{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T13:03:45Z","timestamp":1791464625403,"version":"4.3.4"},"reference-count":46,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Lundbeck Foundation","award":["R324-2019-1375"],"award-info":[{"award-number":["R324-2019-1375"]}]},{"name":"Lundbeck Foundation","award":["R335-2019-2052"],"award-info":[{"award-number":["R335-2019-2052"]}]},{"award":["R324-2019-1375"],"award-info":[{"award-number":["R324-2019-1375"]}],"id":[{"id":"https:\/\/ror.org\/03hz8wd80","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R335-2019-2052"],"award-info":[{"award-number":["R335-2019-2052"]}],"id":[{"id":"https:\/\/ror.org\/03hz8wd80","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Novo Nordisk Hallas-M\u00f8ller Ascending Investigator","award":["NNF24OC0088618"],"award-info":[{"award-number":["NNF24OC0088618"]}]},{"name":"Mauritzen La Fontaine Fonden"},{"name":"Distinguished Investigator and Innovator grants from the Novo Nordisk Foundation","award":["NNF19OC0054518"],"award-info":[{"award-number":["NNF19OC0054518"]}]},{"name":"Distinguished Investigator and Innovator grants from the Novo Nordisk Foundation","award":["NNF23OC0087091"],"award-info":[{"award-number":["NNF23OC0087091"]}]},{"award":["NNF19OC0054518"],"award-info":[{"award-number":["NNF19OC0054518"]}],"id":[{"id":"https:\/\/ror.org\/04txyc737","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NNF23OC0087091"],"award-info":[{"award-number":["NNF23OC0087091"]}],"id":[{"id":"https:\/\/ror.org\/04txyc737","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Hepatitis C virus (HCV) infection remains a major global health burden, and no vaccine preventing chronic infection is available. The envelope glycoproteins, E1 and E2, form a complex essential for viral entry; however, the mechanisms governing E1\/E2 assembly and stability remain incompletely defined. Here, we investigated the role of the E1\/E2 transmembrane (TM) regions in HCV infectivity using chimeras of JFH1-based recombinants with isolate-specific Core-NS2 sequences in which the C-terminal TM domains of E1 (TME1), E2 (TME2), or both (TME1E2) from the H77 isolate (genotype 1a) replaced those of isolates representing genotypes 1\u20136. We further introduced the TM domains of S52 (genotype 3a) or J6 (genotype 2a) into H77 and included reciprocal swaps between J6 and S52. Most TM-swap chimeras displayed impaired infectivity; however, serial passaging led to partial recovery associated with adaptive mutations in E1\/E2 mapping not only to the C-terminal TM regions but also to the E1 stem and the internal E1 TM region (iTME1). Extending the TME1 swap to include upstream \u03b1-helical segments improved infectivity in selected chimeras, whereas inclusion of iTME1 abolished infectivity. These findings support functional interactions between membrane-associated regions of E1\/E2 and their ectodomains and highlight their relevance for E1\/E2-based HCV vaccine design.<\/jats:p>","DOI":"10.3390\/v18060616","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T12:09:07Z","timestamp":1779970147000},"page":"616","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Mapping Determinants of Hepatitis C Virus E1\/E2 Transmembrane Interactions Using Intergenotypic Chimeras"],"prefix":"10.3390","volume":"18","author":[{"given":"Margherita","family":"Fanalista","sequence":"first","affiliation":[{"name":"Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, 2650 Hvidovre, Denmark"},{"name":"Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0575-1597","authenticated-orcid":false,"given":"Christina Holmboe","family":"Olesen","sequence":"additional","affiliation":[{"name":"Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, 2650 Hvidovre, Denmark"},{"name":"Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo","family":"Vel\u00e1zquez-Moctezuma","sequence":"additional","affiliation":[{"name":"Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, 2650 Hvidovre, Denmark"},{"name":"Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark"},{"name":"Department of Biomedical Sciences (BMI), Division for Molecular and Translational Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7815-4806","authenticated-orcid":false,"given":"Jens","family":"Bukh","sequence":"additional","affiliation":[{"name":"Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, 2650 Hvidovre, Denmark"},{"name":"Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jannick","family":"Prentoe","sequence":"additional","affiliation":[{"name":"Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, 2650 Hvidovre, Denmark"},{"name":"Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark"},{"name":"Department of Biomedical Sciences (BMI), Division for Molecular and Translational Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2026, March 13). 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