{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T01:25:46Z","timestamp":1788830746134,"version":"build-2803163510"},"reference-count":135,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2017,7,13]],"date-time":"2017-07-13T00:00:00Z","timestamp":1499904000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Virus-specific cluster of differentiation 8 (CD8+) cytotoxic T cells (CTL) recognize viral antigens presented on major histocompatibility complex (MHC) class I chains on infected hepatocytes, with help from CD4+ T cells. However, this CTL response is frequently weak or undetectable in patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are receptors in the CD28 family of costimulatory molecules, providing inhibitory signals to T cells. The overexpressions of PD-1 and CTLA-4 in patients with viral infection have been shown to associate with functional impairment of virus-specific T cells. In acute viral hepatitis, PD-1 and CTLA-4 are up-regulated during the symptomatic phase, and then down-regulated after recovery. These findings suggest that PD-1 and CTLA-4 have protective effects as inhibitory molecules to suppress cytotoxic T cells which induce harmful destruction of viral infected hepatocytes in self-limited viral hepatitis. In chronic viral hepatitis, the extended upregulations of PD-1 and CTLA-4 are associated with T cell exhaustion and persistent viral infection, suggesting positive correlations between expression of immune inhibitory factors and the chronicity of viral disease. In this review, we summarize recent literature relating to PD-1, CTLA-4, and other inhibitory receptors in antigen-specific T cell exhaustion in viral hepatitis, including hepatitis A, B, C, and others.<\/jats:p>","DOI":"10.3390\/ijms18071517","type":"journal-article","created":{"date-parts":[[2017,7,13]],"date-time":"2017-07-13T10:31:57Z","timestamp":1499941917000},"page":"1517","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":84,"title":["Programmed Cell Death 1 (PD-1) and Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) in Viral Hepatitis"],"prefix":"10.3390","volume":"18","author":[{"given":"Hyosun","family":"Cho","sequence":"first","affiliation":[{"name":"College of Pharmacy, Duksung Women\u2019s University, Seoul 01369, Korea"},{"name":"Innovative Drug Center, Duksung Women\u2019s University, Seoul 01369, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyojeung","family":"Kang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Research Institute of Pharmaceutical Sciences and Institute for Microorganisms, Kyungpook National University, Daegu 41566, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hwan","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Duksung Women\u2019s University, Seoul 01369, Korea"},{"name":"Innovative Drug Center, Duksung Women\u2019s University, Seoul 01369, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,7,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/nri3169","article-title":"Living in the liver: Hepatic infections","volume":"12","author":"Protzer","year":"2012","journal-title":"Nat. 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