{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T07:36:24Z","timestamp":1790753784628,"version":"4.1.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2018,9,27]],"date-time":"2018-09-27T00:00:00Z","timestamp":1538006400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2018,12]]},"abstract":"<jats:p>The liver bears unique immune properties that support both immune tolerance and immunity, but the mechanisms responsible for clearance versus persistence of virus\u2010infected hepatocytes remain unclear. Here, we dissect the factors determining the outcome of antiviral immunity using recombinant adenoviruses that reflect the hepatropism and hepatrophism of hepatitis viruses. We generated replication\u2010deficient adenoviruses with equimolar expression of ovalbumin, luciferase, and green fluorescent protein driven by a strong ubiquitous cytomegalovirus (CMV) promoter (Ad\u2010CMV\u2010GOL) or by 100\u2010fold weaker, yet hepatocyte\u2010specific, transthyretin (TTR) promoter (Ad\u2010TTR\u2010GOL). Using <jats:italic toggle=\"yes\">in\u00a0vivo<\/jats:italic> bioluminescence to quantitatively and dynamically image luciferase activity, we demonstrated that Ad\u2010TTR\u2010GOL infection always persists, whereas Ad\u2010CMV\u2010GOL infection is always cleared, independent of the number of infected hepatocytes. Failure to clear Ad\u2010TTR\u2010GOL infection involved mechanisms acting during initiation as well as execution of antigen\u2010specific immunity. First, hepatocyte\u2010restricted antigen expression led to delayed and curtailed T\u2010cell expansion\u201410,000\u2010fold after Ad\u2010CMV\u2010GOL versus 150\u2010fold after Ad\u2010TTR\u2010GOL\u2010infection. Second, CD8 T\u2010cells primed toward antigens selectively expressed by hepatocytes showed high PD\u20101\/Tim\u20103\/LAG\u20103\/CTLA\u20104\/CD160 expression levels similar to that seen in chronic hepatitis B. Third, Ad\u2010TTR\u2010GOL but not Ad\u2010CMV\u2010GOL\u2010infected hepatocytes escaped being killed by effector T\u2010cells while still inducing high PD\u20101\/Tim\u20103\/LAG\u20103\/CTLA\u20104\/CD160 expression, indicating different thresholds of T\u2010cell receptor signaling relevant for triggering effector functions compared with exhaustion. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Our study identifies deficits in the generation of CD8 T\u2010cell immunity toward hepatocyte\u2010expressed antigens and escape of infected hepatocytes expressing low viral antigen levels from effector T\u2010cell killing as independent factors promoting viral persistence. This highlights the importance of addressing both the restauration of CD8 T\u2010cell dysfunction and overcoming local hurdles of effector T\u2010cell function to eliminate virus\u2010infected hepatocytes.<\/jats:p>","DOI":"10.1002\/hep.30080","type":"journal-article","created":{"date-parts":[[2018,5,5]],"date-time":"2018-05-05T19:40:46Z","timestamp":1525549246000},"page":"2089-2105","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":11,"title":["Outcome of Antiviral Immunity in the Liver Is Shaped by the Level of Antigen Expressed in Infected Hepatocytes"],"prefix":"10.1097","volume":"68","author":[{"given":"Katrin","family":"Manske","sequence":"first","affiliation":[{"name":"Institute of Molecular Immunology and Experimental Oncology, Klinikum Rechts der Isar,Technical University of Munich,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Kallin","sequence":"additional","affiliation":[{"name":"Institute of Molecular Immunology and Experimental Oncology, Klinikum Rechts der Isar,Technical University of Munich,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"K\u00f6nig","sequence":"additional","affiliation":[{"name":"Institute of Molecular Immunology and Experimental Oncology, Klinikum Rechts der Isar,Technical University of Munich,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika","family":"Schneider","sequence":"additional","affiliation":[{"name":"Institute of Molecular Immunology and Experimental Oncology, Klinikum Rechts der Isar,Technical University of Munich,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Kurz","sequence":"additional","affiliation":[{"name":"Institute of Molecular Immunology and Experimental Oncology, Klinikum Rechts der Isar,Technical University of Munich,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Bosch","sequence":"additional","affiliation":[{"name":"Institute of Molecular Immunology and Experimental Oncology, Klinikum Rechts der Isar,Technical University of Munich,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meike","family":"Welz","sequence":"additional","affiliation":[{"name":"Institute of Experimental Immunology,University Hospital Bonn, University of Bonn,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ru\u2010Lin","family":"Cheng","sequence":"additional","affiliation":[{"name":"Institute of Experimental Immunology,University Hospital Bonn, University of Bonn,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertram","family":"Bengsch","sequence":"additional","affiliation":[{"name":"University Hospital Freiburg,University of 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