{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,14]],"date-time":"2026-11-14T22:49:38Z","timestamp":1794696578481,"version":"4.9.1"},"reference-count":74,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,9,29]],"date-time":"2020-09-29T00:00:00Z","timestamp":1601337600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,9,29]],"date-time":"2020-09-29T00:00:00Z","timestamp":1601337600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["UMO-2015\/19\/D\/NZ6\/01303"],"award-info":[{"award-number":["UMO-2015\/19\/D\/NZ6\/01303"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004895","name":"European Social Fund","doi-asserted-by":"publisher","award":["POWR.03.02.00-00-I041\/16-00"],"award-info":[{"award-number":["POWR.03.02.00-00-I041\/16-00"]}],"id":[{"id":"10.13039\/501100004895","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>During chronic hepatitis C virus (HCV) infection, both CD4<jats:sup>+<\/jats:sup>and CD8<jats:sup>+<\/jats:sup>T-cells become functionally exhausted, which is reflected by increased expression of programmed cell death-1 (PD-1) and T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3), and elevated anti-inflammatory interleukin 10 (IL-10) plasma levels. We studied 76 DAA-treated HCV-positive patients and 18 non-infected controls. Flow cytometry measured pretreatment frequencies of CD4<jats:sup>+<\/jats:sup>PD-1<jats:sup>+<\/jats:sup>, CD4<jats:sup>+<\/jats:sup>PD-1<jats:sup>+<\/jats:sup>Tim-3<jats:sup>+<\/jats:sup>and CD8<jats:sup>+<\/jats:sup>PD-1<jats:sup>+<\/jats:sup>Tim-3<jats:sup>+<\/jats:sup>T-cells and IL-10 levels measured by ELISA were significantly higher and CD4<jats:sup>+<\/jats:sup>PD-1<jats:sup>\u2212<\/jats:sup>Tim-3<jats:sup>\u2212<\/jats:sup>and CD8<jats:sup>+<\/jats:sup>PD-1<jats:sup>\u2212<\/jats:sup>Tim-3<jats:sup>\u2212<\/jats:sup>T-cells were significantly lower in patients than in controls. Treatment resulted in significant decrease of CD4<jats:sup>+<\/jats:sup>Tim-3<jats:sup>+<\/jats:sup>, CD8<jats:sup>+<\/jats:sup>Tim-3<jats:sup>+<\/jats:sup>, CD4<jats:sup>+<\/jats:sup>PD-1<jats:sup>+<\/jats:sup>Tim-3<jats:sup>+<\/jats:sup>and CD8<jats:sup>+<\/jats:sup>PD-1<jats:sup>+<\/jats:sup>Tim-3<jats:sup>+<\/jats:sup>T-cell frequencies as well as IL-10 levels and increase in CD4<jats:sup>+<\/jats:sup>PD-1<jats:sup>\u2212<\/jats:sup>Tim-3<jats:sup>\u2212<\/jats:sup>and CD8<jats:sup>+<\/jats:sup>PD-1<jats:sup>\u2212<\/jats:sup>Tim-3<jats:sup>\u2212<\/jats:sup>T-cells. There were no significant changes in the frequencies of CD4<jats:sup>+<\/jats:sup>PD-1<jats:sup>+<\/jats:sup>T-cells, while CD8<jats:sup>+<\/jats:sup>PD-1<jats:sup>+<\/jats:sup>T-cells increased. Patients with advanced liver fibrosis had higher PD-1 and lower Tim-3 expression on CD4<jats:sup>+<\/jats:sup>T-cells and treatment had little or no effect on the exhaustion markers. HCV-specific CD8<jats:sup>+<\/jats:sup>T-cells frequency has declined significantly after treatment, but their PD-1 and Tim-3 expression did not change. Successful treatment of chronic hepatitis C with DAA is associated with reversal of immune exhaustion phenotype, but this effect is absent in patients with advanced liver fibrosis.