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Greater understanding of HCV pathogenesis and vaccine development has been hampered by the lack of a fully immunocompetent small-animal model permissive to infection. Rodents are resistant to HCV infection due to a variety of factors at the levels of entry and replication, many of which have been discovered within the past decade. We hypothesized that genetically altering these factors in mice would provide a host environment conducive to infection. Here, we present the generation and characterization of a series of mouse lines bearing humanized alleles for CD81, occludin, TRIM26, and CypA, the murine orthologs for which do not support HCV uptake and replication. Additionally, we knocked out CD302 and CR1L, which restrict HCV infection in mouse hepatocytes. Intravenously, inoculation of mice harboring some or all of these mutant alleles did not increase viremia. To ascertain that mouse adaptive immune responses do not rapidly clear any putative low-level viremia, we engrafted hepatocytes from these genetically complex lines into immunodeficient liver-injury strains. No cohort of mice presented with sustained HC viremia, although we detected low-level viremia in a subset of transplant-recipient mice. Collectively, although these mouse models did not support robust, sustained viremia, these mouse mutant lines represent the most genetically advanced mouse model of HCV infection and will provide an important platform for future genetic host adaptations and\/or complementary viral adaptation approaches.<\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>Hepatitis C virus (HCV) presents a significant threat to global health. Despite its prevalence worldwide, there remain significant knowledge gaps regarding immunopathogenesis, oncogenesis, and determinants for vaccine efficacy. This is due to the scarcity of small-animal models for HCV, a virus that only robustly infects human and chimpanzee hepatocytes. In this work, we genetically engineer mice to either humanize or remove several factors that are known to limit HCV infection in mice. We then expose these mice to HCV and assess whether they develop infection over time. To see whether the immune system impacts infection in these modified mice, we transplant liver cells from those mice into ones that lack immune cells and then assess their ability to develop HCV infection. While we did not succeed in generating a mouse that sustains robust viremia, these complex strains nevertheless represent an important platform for further model development.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.00793-25","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T13:00:11Z","timestamp":1756904411000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Assessment of hepatitis C virus permissiveness in iteratively genetically humanized mice"],"prefix":"10.1128","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8068-0509","authenticated-orcid":true,"given":"Michael P.","family":"Schwoerer","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00hx57361","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular Biology, Princeton University","place":["Princeton, 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