{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:16:38Z","timestamp":1792790198479,"version":"4.5.0"},"reference-count":54,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T00:00:00Z","timestamp":1661212800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31872641"],"award-info":[{"award-number":["31872641"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2019A1515010148"],"award-info":[{"award-number":["2019A1515010148"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Natural Science Foundation of Guangdong Provinc","award":["31872641"],"award-info":[{"award-number":["31872641"]}]},{"name":"Natural Science Foundation of Guangdong Provinc","award":["2019A1515010148"],"award-info":[{"award-number":["2019A1515010148"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The second human pegivirus (HPgV-2) is a virus discovered in the plasma of a hepatitis C virus (HCV)-infected patient in 2015 belonging to the pegiviruses of the family Flaviviridae. HPgV-2 has been proved to be epidemiologically associated with and structurally similar to HCV but unrelated to HCV disease and non-pathogenic, but its natural history and tissue tropism remain unclear. HPgV-2 is a unique RNA virus sharing the features of HCV and the first human pegivirus (HPgV-1 or GBV-C). Moreover, distinct from most RNA viruses such as HCV, HPgV-1 and human immunodeficiency virus (HIV), HPgV-2 exhibits much lower genomic diversity, with a high global sequence identity ranging from 93.5 to 97.5% and significantly lower intra-host variation than HCV. The mechanisms underlying the conservation of the HPgV-2 genome are not clear but may include efficient innate immune responses, low immune selection pressure and, possibly, the unique features of the viral RNA-dependent RNA polymerase (RdRP). In this review, we summarize the prevalence, pathogenicity and genetic diversity of HPgV-2 and discuss the possible reasons for the uniformity of its genome sequence, which should elucidate the implications of RNA virus fidelity for attenuated viral vaccines.<\/jats:p>","DOI":"10.3390\/v14091844","type":"journal-article","created":{"date-parts":[[2022,8,24]],"date-time":"2022-08-24T02:55:34Z","timestamp":1661309734000},"page":"1844","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The Second Human Pegivirus, a Non-Pathogenic RNA Virus with Low Prevalence and Minimal Genetic Diversity"],"prefix":"10.3390","volume":"14","author":[{"given":"Shuyi","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiying","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7475-6420","authenticated-orcid":false,"given":"Emmanuel Enoch","family":"Dzakah","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biotechnology, School of Biological Sciences, College of Agriculture and Natural Sciences, University of Cape Coast, Cape Coast CC 033, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1017-7769","authenticated-orcid":false,"given":"Farooq","family":"Rashid","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9908-1001","authenticated-orcid":false,"given":"Jufang","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shixing","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3401","DOI":"10.1073\/pnas.92.8.3401","article-title":"Identification of two flavivirus-like genomes in the GB hepatitis agent","volume":"92","author":"Simons","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1002\/(SICI)1096-9071(199710)53:2<167::AID-JMV10>3.0.CO;2-G","article-title":"Seroprevalence of GB virus C and persistence of RNA and antibody","volume":"53","author":"Gutierrez","year":"1997","journal-title":"J. Med. Virol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1111\/j.1365-2893.2009.01194.x","article-title":"GB virus type C interactions with HIV: The role of envelope glycoproteins","volume":"16","author":"Mohr","year":"2009","journal-title":"J. Viral Hepat."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.tim.2012.01.004","article-title":"GB virus C: The good boy virus?","volume":"20","author":"Bhattarai","year":"2012","journal-title":"Trends Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1586\/eri.12.37","article-title":"Role of GB virus C in modulating HIV disease","volume":"10","author":"Blackard","year":"2012","journal-title":"Expert Rev. Anti-Infect. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0166-3542(01)00172-3","article-title":"GB virus-C infection in patients infected with the human immunodeficiency virus","volume":"52","author":"Tillmann","year":"2001","journal-title":"Antivir. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2425","DOI":"10.1128\/JVI.02752-14","article-title":"GB virus C coinfections in west African ebola patients","volume":"89","author":"Lauck","year":"2015","journal-title":"J. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e01466-15","DOI":"10.1128\/mBio.01466-15","article-title":"Virome analysis of transfusion recipients reveals a novel human virus that shares genomic features with hepaciviruses and pegiviruses","volume":"6","author":"Kapoor","year":"2015","journal-title":"mBio"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Berg, M.G., Lee, D., Coller, K., Frankel, M., Aronsohn, A., Cheng, K., Forberg, K., Marcinkus, M., Naccache, S.N., and Dawson, G. (2015). Discovery of a novel human pegivirus in blood associated with HEPATITIS C virus Co-infection. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1005325"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"671","DOI":"10.3201\/eid2204.151812","article-title":"Evaluation of viremia frequencies of a novel human pegivirus by using bioinformatic screening and PCR","volume":"22","author":"Bonsall","year":"2016","journal-title":"Emerg. Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1093\/cid\/cix748","article-title":"A novel human pegivirus, HPgV-2 (HHpgV-1), is tightly associated with hepatitis C virus (HCV) infection and HCV\/human immunodeficiency virus type 1 coinfection","volume":"66","author":"Wang","year":"2017","journal-title":"Clin. Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"E1407","DOI":"10.1073\/pnas.1219217110","article-title":"Identification of a previously undescribed divergent virus from the Flaviviridae family in an outbreak of equine serum hepatitis","volume":"110","author":"Chandriani","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7326\/M17-0085","article-title":"Presence of human Hepegivirus-1 in a cohort of people who inject drugs","volume":"167","author":"Kandathil","year":"2017","journal-title":"Ann. Intern. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.3201\/eid2411.180668","article-title":"Detection and characterization of human pegivirus 2, vietnam","volume":"24","author":"Anh","year":"2018","journal-title":"Emerg. Infect. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.virol.2019.10.012","article-title":"Human pegivirus 2 exhibits minimal geographic and temporal genetic diversity","volume":"539","author":"Forberg","year":"2019","journal-title":"Virology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5036","DOI":"10.1038\/s41598-018-23490-4","article-title":"First detection of human hepegivirus-1 (HHpgV-1) in Iranian patients with hemophilia","volume":"8","author":"Bijvand","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"908","DOI":"10.3201\/eid2405.161162","article-title":"Second human pegivirus in hepatitis C virus\u2013infected and Hepatitis C virus\/HIV-1\u2013co-infected persons who inject drugs, China","volume":"24","author":"Wang","year":"2018","journal-title":"Emerg. Infect. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1111\/jvh.12996","article-title":"Hepatitis C virus surveillance and identification of human pegivirus 2 in a large Cameroonian cohort","volume":"26","author":"Rodgers","year":"2018","journal-title":"J. Viral Hepat."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.antiviral.2014.12.014","article-title":"Surveying the global virome: Identification and characterization of HCV-related animal hepaciviruses","volume":"115","author":"Scheel","year":"2015","journal-title":"Antivir. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1002\/hep.26744","article-title":"Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: Updated criteria and genotype assignment web resource","volume":"59","author":"Smith","year":"2013","journal-title":"Hepatology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12985-022-01769-3","article-title":"Clinical and molecular aspects of human pegiviruses in the interaction host and infectious agent","volume":"19","author":"Samadi","year":"2022","journal-title":"Virol. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1080\/21505594.2022.2029328","article-title":"Review of human pegivirus: Prevalence, transmission, pathogenesis, and clinical implication","volume":"13","author":"Yu","year":"2022","journal-title":"Virulence"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"265","DOI":"10.3201\/eid2602.190434","article-title":"Chronic human Pegivirus 2 without Hepatitis C virus co-infection","volume":"26","author":"Coller","year":"2020","journal-title":"Emerg. Infect. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1128\/JCM.00515-16","article-title":"Antibodies to the novel human Pegivirus 2 are associated with active and resolved infections","volume":"54","author":"Coller","year":"2016","journal-title":"J. Clin. Microbiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1099\/vir.0.063016-0","article-title":"Human pegivirus RNA is found in multiple blood mononuclear cells in vivo and serum-derived viral RNA-containing particles are infectious in vitro","volume":"95","author":"Chivero","year":"2014","journal-title":"J. Gen. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1099\/vir.0.000086","article-title":"Tropism of human pegivirus (formerly known as GB virus C\/hepatitis G virus) and host immunomodulation: Insights into a highly successful viral infection","volume":"96","author":"Chivero","year":"2015","journal-title":"J. Gen. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1111\/bjh.15416","article-title":"Human Pegivirus infection and lymphoma risk and prognosis: A North American study","volume":"182","author":"Fama","year":"2018","journal-title":"Br. J. Haematol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1080\/22221751.2020.1730247","article-title":"Evidence that the second human pegivirus (HPgV-2) is primarily a lymphotropic virus and can replicate independent of HCV replication","volume":"9","author":"Wan","year":"2020","journal-title":"Emerg. Microbes Infect."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"728415","DOI":"10.3389\/fcimb.2021.728415","article-title":"Difference of intrahost dynamics of the second human pegivirus and hepatitis C virus in HPgV-2\/HCV-coinfected patients","volume":"11","author":"Liang","year":"2021","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1146\/annurev-virology-031413-085507","article-title":"Thinking outside the triangle: Replication fidelity of the largest RNA viruses","volume":"1","author":"Smith","year":"2014","journal-title":"Annu. Rev. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/j.molcel.2016.05.003","article-title":"DNA replication-a matter of fidelity","volume":"62","author":"Ganai","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1007\/s00294-018-0820-1","article-title":"Fidelity of DNA replication-a matter of proofreading","volume":"64","author":"Bebenek","year":"2018","journal-title":"Curr. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/0378-1119(92)90216-C","article-title":"Lack of evidence for proofreading mechanisms associated with an RNA virus polymerase","volume":"122","author":"Steinhauer","year":"1992","journal-title":"Gene"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4433","DOI":"10.1007\/s00018-016-2299-6","article-title":"Mechanisms of viral mutation","volume":"73","author":"Sanjuan","year":"2016","journal-title":"Cell Mol. Life. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1146\/annurev-virology-010320-061642","article-title":"Within-host viral diversity: A window into viral evolution","volume":"7","author":"Lauring","year":"2020","journal-title":"Annu. Rev. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Holmes, E.C. (2009). The Evolution and Emergence of RNA Viruses, Oxford University Press.","DOI":"10.1093\/oso\/9780199211128.001.0001"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7289","DOI":"10.1073\/pnas.1232294100","article-title":"A single mutation in poliovirus RNA-dependent RNA polymerase confers resistance to mutagenic nucleotide analogs via increased fidelity","volume":"100","author":"Pfeiffer","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Pfeiffer, J.K., and Kirkegaard, K. (2005). Increased fidelity reduces poliovirus fitness and virulence under selective pressure in mice. PLoS Pathog., 1.","DOI":"10.1371\/journal.ppat.0010011"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ncomms5794","article-title":"Generation and characterization of influenza A viruses with altered polymerase fidelity","volume":"5","author":"Cheung","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"25706","DOI":"10.1074\/jbc.M503444200","article-title":"Remote site control of an active site fidelity checkpoint in a viral RNA-dependent RNA polymerase","volume":"280","author":"Arnold","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1128\/JVI.01374-07","article-title":"Amiloride derivatives inhibit coxsackievirus B3 RNA replication","volume":"82","author":"Harrison","year":"2008","journal-title":"J. Virol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/nm1726","article-title":"Engineering attenuated virus vaccines by controlling replication fidelity","volume":"14","author":"Vignuzzi","year":"2008","journal-title":"Nat. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"16038","DOI":"10.1073\/pnas.1111650108","article-title":"Arbovirus high fidelity variant loses fitness in mosquitoes and mice","volume":"108","author":"Coffey","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","first-page":"E2294","article-title":"Coxsackievirus B3 mutator strains are attenuated in vivo","volume":"109","author":"Beaucourt","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"32753","DOI":"10.1074\/jbc.M113.484428","article-title":"Vaccine-derived mutation in motif D of poliovirus RNA-dependent RNA polymerase lowers nucleotide incorporation fidelity","volume":"288","author":"Liu","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.virusres.2013.06.019","article-title":"A study of the virulence in mice of high copying fidelity variants of human enterovirus 71","volume":"176","author":"Sadeghipour","year":"2013","journal-title":"Virus Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.antiviral.2013.07.008","article-title":"An increased replication fidelity mutant of foot-and-mouth disease virus retains fitness in vitro and virulence in vivo","volume":"100","author":"Zeng","year":"2013","journal-title":"Antivir. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4008","DOI":"10.1128\/JVI.03594-13","article-title":"Ribavirin-resistant variants of foot-and-mouth disease virus: The effect of restricted quasispecies diversity on viral virulence","volume":"88","author":"Zeng","year":"2014","journal-title":"J. Virol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e00081-17","DOI":"10.1128\/JVI.00081-17","article-title":"Attenuation of foot-and-mouth disease virus by engineered viral polymerase fidelity","volume":"91","author":"Rai","year":"2017","journal-title":"J. Virol."},{"key":"ref_50","first-page":"10840","article-title":"A unique intra-molecular fidelity-modulating mechanism identified in a viral RNA-dependent RNA polymerase","volume":"46","author":"Liu","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"8796","DOI":"10.1093\/nar\/gkab660","article-title":"A novel mechanism of enhanced transcription activity and fidelity for influenza A viral RNA-dependent RNA polymerase","volume":"49","author":"Xu","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"10233","DOI":"10.1073\/pnas.0501062102","article-title":"The cost of replication fidelity in an RNA virus","volume":"102","author":"Furio","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","first-page":"20122047","article-title":"Viral mutation rates: Modelling the roles of within-host viral dynamics and the trade-off between replication fidelity and speed","volume":"280","author":"Regoes","year":"2013","journal-title":"Proc. Biol. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Fitzsimmons, W.J., Woods, R.J., McCrone, J.T., Woodman, A., Arnold, J.J., Yennawar, M., Evans, R., Cameron, C.E., and Lauring, A.S. (2018). A speed\u2013fidelity trade-off determines the mutation rate and virulence of an RNA virus. PLoS Biol., 16.","DOI":"10.1101\/309880"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/9\/1844\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:14:02Z","timestamp":1760141642000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/9\/1844"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,23]]},"references-count":54,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["v14091844"],"URL":"https:\/\/doi.org\/10.3390\/v14091844","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,23]]}}}