o:1798 Intra-host analysis of hepaciviral glycoprotein evolution reveals signatures associated with viral persistence and clearance en 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 1552099 10.1093/ve/veac007 2023-07-03T15:13:36.214Z 44 yes 46 André Gömer Ruhr University Bochum 0000-0002-4567-0441 Richard J. P. Brown Paul Ehrlich Institute person 0000-0002-3292-6671 Stephanie Pfaender Ruhr University Bochum person Katja Deterding Hannover Medical School person Gábor Reuter University of Pécs person Richard Orton University of Glasgow person 0000-0002-3389-4325 Stefan Seitz University of Heidelberg person C-Thomas Bock Robert Koch Institute person Jessika M. V. Cavalleri University of Veterinary Medicine Vienna person 0000-0002-8575-7402 Thomas Pietschmann Twincore person Heiner Wedemeyer Hannover Medical School person Eike Steinmann Ruhr University Bochum person Daniel Todt Ruhr University Bochum person 0000-0002-3564-1014 application/pdf 4125535 https://phaidra.vetmeduni.ac.at/o:1798 no yes 17 70 1552253 Virus Evolution 14 8 1 Oxford University Press 2022