{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T06:26:05Z","timestamp":1790663165605,"version":"4.1.0"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T00:00:00Z","timestamp":1652313600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>\n                      Lack of tractable immunocompetent animal models amenable to robust experimental challenge impedes vaccine efforts for HCV. Infection with rodent hepacivirus from\n                      <jats:italic toggle=\"yes\">Rattus norvegicus<\/jats:italic>\n                      (RHV\u2010rn1) in rats shares HCV\u2010defining characteristics, including liver tropism, chronicity, and pathology. RHV in vitro cultivation would facilitate genetic studies on particle production, host factor interactions, and evaluation of antibody neutralization guiding HCV vaccine approaches.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and Results<\/jats:title>\n                    <jats:p>We report an infectious reverse genetic cell culture system for RHV\u2010rn1 using highly permissive rat hepatoma cells and adaptive mutations in the E2, NS4B, and NS5A viral proteins. Cell culture\u2013derived RHV\u2010rn1 particles (RHVcc) share hallmark biophysical characteristics of HCV and are infectious in mice and rats. Culture adaptive mutations attenuated RHVcc in immunocompetent rats, and the mutations reverted following prolonged infection, but not in severe combined immunodeficiency (SCID) mice, suggesting that adaptive immune pressure is a primary driver of reversion. Accordingly, sera from RHVcc\u2010infected SCID mice or the early acute phase of immunocompetent mice and rats were infectious in culture. We further established an in vitro RHVcc neutralization assay, and observed neutralizing activity of rat sera specifically from the chronic phase of infection. Finally, we found that scavenger receptor class B type I promoted RHV\u2010rn1 entry in vitro and in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The RHV\u2010rn1 infectious cell culture system enables studies of humoral immune responses against hepacivirus infection. Moreover, recapitulation of the entire RHV\u2010rn1 infectious cycle in cell culture will facilitate reverse genetic studies and the exploration of tropism and virus\u2013host interactions.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.32535","type":"journal-article","created":{"date-parts":[[2022,4,21]],"date-time":"2022-04-21T03:03:34Z","timestamp":1650510214000},"page":"1506-1519","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":25,"title":["Neutralization and receptor use of infectious culture\u2013derived rat hepacivirus as a model for HCV"],"prefix":"10.1097","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6191-2084","authenticated-orcid":false,"given":"Raphael","family":"Wolfisberg","sequence":"first","affiliation":[{"name":"Copenhagen Hepatitis C Program,Department of Infectious Diseases,Hvidovre Hospital,Copenhagen,Denmark"},{"name":"4321,Department of Immunology and Microbiology,University of Copenhagen,Copenhagen,Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline E.","family":"Thorselius","sequence":"additional","affiliation":[{"name":"Copenhagen Hepatitis C Program,Department of Infectious Diseases,Hvidovre Hospital,Copenhagen,Denmark"},{"name":"4321,Department of Immunology and Microbiology,University of Copenhagen,Copenhagen,Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Salinas","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center,Division of Microbiology and Immunology,Yerkes Research Primate Center,Emory University School of Medicine,Atlanta,Georgia,USA"},{"name":"Division of Infectious Diseases,Department of Medicine,Emory University School of Medicine,Atlanta,Georgia,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Elrod","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center,Division of Microbiology and Immunology,Yerkes Research Primate Center,Emory University School of Medicine,Atlanta,Georgia,USA"},{"name":"Division of Infectious Diseases,Department of Medicine,Emory University School of Medicine,Atlanta,Georgia,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheetal","family":"Trivedi","sequence":"additional","affiliation":[{"name":"Center for Vaccines and Immunity,Research Institute at Nationwide Children\u2019s Hospital,Columbus,Ohio,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Copenhagen Hepatitis C Program,Department of Infectious Diseases,Hvidovre Hospital,Copenhagen,Denmark"},{"name":"4321,Department of Immunology and Microbiology,University of Copenhagen,Copenhagen,Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrik","family":"Fahn\u00f8e","sequence":"additional","affiliation":[{"name":"Copenhagen Hepatitis C Program,Department of Infectious Diseases,Hvidovre Hospital,Copenhagen,Denmark"},{"name":"4321,Department of Immunology and Microbiology,University of Copenhagen,Copenhagen,Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Kapoor","sequence":"additional","affiliation":[{"name":"Center for Vaccines and Immunity,Research Institute at Nationwide Children\u2019s Hospital,Columbus,Ohio,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arash","family":"Grakoui","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center,Division of Microbiology and Immunology,Yerkes Research Primate Center,Emory University School of Medicine,Atlanta,Georgia,USA"},{"name":"Division of Infectious Diseases,Department of Medicine,Emory University School of Medicine,Atlanta,Georgia,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles M.","family":"Rice","sequence":"additional","affiliation":[{"name":"Laboratory of Virology and Infectious Disease,The Rockefeller University,New York,New York,USA"}],"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,Department of Infectious Diseases,Hvidovre Hospital,Copenhagen,Denmark"},{"name":"4321,Department of Immunology and Microbiology,University of Copenhagen,Copenhagen,Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenn","family":"Holmbeck","sequence":"additional","affiliation":[{"name":"Copenhagen Hepatitis C Program,Department of Infectious Diseases,Hvidovre Hospital,Copenhagen,Denmark"},{"name":"4321,Department of Immunology and Microbiology,University of Copenhagen,Copenhagen,Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1545-4067","authenticated-orcid":false,"given":"Troels K. 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