<\/jats:p>","DOI":"10.1038\/s41598-020-73137-6","type":"journal-article","created":{"date-parts":[[2020,9,29]],"date-time":"2020-09-29T10:03:40Z","timestamp":1601373820000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Decrease of T-cells exhaustion markers programmed cell death-1 and T-cell immunoglobulin and mucin domain-containing protein 3 and plasma IL-10 levels after successful treatment of chronic hepatitis C"],"prefix":"10.1038","volume":"10","author":[{"given":"Sylwia","family":"Osuch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Laskus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Berak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karol","family":"Perlejewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin J.","family":"Metzner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcin","family":"Paciorek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marek","family":"Radkowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamila","family":"Caraballo Cort\u00e9s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,9,29]]},"reference":[{"key":"73137_CR1","unstructured":"World Health Organization. https:\/\/www.who.int\/hepatitis\/publications\/global-hepatitis-report2017\/en\/."},{"key":"73137_CR2","doi-asserted-by":"publisher","first-page":"15S","DOI":"10.1002\/hep.510260703","volume":"26","author":"JH Hoofnagle","year":"1997","unstructured":"Hoofnagle, J. H. Hepatitis C: the clinical spectrum of disease. Hepatology 26, 15S-20S. https:\/\/doi.org\/10.1002\/hep.510260703 (1997).","journal-title":"Hepatology"},{"key":"73137_CR3","doi-asserted-by":"publisher","first-page":"2205","DOI":"10.1084\/jem.188.12.2205","volume":"188","author":"AJ Zajac","year":"1998","unstructured":"Zajac, A. J. et al. Viral immune evasion due to persistence of activated T cells without effector function. J. Exp. Med. 188, 2205\u20132213 (1998).","journal-title":"J. Exp. Med."},{"key":"73137_CR4","first-page":"227","volume":"25","author":"AJ Weiner","year":"1995","unstructured":"Weiner, A. J. et al. Association of cytotoxic T lymphocyte (CTL) escape mutations with persistent hepatitis C virus (HCV) infection. Princess Takamatsu Symp. 25, 227\u2013235 (1995).","journal-title":"Princess Takamatsu Symp."},{"key":"73137_CR5","doi-asserted-by":"publisher","first-page":"1395","DOI":"10.1084\/jem.194.10.1395","volume":"194","author":"R Thimme","year":"2001","unstructured":"Thimme, R. et al. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J. Exp. Med. 194, 1395\u20131406. https:\/\/doi.org\/10.1084\/jem.194.10.1395 (2001).","journal-title":"J. Exp. Med."},{"key":"73137_CR6","doi-asserted-by":"publisher","first-page":"2569","DOI":"10.3389\/fimmu.2018.02569","volume":"9","author":"A Saeidi","year":"2018","unstructured":"Saeidi, A. et al. T-cell exhaustion in chronic infections: reversing the state of exhaustion and reinvigorating optimal protective Immune responses. Front. Immunol. 9, 2569. https:\/\/doi.org\/10.3389\/fimmu.2018.02569 (2018).","journal-title":"Front. Immunol."},{"key":"73137_CR7","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1111\/j.1365-2567.2010.03255.x","volume":"129","author":"JS Yi","year":"2010","unstructured":"Yi, J. S., Cox, M. A. & Zajac, A. J. T-cell exhaustion: characteristics, causes and conversion. Immunology 129, 474\u2013481. https:\/\/doi.org\/10.1111\/j.1365-2567.2010.03255.x (2010).","journal-title":"Immunology"},{"key":"73137_CR8","doi-asserted-by":"publisher","first-page":"e47648","DOI":"10.1371\/journal.pone.0047648","volume":"7","author":"G Nebbia","year":"2012","unstructured":"Nebbia, G. et al. Upregulation of the Tim-3\/galectin-9 pathway of T cell exhaustion in chronic hepatitis B virus infection. PLoS ONE 7, e47648. https:\/\/doi.org\/10.1371\/journal.pone.0047648 (2012).","journal-title":"PLoS ONE"},{"key":"73137_CR9","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1038\/nature05115","volume":"443","author":"CL Day","year":"2006","unstructured":"Day, C. L. et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443, 350\u2013354. https:\/\/doi.org\/10.1038\/nature05115 (2006).","journal-title":"Nature"},{"key":"73137_CR10","doi-asserted-by":"publisher","first-page":"4215","DOI":"10.1128\/JVI.02844-06","volume":"81","author":"C Boni","year":"2007","unstructured":"Boni, C. et al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J. Virol. 