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A vaccine could prevent spread of this pervasive human pathogen, but has proven difficult to develop, partly due to neutralizing antibody evasion mechanisms that are inherent features of the virus envelope glycoproteins, E1 and E2. A central actor is the E2 motif, hypervariable region 1 (HVR1), which protects several non-overlapping neutralization epitopes through an incompletely understood mechanism. Here, we show that introducing different HVR1-isolate sequences into cell-culture infectious JFH1-based H77 (genotype 1a) and J4 (genotype 1b) Core-NS2 recombinants can lead to severe viral attenuation. Culture adaptation of attenuated HVR1-swapped recombinants permitted us to identify E1\/E2 substitutions at conserved positions both within and outside HVR1 that increased the infectivity of attenuated HVR1-swapped recombinants but were not adaptive for original recombinants. H77 recombinants with HVR1 from multiple other isolates consistently acquired substitutions at position 348 in E1 and position 385 in HVR1 of E2. Interestingly, HVR1-swapped J4 recombinants primarily acquired other substitutions: F291I (E1), F438V (E2), F447L\/V\/I (E2) and V710L (E2), indicating a different adaptation pathway. For H77 recombinants, the adaptive E1\/E2 substitutions increased sensitivity to the neutralizing monoclonal antibodies AR3A and AR4A, whereas for J4 recombinants, they increased sensitivity to AR3A, while having no effect on sensitivity to AR4A. To evaluate effects of the substitutions on AR3A and AR4A binding, we performed ELISAs on extracted E1\/E2 protein and performed immunoprecipitation of relevant viruses. However, extracted E1\/E2 protein and immunoprecipitation of HCV particles only reproduced the neutralization phenotypes of the J4 recombinants. Finally, we found that the HVR1-swap E1\/E2 substitutions decrease virus entry dependency on co-receptor SR-BI. Our study identifies E1\/E2 positions that could be critical for intra-complex HVR1 interactions while emphasizing the need for developing novel tools for molecular studies of E1\/E2 interactions.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009720","type":"journal-article","created":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T17:33:33Z","timestamp":1626716013000},"page":"e1009720","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["In vitro adaptation and characterization of attenuated hypervariable region 1 swap chimeras of hepatitis C virus"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0575-1597","authenticated-orcid":true,"given":"Christina Holmboe","family":"Olesen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elias H.","family":"Augestad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fulvia","family":"Troise","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7815-4806","authenticated-orcid":true,"given":"Jens","family":"Bukh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jannick","family":"Prentoe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,7,19]]},"reference":[{"key":"ppat.1009720.ref001","unstructured":"World Health Organization. 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WHO website. 2019."},{"key":"ppat.1009720.ref002","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1136\/gutjnl-2015-310421","article-title":"Hepatitis C virus treatment in the real world: optimising treatment and access to therapies","volume":"64","author":"F Zoulim","year":"2015","journal-title":"Gut"},{"key":"ppat.1009720.ref003","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1056\/NEJMra1810477","article-title":"Global Elimination of Chronic Hepatitis","volume":"380","author":"DL Thomas","year":"2019","journal-title":"N Engl J Med"},{"key":"ppat.1009720.ref004","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.virusres.2018.02.016","article-title":"Critical challenges and emerging opportunities in hepatitis C virus research in an era of potent antiviral therapy: Considerations for scientists and funding agencies","volume":"248","author":"R Bartenschlager","year":"2018","journal-title":"Virus Res"},{"key":"ppat.1009720.ref005","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2018.02146","article-title":"Hypervariable Region 1 in Envelope Protein 2 of Hepatitis C Virus: A Linchpin in Neutralizing Antibody Evasion and Viral Entry.","volume":"9","author":"J Prentoe","year":"2018","journal-title":"Front Immunol."},{"key":"ppat.1009720.ref006","doi-asserted-by":"crossref","DOI":"10.1016\/j.jhep.2016.07.035","article-title":"The history of hepatitis C virus (HCV): Basic research reveals unique features in phylogeny, evolution and the viral life cycle with new perspectives for epidemic control","volume":"65","author":"J. Bukh","year":"2016","journal-title":"J Hepatol"},{"key":"ppat.1009720.ref007","doi-asserted-by":"crossref","DOI":"10.1099\/vir.0.035956-0","article-title":"The role of neutralizing antibodies in hepatitis C virus infection","volume":"93","author":"VC Edwards","year":"2012","journal-title":"J Gen Virol"},{"key":"ppat.1009720.ref008","article-title":"Global and local envelope protein dynamics of hepatitis C virus determine broad antibody sensitivity.","author":"EH Augestad","year":"2020","journal-title":"Sci Adv."