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Norway rat hepacivirus 1 (NrHV) is a promising candidate, mirroring HCV genetic structure, pathogenesis, and immunity. However, NrHV experimental tools are limited to a single variant, RHV-rn1, and do not represent the vast genetic heterogeneity of HCV. To increase NrHV utility for HCV vaccine research, we characterized a novel variant and developed recombinant tools to study cross-reactive neutralizing antibody responses. We sequenced the isolate, NrHV-K, and created a molecular consensus clone, pNrHV-K, closely related to the original NrHV prototype strain, NYC-C12. Intrahepatically inoculated RNA-transcripts from pNrHV-K resulted in chronic infection in Lewis rats. Passaging of NrHV-K in severe combined immunodeficiency mice led to persistent infection. However, the mouse-passaged virus did not prolong infection in immunocompetent mice compared with the wild-type NrHV-K variant. Infection in na\u00efve Lewis rats with mouse-passaged virus resulted in a subset of rats clearing the infection during the acute phase, demonstrating a dichotomous infection outcome in inbred rats. We further adapted NrHV-K to efficiently infect rat hepatoma cells and showed that antibodies from RHV-rn1 and NrHV-K infected rats cross-neutralized both variants. The development of additional experimental systems for NrHV variants permits studies addressing the importance of strain diversity. This advancement aids in the quest for multivalent immune responses against diverse NrHV isolates, offering insights into cross-reacting immunity important for future HCV vaccine design.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013127","type":"journal-article","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T17:47:26Z","timestamp":1758822446000},"page":"e1013127","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["In vivo and in vitro recombinant systems of a novel variant demonstrate cross-reactive neutralization for the HCV model virus, Norway rat hepacivirus"],"prefix":"10.1371","volume":"21","author":[{"given":"Caroline E.","family":"Thorselius","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Kok","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raphael","family":"Wolfisberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrik","family":"Fahn\u00f8e","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew J.","family":"Kennedy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma A.","family":"Lundsgaard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lotte","family":"Mikkelsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mads K.","family":"Larsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satyapramod","family":"Murthy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheetal","family":"Trivedi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amit","family":"Kapoor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Troels K. 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