOI":"10.1093\/nar\/gky273","article-title":"miR-122 does not impact recognition of the HCV genome by innate sensors of RNA but rather protects the 5\u2032 end from the cellular pyrophosphatases, DOM3Z and DUSP11","volume":"46","author":"Bernier","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"8197","DOI":"10.1073\/pnas.1802326115","article-title":"RNA triphosphatase DUSP11 enables exonuclease XRN-mediated restriction of hepatitis C virus","volume":"115","author":"Kincaid","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.chom.2014.12.014","article-title":"miR-122 Stimulates Hepatitis C Virus RNA Synthesis by Altering the Balance of Viral RNAs Engaged in Replication versus Translation","volume":"17","author":"Masaki","year":"2015","journal-title":"Cell Host Microbe"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"919","DOI":"10.4161\/rna.25137","article-title":"miR-122 and the Hepatitis C RNA genome","volume":"10","author":"Li","year":"2013","journal-title":"RNA Biol."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Conrad, K.D., Giering, F., Erfurth, C., Neumann, A., Fehr, C., Meister, G., and Niepmann, M. (2013). microRNA-122 Dependent Binding of Ago2 Protein to Hepatitis C Virus RNA Is Associated with Enhanced RNA Stability and Translation Stimulation. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0056272"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"4368","DOI":"10.1093\/nar\/gkh754","article-title":"Sequential dimerization of human zipcode-binding protein IMP1 on RNA: A cooperative mechanism providing RNP stability","volume":"32","author":"Nielsen","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"7954","DOI":"10.1128\/JVI.00339-11","article-title":"Poly(C)-binding protein 2 interacts with sequences required for viral replication in the hepatitis C virus (HCV) 5\u2032 untranslated region and directs HCV RNA replication through circularizing the viral genome","volume":"85","author":"Wang","year":"2011","journal-title":"J. Virol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"10126","DOI":"10.1128\/JVI.79.16.10126-10137.2005","article-title":"Hepatitis C virus internal ribosome entry site-dependent translation in Saccharomyces cerevisiae is independent of polypyrimidine tract-binding protein, poly(rC)-binding protein 2, and La protein","volume":"79","author":"Rosenfeld","year":"2005","journal-title":"J. Virol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"6367","DOI":"10.1128\/jvi.69.10.6367-6375.1995","article-title":"Interaction of polypyrimidine tract-binding protein with the 5\u2032 noncoding region of the hepatitis C virus RNA genome and its functional requirement in internal initiation of translation","volume":"69","author":"Ali","year":"1995","journal-title":"J. Virol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1006\/viro.1998.9541","article-title":"An internal polypyrimidine-tract-binding protein-binding site in the hepatitis C virus RNA attenuates translation, which is relieved by the 3\u2032-untranslated sequence","volume":"254","author":"Ito","year":"1999","journal-title":"Virology"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1093\/nar\/27.6.1457","article-title":"hnRNP C and polypyrimidine tract-binding protein specifically interact with the pyrimidine-rich region within the 3\u2032NTR of the HCV RNA genome","volume":"27","author":"Gontarek","year":"1999","journal-title":"Nucleic Acids Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"7199","DOI":"10.1128\/JVI.00225-14","article-title":"hnRNP L and NF90 Interact with Hepatitis C Virus 5\u2032-Terminal Untranslated RNA and Promote Efficient Replication","volume":"88","author":"Li","year":"2014","journal-title":"J. Virol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1261\/rna.594207","article-title":"Nuclear factors are involved in hepatitis C virus RNA replication","volume":"13","author":"Isken","year":"2007","journal-title":"RNA N. Y. N"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1261\/rna.1578409","article-title":"IGF2BP1 enhances HCV IRES-mediated translation initiation via the 3\u2032UTR","volume":"15","author":"Weinlich","year":"2009","journal-title":"RNA"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1093\/nar\/gkt941","article-title":"The P body protein LSm1 contributes to stimulation of hepatitis C virus translation, but not replication, by microRNA-122","volume":"42","author":"Roberts","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"7878","DOI":"10.1128\/MCB.24.18.7878-7890.2004","article-title":"A Cellular RNA-Binding Protein Enhances Internal Ribosomal Entry Site-Dependent Translation through an Interaction Downstream of the Hepatitis C Virus Polyprotein Initiation Codon","volume":"24","author":"Kim","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"13153","DOI":"10.1128\/JVI.78.23.13153-13162.2004","article-title":"SYNCRIP, a Member of the Heterogeneous Nuclear Ribonucleoprotein Family, Is Involved in Mouse Hepatitis Virus RNA Synthesis","volume":"78","author":"Choi","year":"2004","journal-title":"J. Virol."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Huys, A., Thibault, P.A., and Wilson, J.A. (2013). Modulation of Hepatitis C Virus RNA Accumulation and Translation by DDX6 and miR-122 Are Mediated by Separate Mechanisms. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0067437"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"12441","DOI":"10.1093\/nar\/gkx931","article-title":"NF90\u2013NF45 is a selective RNA chaperone that rearranges viral and cellular riboswitches: Biochemical analysis of a virus host factor activity","volume":"45","author":"Schmidt","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.3389\/fimmu.2019.02525","article-title":"Liver-Mediated Adaptive Immune Tolerance","volume":"10","author":"Zheng","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1099\/jgv.0.000445","article-title":"Functional analysis of microRNA-122 binding sequences of hepatitis C virus and identification of variants with high resistance against a specific antagomir","volume":"97","author":"Li","year":"2016","journal-title":"J. Gen. Virol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"5408","DOI":"10.1038\/ncomms6408","article-title":"Hepatitis C virus genetics affects miR-122 requirements and response to miR-122 