},{"key":"ppat.1009720.ref009","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.00622-20","article-title":"A novel approach to display structural proteins of hepatitis C virus quasispecies in patients reveals a key role of E2 HVR1 in viral evolution","volume":"94","author":"Y Tong","year":"2020","journal-title":"J Virol"},{"key":"ppat.1009720.ref010","doi-asserted-by":"crossref","DOI":"10.1002\/hep.28705","article-title":"Hypervariable region 1 shielding of hepatitis C virus is a main contributor to genotypic differences in neutralization sensitivity","volume":"64","author":"J Prentoe","year":"2016","journal-title":"Hepatology"},{"key":"ppat.1009720.ref011","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.01594-10","article-title":"Hypervariable Region 1 Differentially Impacts Viability of Hepatitis C Virus Strains of Genotypes 1 to 6 and Impairs Virus Neutralization","volume":"85","author":"J Prentoe","year":"2011","journal-title":"J Virol"},{"key":"ppat.1009720.ref012","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.02200-09","article-title":"Hepatitis C virus hypervariable region 1 modulates receptor interactions, conceals the CD81 binding site, and protects conserved neutralizing epitopes","volume":"84","author":"D Bankwitz","year":"2010","journal-title":"J Virol"},{"key":"ppat.1009720.ref013","doi-asserted-by":"crossref","DOI":"10.1136\/gutjnl-2015-310300","article-title":"HVR1-mediated antibody evasion of highly infectious in vivo adapted HCV in 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Gopal","year":"2017","journal-title":"PLoS Pathog"},{"key":"ppat.1009720.ref036","doi-asserted-by":"crossref","DOI":"10.1093\/glycob\/cws171","article-title":"Mass spectrometric analysis of hepatitis C viral envelope protein E2 reveals extended microheterogeneity of mucin-type O-linked glycosylation","volume":"23","author":"J Br\u00e4utigam","year":"2013","journal-title":"Glycobiology"},{"key":"ppat.1009720.ref037","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1006235","article-title":"Extra-epitopic hepatitis C virus polymorphisms confer resistance to broadly neutralizing antibodies by modulating binding to scavenger receptor B1.","volume":"13","author":"R El-Diwany","year":"2017","journal-title":"PLoS Pathog."},{"key":"ppat.1009720.ref038","article-title":"Breadth of neutralization and synergy of clinically relevant human monoclonal antibodies against HCV genotype 1a, 1b, 2a, 2b, 2c and 3a","volume":"60","author":"THR 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(80-)."},{"key":"ppat.1009720.ref052","doi-asserted-by":"crossref","DOI":"10.1006\/viro.1999.9889","article-title":"Hepatitis C virus: An infectious molecular clone of a second major genotype (2a) and lack of viability of intertypic 1a and 2a chimeras.","volume":"262","author":"M Yanagi","year":"1999","journal-title":"Virology"},{"key":"ppat.1009720.ref053","doi-asserted-by":"crossref","DOI":"10.1053\/j.gastro.2007.08.005","article-title":"Robust Hepatitis C Genotype 3a Cell Culture Releasing Adapted Intergenotypic 3a\/2a (S52\/JFH1) Viruses.","volume":"133","author":"JM Gottwein","year":"2007","journal-title":"Gastroenterology."},{"key":"ppat.1009720.ref054","doi-asserted-by":"crossref","DOI":"10.1002\/hep.24692","article-title":"A Human monoclonal antibody targeting scavenger receptor class B type I precludes hepatitis C virus infection and viral spread in vitro and in vivo","volume":"55","author":"P Meuleman","year":"2012","journal-title":"Hepatology"},{"key":"ppat.1009720.ref055","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.01939-12","article-title":"Structure of Hepatitis C Virus Envelope Glycoprotein E2 Antigenic Site 412 to 423 in Complex with Antibody AP33","volume":"86","author":"L Kong","year":"2012","journal-title":"J Virol"},{"key":"ppat.1009720.ref056","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.02667-09","article-title":"Novel Infectious cDNA Clones of Hepatitis C Virus Genotype 3a (Strain S52) and 4a (Strain ED43): Genetic Analyses and In Vivo Pathogenesis Studies.","volume":"84","author":"JM Gottwein","year":"2010","journal-title":"J Virol"},{"key":"ppat.1009720.ref057","article-title":"Mutations in Hepatitis C Virus E2 Located outside the CD81 Binding Sites Lead to Escape from Broadly Neutralizing Antibodies but Compromise Virus Infectivity.","volume":"83","author":"Z -y. Keck","year":"2009","journal-title":"J Virol"},{"key":"ppat.1009720.ref058","doi-asserted-by":"crossref","DOI":"10.1084\/jem.20021756","article-title":"Infectious Hepatitis C Virus Pseudo-particles Containing Functional E1\u2013E2 Envelope Protein Complexes","volume":"197","author":"B Bartosch","year":"2003","journal-title":"J Exp Med"},{"key":"ppat.1009720.ref059","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.0607026104","article-title":"Rapid induction of virus-neutralizing antibodies and viral clearance in a single-source outbreak of hepatitis C.","volume":"104","author":"JM Pestka","year":"2007","journal-title":"PNAS."}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1009720","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T00:00:00Z","timestamp":1627516800000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1009720","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T18:54:02Z","timestamp":1627584842000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1009720"}},"subtitle":[],"editor":[{"given":"Alexander","family":"Ploss","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,7,19]]},"references-count":59,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7,19]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1009720","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.ppat.1009720","asserted-by":"object"}]},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,19]]}}}