81, 4215\u20134225. https:\/\/doi.org\/10.1128\/JVI.02844-06 (2007).","journal-title":"J. Virol."},{"key":"73137_CR11","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1002\/eji.201646875","volume":"47","author":"L Dyck","year":"2017","unstructured":"Dyck, L. & Mills, K. H. G. Immune checkpoints and their inhibition in cancer and infectious diseases. Eur. J. Immunol. 47, 765\u2013779. https:\/\/doi.org\/10.1002\/eji.201646875 (2017).","journal-title":"Eur. J. Immunol."},{"key":"73137_CR12","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1038\/ni.2035","volume":"12","author":"EJ Wherry","year":"2011","unstructured":"Wherry, E. J. T cell exhaustion. Nat. Immunol. 12, 492\u2013499 (2011).","journal-title":"Nat. Immunol."},{"key":"73137_CR13","doi-asserted-by":"publisher","first-page":"310","DOI":"10.3389\/fimmu.2015.00310","volume":"6","author":"SA Fuertes Marraco","year":"2015","unstructured":"Fuertes Marraco, S. A., Neubert, N. J., Verdeil, G. & Speiser, D. E. Inhibitory Receptors Beyond T Cell Exhaustion. Front. Immunol. 6, 310. https:\/\/doi.org\/10.3389\/fimmu.2015.00310 (2015).","journal-title":"Front. Immunol."},{"key":"73137_CR14","doi-asserted-by":"publisher","first-page":"1147","DOI":"10.1038\/nm.2232","volume":"16","author":"M Quigley","year":"2010","unstructured":"Quigley, M. et al. Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat. Med. 16, 1147\u20131151. https:\/\/doi.org\/10.1038\/nm.2232 (2010).","journal-title":"Nat. Med."},{"key":"73137_CR15","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/j.immuni.2004.06.017","volume":"21","author":"T Pentcheva-Hoang","year":"2004","unstructured":"Pentcheva-Hoang, T., Egen, J. G., Wojnoonski, K. & Allison, J. P. B7\u20131 and B7\u20132 selectively recruit CTLA-4 and CD28 to the immunological synapse. Immunity 21, 401\u2013413. https:\/\/doi.org\/10.1016\/j.immuni.2004.06.017 (2004).","journal-title":"Immunity"},{"key":"73137_CR16","doi-asserted-by":"publisher","first-page":"2957","DOI":"10.4049\/jimmunol.1100038","volume":"188","author":"PM Odorizzi","year":"2012","unstructured":"Odorizzi, P. M. & Wherry, E. J. Inhibitory receptors on lymphocytes: insights from infections. J. Immunol. 188, 2957\u20132965. https:\/\/doi.org\/10.4049\/jimmunol.1100038 (2012).","journal-title":"J. Immunol."},{"key":"73137_CR17","doi-asserted-by":"publisher","first-page":"4546","DOI":"10.1172\/JCI43127","volume":"120","author":"RH McMahan","year":"2010","unstructured":"McMahan, R. H. et al. Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity. J. Clin. Investig. 120, 4546\u20134557. https:\/\/doi.org\/10.1172\/JCI43127 (2010).","journal-title":"J. Clin. Investig."},{"key":"73137_CR18","doi-asserted-by":"publisher","first-page":"1537","DOI":"10.1182\/blood-2008-12-195792","volume":"114","author":"M Ahmadzadeh","year":"2009","unstructured":"Ahmadzadeh, M. et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 114, 1537\u20131544. https:\/\/doi.org\/10.1182\/blood-2008-12-195792 (2009).","journal-title":"Blood"},{"key":"73137_CR19","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1093\/infdis\/jis304","volume":"206","author":"R Bhadra","year":"2012","unstructured":"Bhadra, R., Gigley, J. P. & Khan, I. A. PD-1-mediated attrition of polyfunctional memory CD8+ T cells in chronic toxoplasma infection. J. Infect. Dis. 206, 125\u2013134. https:\/\/doi.org\/10.1093\/infdis\/jis304 (2012).","journal-title":"J. Infect. Dis."