inhibitors","volume":"5","author":"Israelow","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"13882","DOI":"10.1038\/ncomms13882","article-title":"Hepatitis C virus has a genetically determined lymphotropism through co-receptor B7.2","volume":"8","author":"Chen","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"3723","DOI":"10.1128\/JVI.06956-11","article-title":"Hepatitis C Virus Infection of Human T Lymphocytes Is Mediated by CD5","volume":"86","author":"Sarhan","year":"2012","journal-title":"J. Virol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2979","DOI":"10.1038\/onc.2015.364","article-title":"Hepatitis C virus upregulates B-cell receptor signaling: A novel mechanism for HCV-associated B-cell lymphoproliferative disorders","volume":"35","author":"Dai","year":"2016","journal-title":"Oncogene"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1016\/0016-5085(94)90022-1","article-title":"Cryoglobulinemia in chronic liver diseases: Role of hepatitis C virus and liver damage","volume":"106","author":"Lunel","year":"1994","journal-title":"Gastroenterology"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1404","DOI":"10.1093\/annonc\/mdu166","article-title":"Antiviral treatment in patients with indolent B-cell lymphomas associated with HCV infection: A study of the Fondazione Italiana Linfomi","volume":"25","author":"Arcaini","year":"2014","journal-title":"Ann. Oncol. Off. J. Eur. Soc. Med. Oncol."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Akuma, P., Okagu, O.D., and Udenigwe, C.C. (2019). Naturally Occurring Exosome Vesicles as Potential Delivery Vehicle for Bioactive Compounds. Front. Sustain. Food Syst., 3.","DOI":"10.3389\/fsufs.2019.00023"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"142","DOI":"10.2174\/1566523214666141224095610","article-title":"miR-122 is a Unique Molecule with Great Potential in Diagnosis, Prognosis of Liver Disease, and Therapy Both as miRNA Mimic and Antimir","volume":"15","author":"Thakral","year":"2015","journal-title":"Curr. Gene Ther."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1056\/NEJMoa1209026","article-title":"Treatment of HCV Infection by Targeting MicroRNA","volume":"368","author":"Janssen","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"30939","DOI":"10.1038\/srep30939","article-title":"Efficient Suppression of Hepatitis C Virus Replication by Combination Treatment with miR-122 Antagonism and Direct-acting Antivirals in Cell Culture Systems","volume":"6","author":"Liu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1016\/S0140-6736(17)30043-0","article-title":"Clinical development of hepatitis C virus host-targeting agents","volume":"389","author":"Zeisel","year":"2017","journal-title":"Lancet Lond. Engl."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Mata, M., Neben, S., Majzoub, K., Carette, J., Ramanathan, M., Khavari, P.A., and Sarnow, P. (2019). Impact of a patient-derived hepatitis C viral RNA genome with a mutated microRNA binding site. PLoS Pathog., 15.","DOI":"10.1371\/journal.ppat.1007467"},{"key":"ref_102","first-page":"175","article-title":"Extracellular\/Circulating MicroRNAs: Release Mechanisms, Functions and Challenges","volume":"10","author":"Sohel","year":"2016","journal-title":"Achiev. Life Sci."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Kawaguchi, T., Komatsu, S., Ichikawa, D., Tsujiura, M., Takeshita, H., Hirajima, S., Miyamae, M., Okajima, W., Ohashi, T., and Imamura, T. (2016). Circulating MicroRNAs: A Next-Generation Clinical Biomarker for Digestive System Cancers. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17091459"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"BSR20190900","DOI":"10.1042\/BSR20190900","article-title":"Diagnostic value of circulating miRNA-122 for hepatitis B virus and\/or hepatitis C virus-associated chronic viral hepatitis","volume":"39","author":"Zhou","year":"2019","journal-title":"Biosci. Rep."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"e01933-14","DOI":"10.1128\/mBio.01933-14","article-title":"Detection of zoonotic pathogens and characterization of novel viruses carried by commensal Rattus norvegicus in New York City","volume":"5","author":"Firth","year":"2014","journal-title":"mBio"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"JVI.01974\u201317","DOI":"10.1128\/JVI.01974-17","article-title":"Mutational Analysis of the Bovine Hepacivirus Internal Ribosome Entry Site","volume":"92","author":"Baron","year":"2018","journal-title":"J. Virol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"2192","DOI":"10.1073\/pnas.1500265112","article-title":"Characterization of nonprimate hepacivirus and construction of a functional molecular clone","volume":"112","author":"Scheel","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1002\/hep.29494","article-title":"Viral persistence, liver disease, and host response in a hepatitis C-like virus rat model","volume":"68","author":"Trivedi","year":"2018","journal-title":"Hepatol. Baltim. Md."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"7338","DOI":"10.1128\/JVI.00378-13","article-title":"Modulation of GB Virus B RNA Abundance by MicroRNA-122: Dependence on and Escape from MicroRNA-122 Restriction","volume":"87","author":"Sagan","year":"2013","journal-title":"J. Virol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.chom.2016.02.007","article-title":"A broad RNA virus survey reveals both miRNA dependence and functional sequestration","volume":"19","author":"Scheel","year":"2016","journal-title":"Cell Host Microbe"},{"key":"ref_111","unstructured":"Knipe, D.M., and Howley, P. (2013). Fields Virology, Lippincott Williams & Wilkins."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"5555","DOI":"10.1093\/nar\/gkaa300","article-title":"Evolutionary selection of pestivirus variants with altered or no microRNA dependency","volume":"48","author":"Kokkonos","year":"2020","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/16\/5677\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:58:03Z","timestamp":1760176683000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/16\/5677"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,7]]},"references-count":112,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2020,8]]}},"alternative-id":["ijms21165677"],"URL":"https:\/\/doi.org\/10.3390\/ijms21165677","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,7]]}}}