{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T03:16:31Z","timestamp":1774926991665,"version":"3.50.1"},"reference-count":56,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T00:00:00Z","timestamp":1676592000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/ http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,3]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims:<\/jats:title>\n            <jats:p>HCV evasion of neutralizing antibodies (nAb) results in viral persistence and poses challenges to the development of an urgently needed vaccine. N\u2010linked glycosylation of viral envelope proteins is a key mechanism for such evasion. To facilitate rational vaccine design, we aimed to identify determinants of protection of conserved neutralizing epitopes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results:<\/jats:title>\n            <jats:p>Using a reverse evolutionary approach, we passaged genotype 1a, 1b, 2a, 3a, and 4a HCV with envelope proteins (E1 and E2) derived from chronically infected patients without selective pressure by nAb in cell culture. Compared with the original viruses, HCV recombinants, engineered to harbor substitutions identified in polyclonal cell culture\u2013passaged viruses, showed highly increased fitness and exposure of conserved neutralizing epitopes in antigenic regions 3 and 4, associated with protection from chronic infection. Further reverse genetic studies of acquired E1\/E2 substitutions identified positions 418 and 532 in the N1 and N6 glycosylation motifs, localizing to adjacent E2 areas, as key regulators of changes of the E1\/E2 conformational state, which governed viral sensitivity to nAb. These effects were independent of predicted glycan occupancy.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>We show how N\u2010linked glycosylation motifs can trigger dramatic changes in HCV sensitivity to nAb, independent of glycan occupancy. These findings aid in the understanding of HCV nAb evasion and rational vaccine design, as they can be exploited to stabilize the structurally flexible envelope proteins in an open conformation, exposing important neutralizing epitopes. Finally, this work resulted in a panel of highly fit cell culture infectious HCV recombinants.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.32772","type":"journal-article","created":{"date-parts":[[2022,9,3]],"date-time":"2022-09-03T03:08:40Z","timestamp":1662174520000},"page":"982-996","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":11,"title":["Identification of novel neutralizing determinants for protection against HCV"],"prefix":"10.1097","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9139-9915","authenticated-orcid":false,"given":"Garazi P.","family":"Alzua","sequence":"first","affiliation":[{"name":"Copenhagen Hepatitis C Program (CO\u2010HEP), Department of Infectious Diseases, Copenhagen University Hospital\u2013Hvidovre, Hvidovre, Denmark"},{"name":"Copenhagen Hepatitis C Program (CO\u2010HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5125-6725","authenticated-orcid":false,"given":"Anne F.","family":"Pihl","sequence":"additional","affiliation":[{"name":"Copenhagen Hepatitis C Program (CO\u2010HEP), Department of Infectious Diseases, Copenhagen University Hospital\u2013Hvidovre, Hvidovre, Denmark"},{"name":"Copenhagen Hepatitis C Program (CO\u2010HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7748-2840","authenticated-orcid":false,"given":"Anna","family":"Offersgaard","sequence":"additional","affiliation":[{"name":"Copenhagen Hepatitis C Program (CO\u2010HEP), Department of Infectious Diseases, Copenhagen University Hospital\u2013Hvidovre, Hvidovre, Denmark"},{"name":"Copenhagen Hepatitis C Program (CO\u2010HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodrigo","family":"Vel\u00e1zquez\u2010Moctezuma","sequence":"additional","affiliation":[{"name":"Copenhagen Hepatitis C Program (CO\u2010HEP), Department of Infectious Diseases, Copenhagen University Hospital\u2013Hvidovre, Hvidovre, Denmark"},{"name":"Copenhagen Hepatitis C Program (CO\u2010HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos R.","family":"Duarte Hernandez","sequence":"additional","affiliation":[{"name":"Copenhagen Hepatitis C Program (CO\u2010HEP), Department of Infectious Diseases, Copenhagen University Hospital\u2013Hvidovre, Hvidovre, Denmark"},{"name":"Copenhagen Hepatitis C Program (CO\u2010HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elias H.","family":"Augestad","sequence":"additional","affiliation":[{"name":"Copenhagen Hepatitis C Program (CO\u2010HEP), Department of Infectious Diseases, Copenhagen University Hospital\u2013Hvidovre, Hvidovre, Denmark"},{"name":"Copenhagen Hepatitis C Program (CO\u2010HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrik","family":"Fahn\u00f8e","sequence":"additional","affiliation":[{"name":"Copenhagen Hepatitis C Program (CO\u2010HEP), Department of Infectious Diseases, Copenhagen University Hospital\u2013Hvidovre, Hvidovre, Denmark"},{"name":"Copenhagen Hepatitis C Program (CO\u2010HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian K.","family":"Mathiesen","sequence":"additional","affiliation":[{"name":"Copenhagen Hepatitis C Program (CO\u2010HEP), Department of Infectious Diseases, Copenhagen University Hospital\u2013Hvidovre, Hvidovre, Denmark"},{"name":"Copenhagen Hepatitis C Program (CO\u2010HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5294-2428","authenticated-orcid":false,"given":"Henrik","family":"Krarup","sequence":"additional","affiliation":[{"name":"Department of Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark"},{"name":"Department of Clinical Medicine, Aalborg University, Aalborg, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mansun","family":"Law","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jannick","family":"Prentoe","sequence":"additional","affiliation":[{"name":"Copenhagen Hepatitis C Program (CO\u2010HEP), Department of Infectious Diseases, Copenhagen University Hospital\u2013Hvidovre, Hvidovre, Denmark"},{"name":"Copenhagen Hepatitis C Program (CO\u2010HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7815-4806","authenticated-orcid":false,"given":"Jens","family":"Bukh","sequence":"additional","affiliation":[{"name":"Copenhagen Hepatitis C Program (CO\u2010HEP), Department of Infectious Diseases, Copenhagen University Hospital\u2013Hvidovre, Hvidovre, Denmark"},{"name":"Copenhagen Hepatitis C Program (CO\u2010HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2805-0256","authenticated-orcid":false,"given":"Judith M.","family":"Gottwein","sequence":"additional","affiliation":[{"name":"Copenhagen Hepatitis C Program (CO\u2010HEP), Department of Infectious Diseases, Copenhagen University Hospital\u2013Hvidovre, Hvidovre, Denmark"},{"name":"Copenhagen Hepatitis C Program (CO\u2010HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 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