},{"key":"73137_CR20","doi-asserted-by":"publisher","first-page":"2222","DOI":"10.4049\/jimmunol.1101122","volume":"187","author":"CL Day","year":"2011","unstructured":"Day, C. L. et al. Functional capacity of Mycobacterium tuberculosis-specific T cell responses in humans is associated with mycobacterial load. J. Immunol. 187, 2222\u20132232. https:\/\/doi.org\/10.4049\/jimmunol.1101122 (2011).","journal-title":"J. Immunol."},{"key":"73137_CR21","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1097\/TP.0000000000000169","volume":"98","author":"N Murakami","year":"2014","unstructured":"Murakami, N. & Riella, L. V. Co-inhibitory pathways and their importance in immune regulation. Transplantation 98, 3\u201314. https:\/\/doi.org\/10.1097\/TP.0000000000000169 (2014).","journal-title":"Transplantation"},{"key":"73137_CR22","doi-asserted-by":"publisher","first-page":"e1792","DOI":"10.1038\/cddis.2015.162","volume":"6","author":"Y Jiang","year":"2015","unstructured":"Jiang, Y., Li, Y. & Zhu, B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis. 6, e1792. https:\/\/doi.org\/10.1038\/cddis.2015.162 (2015).","journal-title":"Cell Death Dis."},{"key":"73137_CR23","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18071517","author":"H Cho","year":"2017","unstructured":"Cho, H., Kang, H., Lee, H. H. & Kim, C. W. Programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) in viral hepatitis. Int. J. Mol. Sci. https:\/\/doi.org\/10.3390\/ijms18071517 (2017).","journal-title":"Int. J. Mol. Sci."},{"key":"73137_CR24","doi-asserted-by":"publisher","first-page":"4200","DOI":"10.4049\/jimmunol.1001783","volume":"186","author":"J Duraiswamy","year":"2011","unstructured":"Duraiswamy, J. et al. Phenotype, function, and gene expression profiles of programmed death-1(hi) CD8 T cells in healthy human adults. J. Immunol. 186, 4200\u20134212. https:\/\/doi.org\/10.4049\/jimmunol.1001783 (2011).","journal-title":"J. Immunol."},{"key":"73137_CR25","doi-asserted-by":"publisher","first-page":"4501","DOI":"10.1182\/blood-2010-10-310425","volume":"117","author":"Q Zhou","year":"2011","unstructured":"Zhou, Q. et al. Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood 117, 4501\u20134510. https:\/\/doi.org\/10.1182\/blood-2010-10-310425 (2011).","journal-title":"Blood"},{"key":"73137_CR26","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1158\/2326-6066.CIR-14-0039","volume":"2","author":"AC Anderson","year":"2014","unstructured":"Anderson, A. C. Tim-3: an emerging target in the cancer immunotherapy landscape. Cancer Immunol. Res. 2, 393\u2013398. https:\/\/doi.org\/10.1158\/2326-6066.CIR-14-0039 (2014).","journal-title":"Cancer Immunol. Res."},{"key":"73137_CR27","doi-asserted-by":"publisher","first-page":"14733","DOI":"10.1073\/pnas.1009731107","volume":"107","author":"HT Jin","year":"2010","unstructured":"Jin, H. T. et al. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc. Natl. Acad. Sci. USA 107, 14733\u201314738. https:\/\/doi.org\/10.1073\/pnas.1009731107 (2010).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"73137_CR28","doi-asserted-by":"publisher","first-page":"9249","DOI":"10.1128\/JVI.00409-07","volume":"81","author":"L Golden-Mason","year":"2007","unstructured":"Golden-Mason, L. et al. Upregulation of PD-1 expression on circulating and intrahepatic hepatitis C virus-specific CD8+ T cells associated with reversible immune dysfunction. J. Virol. 81, 9249\u20139258. https:\/\/doi.org\/10.1128\/JVI.00409-07 (2007).","journal-title":"J. Virol."},{"key":"73137_CR29","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1016\/j.molimm.2007.07.038","volume":"45","author":"G Peng","year":"2008","unstructured":"Peng, G. et al. PD-1 upregulation is associated with HBV-specific T cell dysfunction in chronic hepatitis B patients. Mol. Immunol. 45, 963\u2013970. https:\/\/doi.org\/10.1016\/j.molimm.2007.07.038 (2008).","journal-title":"Mol. Immunol."