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Reasons for this include the high mutation rate of HCV, which allows the virus to escape immune recognition and the absence of an immunocompetent animal model for vaccine development. Phylogenetically distinct hepaciviruses (genus Hepacivirus, family Flaviviridae) have been isolated from diverse species, each with a narrow host range: the equine hepacivirus (EqHV) is the closest known relative of HCV. In this study, we used amplicon-based deep-sequencing to investigate the viral intra-host population composition of the genomic regions encoding the surface glycoproteins E1 and E2. Patterns of E1E2 substitutional evolution were compared in longitudinally sampled EqHV-positive sera of naturally and experimentally infected horses and HCV-positive patients. Intra-host virus diversity was higher in chronically than in acutely infected horses, a pattern which was similar in the HCV-infected patients. However, overall glycoprotein variability was higher in HCV compared to EqHV. Additionally, selection pressure in HCV populations was higher, especially within the N-terminal region of E2, corresponding to the hypervariable region 1 (HVR1) in HCV. An alignment of glycoprotein sequences from diverse hepaciviruses identified the HVR1 as a unique characteristic of HCV: hepaciviruses from non-human species lack this region. Together, these data indicate that EqHV infection of horses could represent a powerful surrogate animal model to gain insights into hepaciviral evolution and HCVs HVR1-mediated immune evasion strategy.<\/jats:p>","DOI":"10.1093\/ve\/veac007","type":"journal-article","created":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T12:20:12Z","timestamp":1643631612000},"source":"Crossref","is-referenced-by-count":15,"title":["Intra-host analysis of hepaciviral glycoprotein evolution reveals signatures associated with viral persistence and clearance"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4567-0441","authenticated-orcid":false,"given":"Andr\u00e9","family":"G\u00f6mer","sequence":"first","affiliation":[{"name":"Department for Molecular and Medical Virology, Ruhr University Bochum, Universit\u00e4tsstr. 150, Bochum 44801, Germany"},{"name":"Institute of Virology, University of Veterinary Medicine Hannover, Foundation, B\u00fcnteweg 9, Hannover 30559, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3292-6671","authenticated-orcid":false,"given":"Richard J P","family":"Brown","sequence":"additional","affiliation":[{"name":"Division of Veterinary Medicine, Paul Ehrlich Institute, Paul-Ehrlich-Stra\u00dfe 51-59, Langen 63225, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Pfaender","sequence":"additional","affiliation":[{"name":"Department for Molecular and Medical Virology, Ruhr University Bochum, Universit\u00e4tsstr. 150, Bochum 44801, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Deterding","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Stra\u00dfe 1, Hannover 30625, Germany"},{"name":"German Center for Infectious Disease Research (DZIF), HepNet Study-House, Hannover 30625, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00e1bor","family":"Reuter","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Medical School, University of P\u00e9cs, Szigeti \u00fat 12., P\u00e9cs 7624, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3389-4325","authenticated-orcid":false,"given":"Richard","family":"Orton","sequence":"additional","affiliation":[{"name":"MRC-University of Glasgow, Centre for Virus Research, Garscube Campus, 464 Bearsden Road, Glasgow G61 1QH, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Seitz","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Heidelberg 69120, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C- Thomas","family":"Bock","sequence":"additional","affiliation":[{"name":"Division of Viral Gastroenteritis and Hepatitis Pathogens and Enteroviruses, Department of Infectious Diseases, Robert Koch Institute, Berlin 13353, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessika M V","family":"Cavalleri","sequence":"additional","affiliation":[{"name":"Clinical Unit of Equine Internal Medicine, University of Veterinary Medicine Vienna, Veterin\u00e4rplatz 1, Vienna 1210, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Pietschmann","sequence":"additional","affiliation":[{"name":"Twincore, Centre for Experimental and Clinical Infection Research, Institute of Experimental Virology, Hannover 30625, Germany"},{"name":"German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig Site, Hannover 30625, Germany"},{"name":"Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover 30625, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heiner","family":"Wedemeyer","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Stra\u00dfe 1, Hannover 30625, Germany"},{"name":"German Center for Infectious Disease Research (DZIF), HepNet Study-House, Hannover 30625, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eike","family":"Steinmann","sequence":"additional","affiliation":[{"name":"Department for Molecular and Medical Virology, Ruhr University Bochum, Universit\u00e4tsstr. 150, Bochum 44801, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3564-1014","authenticated-orcid":false,"given":"Daniel","family":"Todt","sequence":"additional","affiliation":[{"name":"Department for Molecular and Medical Virology, Ruhr University Bochum, Universit\u00e4tsstr. 150, Bochum 44801, Germany"},{"name":"Twincore, Centre for Experimental and Clinical Infection Research, Institute of Experimental Virology, Hannover 30625, Germany"},{"name":"European Virus Bioinformatics Centre (EVBC), Jena 07743, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,2,2]]},"reference":[{"key":"2022030116494031900_R1","doi-asserted-by":"crossref","first-page":"7007","DOI":"10.1128\/JVI.00534-15","article-title":"Identification of a Novel Hepacivirus in Domestic Cattle from Germany","volume":"89","author":"Baechlein","year":"2015","journal-title":"Journal of Virology"},{"key":"2022030116494031900_R2","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/j.jhep.2017.04.010","article-title":"Maturation of Secreted HCV Particles by Incorporation of Secreted ApoE Protects from Antibodies by Enhancing Infectivity","volume":"67","author":"Bankwitz","year":"2017","journal-title":"Journal of 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