{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T05:59:48Z","timestamp":1791093588954,"version":"4.1.0"},"reference-count":68,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2014,4,1]],"date-time":"2014-04-01T00:00:00Z","timestamp":1396310400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2014,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Persistent infection is a key feature of hepatitis C virus (HCV). However, chimpanzee infections with cell culture-derived viruses (JFH1 or related chimeric viruses that replicate efficiently in cell culture) have been limited to acute-transient infections with no pathogenicity. Here, we report persistent infection with chronic hepatitis in a chimpanzee challenged with cell culture-derived genotype 1a virus (H77S.2) containing 6 cell culture-adaptive mutations. Following acute-transient infection with a chimeric H77\/JFH1 virus (HJ3-5), intravenous (i.v.) challenge with 10\n            <jats:sup>6<\/jats:sup>\n            FFU H77S.2 virus resulted in immediate seroconversion and, following an unusual 4- to 6-week delay, persistent viremia accompanied by alanine aminotransferase (ALT) elevation, intrahepatic innate immune responses, and diffuse hepatopathy. This first persistent infection with cell culture-produced HCV provided a unique opportunity to assess evolution of cell culture-adapted virus\n            <jats:italic>in vivo<\/jats:italic>\n            . Synonymous and nonsynonymous nucleotide substitution rates were greatest during the first 8 weeks of infection. Of 6 cell culture-adaptive mutations in H77S.2, Q1067R (NS3) had reverted to Q1067 and S2204I (NS5A) was replaced by T2204 within 8 weeks of infection. By 62 weeks, 4 of 6 mutations had reverted to the wild-type sequence, and all reverted to the wild-type sequence by 194 weeks. The data suggest H77S.2 virus has greater potential for persistence and pathogenicity than JFH1 and demonstrate both the capacity of a nonfit virus to persist for weeks in the liver in the absence of detectable viremia as well as strong selective pressure against cell culture-adaptive mutations\n            <jats:italic>in vivo<\/jats:italic>\n            .\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            This study shows that mutations promoting the production of infectious genotype 1a HCV in cell culture have the opposite effect and attenuate replication in the liver of the only fully permissive animal species other than humans. It provides the only example to date of persistent infection in a chimpanzee challenged with cell culture-produced virus and provides novel insight into the forces shaping molecular evolution of that virus during 5 years of persistent infection. It demonstrates that a poorly fit virus can replicate for weeks within the liver in the absence of detectable viremia, an observation that expands current concepts of HCV pathogenesis and that is relevant to relapses observed with direct-acting antiviral therapies.\n          <\/jats:p>","DOI":"10.1128\/jvi.03540-13","type":"journal-article","created":{"date-parts":[[2014,1,16]],"date-time":"2014-01-16T04:09:04Z","timestamp":1389845344000},"page":"3678-3694","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":28,"title":["Evolution of a Cell Culture-Derived Genotype 1a Hepatitis C Virus (H77S.2) during Persistent Infection with Chronic Hepatitis in a Chimpanzee"],"prefix":"10.1128","volume":"88","author":[{"given":"MinKyung","family":"Yi","sequence":"first","affiliation":[{"name":"Department of Microbiology &amp; Immunology, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengyu","family":"Hu","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Microbiology &amp; Immunology and the Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"},{"name":"Institute for Infectious Diseases, Guangzhou No. 8 People's Hospital, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Joyce","sequence":"additional","affiliation":[{"name":"Li Ka Shing Institute for Virology and the Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikas","family":"Saxena","sequence":"additional","affiliation":[{"name":"Center for Vaccines and Immunity, The Research Institute at The Nationwide Children's Hospital, and Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Welsch","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, J. W. Goethe University Hospital, Frankfurt\/Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Chavez","sequence":"additional","affiliation":[{"name":"Department of Virology and Immunology, Texas Biomedical Research Institute, and the Southwest National Primate Research Center, San Antonio, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernadette","family":"Guerra","sequence":"additional","affiliation":[{"name":"Department of Virology and Immunology, Texas Biomedical Research Institute, and the Southwest National Primate Research Center, San Antonio, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Yamane","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Microbiology &amp; Immunology and the Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald","family":"Veselenak","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rick","family":"Pyles","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Walker","sequence":"additional","affiliation":[{"name":"Center for Vaccines and Immunity, The Research Institute at The Nationwide Children's Hospital, and Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorne","family":"Tyrrell","sequence":"additional","affiliation":[{"name":"Li Ka Shing Institute for Virology and the Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel","family":"Bourne","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E.","family":"Lanford","sequence":"additional","affiliation":[{"name":"Department of Virology and Immunology, Texas Biomedical Research Institute, and the Southwest National Primate Research Center, San Antonio, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley M.","family":"Lemon","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Microbiology &amp; 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Chimpanzees in biomedical and behavioral research: assessing the necessity. The National Academies Press, Washington, DC"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1178178"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0809879105"},{"key":"e_1_3_2_29_2","first-page":"99","volume-title":"Hepatitis C antiviral drug discovery and development","author":"Lanford RE","year":"2011","unstructured":"LanfordRELemonSMWalkerC. 2011. The chimpanzee model of hepatitis C infections and small animal surrogates, p 99\u2013132. In HeYTanT (ed), Hepatitis C antiviral drug discovery and development. 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