},{"key":"73137_CR30","doi-asserted-by":"publisher","first-page":"1749","DOI":"10.1097\/QAD.0000000000000314","volume":"28","author":"LR Cockerham","year":"2014","unstructured":"Cockerham, L. R. et al. Programmed death-1 expression on CD4(+) and CD8(+) T cells in treated and untreated HIV disease. AIDS 28, 1749\u20131758. https:\/\/doi.org\/10.1097\/QAD.0000000000000314 (2014).","journal-title":"AIDS"},{"key":"73137_CR31","doi-asserted-by":"publisher","first-page":"11398","DOI":"10.1128\/JVI.01177-06","volume":"80","author":"S Urbani","year":"2006","unstructured":"Urbani, S. et al. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J. Virol. 80, 11398\u201311403. https:\/\/doi.org\/10.1128\/JVI.01177-06 (2006).","journal-title":"J. Virol."},{"key":"73137_CR32","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1016\/j.immuni.2016.05.001","volume":"44","author":"AC Anderson","year":"2016","unstructured":"Anderson, A. C., Joller, N. & Kuchroo, V. K. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 44, 989\u20131004. https:\/\/doi.org\/10.1016\/j.immuni.2016.05.001 (2016).","journal-title":"Immunity"},{"key":"73137_CR33","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1016\/j.jhep.2007.12.014","volume":"48","author":"S Urbani","year":"2008","unstructured":"Urbani, S. et al. Restoration of HCV-specific T cell functions by PD-1\/PD-L1 blockade in HCV infection: effect of viremia levels and antiviral treatment. J. Hepatol. 48, 548\u2013558. https:\/\/doi.org\/10.1016\/j.jhep.2007.12.014 (2008).","journal-title":"J. Hepatol."},{"key":"73137_CR34","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/nature19330","volume":"537","author":"SJ Im","year":"2016","unstructured":"Im, S. J. et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537, 417\u2013421. https:\/\/doi.org\/10.1038\/nature19330 (2016).","journal-title":"Nature"},{"key":"73137_CR35","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/j.immuni.2016.07.021","volume":"45","author":"DT Utzschneider","year":"2016","unstructured":"Utzschneider, D. T. et al. T cell factor 1-expressing memory-like CD8(+) T cells sustain the immune response to chronic viral infections. Immunity 45, 415\u2013427. https:\/\/doi.org\/10.1016\/j.immuni.2016.07.021 (2016).","journal-title":"Immunity"},{"key":"73137_CR36","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aai8593","author":"T Wu","year":"2016","unstructured":"Wu, T. et al. The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness. Sci. Immunol. https:\/\/doi.org\/10.1126\/sciimmunol.aai8593 (2016).","journal-title":"Sci. Immunol."},{"key":"73137_CR37","doi-asserted-by":"publisher","first-page":"e1003735","DOI":"10.1371\/journal.ppat.1003735","volume":"9","author":"K Richter","year":"2013","unstructured":"Richter, K. et al. Macrophage and T cell produced IL-10 promotes viral chronicity. PLoS Pathog 9, e1003735. https:\/\/doi.org\/10.1371\/journal.ppat.1003735 (2013).","journal-title":"PLoS Pathog"},{"key":"73137_CR38","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.virol.2014.12.033","volume":"479\u2013480","author":"SM Kahan","year":"2015","unstructured":"Kahan, S. M., Wherry, E. J. & Zajac, A. J. T cell exhaustion during persistent viral infections. Virology 479\u2013480, 180\u2013193. https:\/\/doi.org\/10.1016\/j.virol.2014.12.033 (2015).","journal-title":"Virology"},{"key":"73137_CR39","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1007\/s00251-003-0594-5","volume":"55","author":"S Knapp","year":"2003","unstructured":"Knapp, S. et al. Interleukin-10 promoter polymorphisms and the outcome of hepatitis C virus infection. Immunogenetics 55, 362\u2013369. https:\/\/doi.org\/10.1007\/s00251-003-0594-5 (2003).","journal-title":"Immunogenetics"},{"key":"73137_CR40","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.1038\/nm1492","volume":"12","author":"DG Brooks","year":"2006","unstructured":"Brooks, D. G. et al. Interleukin-10 determines viral clearance or persistence in vivo. Nat. Med. 12, 1301\u20131309. https:\/\/doi.org\/10.1038\/nm1492 (2006).","journal-title":"Nat. Med."