https://phaidra.vetmeduni.ac.at/o:1798 Intra-host analysis of hepaciviral glycoprotein evolution reveals signatures associated with viral persistence and clearance Gömer, André André Gömer 0000-0002-4567-0441 Ruhr University Bochum Todt, Daniel Daniel Todt 0000-0002-3564-1014 Ruhr University Bochum Steinmann, Eike Eike Steinmann Ruhr University Bochum Wedemeyer, Heiner Heiner Wedemeyer Hannover Medical School Pietschmann, Thomas Thomas Pietschmann Twincore Cavalleri, Jessika M. V. Jessika M. V. Cavalleri 0000-0002-8575-7402 University of Veterinary Medicine Vienna Bock, C-Thomas C-Thomas Bock Robert Koch Institute Seitz, Stefan Stefan Seitz University of Heidelberg Orton, Richard Richard Orton 0000-0002-3389-4325 University of Glasgow Reuter, Gábor Gábor Reuter University of Pécs Deterding, Katja Katja Deterding Hannover Medical School Pfaender, Stephanie Stephanie Pfaender Ruhr University Bochum Brown, Richard J. P. Richard J. P. Brown 0000-0002-3292-6671 Paul Ehrlich Institute Oxford University Press text eng Abstract: Even 30 years after the discovery of the hepatitis C virus (HCV) in humans there is still no vaccine available. 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. Hepatitis-C Virus; Hypervariable Region 1; T-Cell Responses; Sequence Stability; Equine Hepacivirus; Antiviral Therapy; Infection; Transmission; Replication; Selection http://creativecommons.org/licenses/by-nc/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:1798/download 10.1093/ve/veac007 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Virus Evolution 8(1) (2022) Virus Evolution 8 1 3.93 MB 2022