},{"key":"73137_CR41","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/1471-2172-8-8","volume":"8","author":"CH Maris","year":"2007","unstructured":"Maris, C. H., Chappell, C. P. & Jacob, J. Interleukin-10 plays an early role in generating virus-specific T cell anergy. BMC Immunol. 8, 8. https:\/\/doi.org\/10.1186\/1471-2172-8-8 (2007).","journal-title":"BMC Immunol."},{"key":"73137_CR42","doi-asserted-by":"publisher","first-page":"2461","DOI":"10.1084\/jem.20061462","volume":"203","author":"M Ejrnaes","year":"2006","unstructured":"Ejrnaes, M. et al. Resolution of a chronic viral infection after interleukin-10 receptor blockade. J. Exp. Med. 203, 2461\u20132472. https:\/\/doi.org\/10.1084\/jem.20061462 (2006).","journal-title":"J. Exp. Med."},{"key":"73137_CR43","doi-asserted-by":"publisher","first-page":"3154","DOI":"10.1128\/JVI.02474-07","volume":"82","author":"V Kasprowicz","year":"2008","unstructured":"Kasprowicz, V. et al. High level of PD-1 expression on hepatitis C virus (HCV)-specific CD8+ and CD4+ T cells during acute HCV infection, irrespective of clinical outcome. J. Virol. 82, 3154\u20133160. https:\/\/doi.org\/10.1128\/JVI.02474-07 (2008).","journal-title":"J. Virol."},{"key":"73137_CR44","doi-asserted-by":"publisher","first-page":"8215","DOI":"10.4049\/jimmunol.181.12.8215","volume":"181","author":"A Rutebemberwa","year":"2008","unstructured":"Rutebemberwa, A. et al. High-programmed death-1 levels on hepatitis C virus-specific T cells during acute infection are associated with viral persistence and require preservation of cognate antigen during chronic infection. J. Immunol. 181, 8215\u20138225. https:\/\/doi.org\/10.4049\/jimmunol.181.12.8215 (2008).","journal-title":"J. Immunol."},{"key":"73137_CR45","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1111\/jvh.13108","volume":"26","author":"K Caraballo Cortes","year":"2019","unstructured":"Caraballo Cortes, K. et al. Expression of programmed cell death protein 1 and T-cell immunoglobulin- and mucin-domain-containing molecule-3 on peripheral blood CD4+CD8+ double positive T cells in patients with chronic hepatitis C virus infection and in subjects who spontaneously cleared the virus. J. Viral. Hepat. 26, 942\u2013950. https:\/\/doi.org\/10.1111\/jvh.13108 (2019).","journal-title":"J. Viral. Hepat."},{"key":"73137_CR46","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1136\/gut.2005.069153","volume":"55","author":"J Foucher","year":"2006","unstructured":"Foucher, J. et al. Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study. Gut 55, 403\u2013408. https:\/\/doi.org\/10.1136\/gut.2005.069153 (2006).","journal-title":"Gut"},{"key":"73137_CR47","doi-asserted-by":"publisher","first-page":"1470","DOI":"10.3389\/fimmu.2019.01470","volume":"10","author":"S Romani","year":"2019","unstructured":"Romani, S. et al. Peripheral PD-1(+) T cells co-expressing inhibitory receptors predict SVR with ultra short duration DAA therapy in HCV infection. Front. Immunol. 10, 1470. https:\/\/doi.org\/10.3389\/fimmu.2019.01470 (2019).","journal-title":"Front. Immunol."},{"key":"73137_CR48","doi-asserted-by":"publisher","first-page":"15050","DOI":"10.1038\/ncomms15050","volume":"8","author":"D Wieland","year":"2017","unstructured":"Wieland, D. et al. TCF1(+) hepatitis C virus-specific CD8(+) T cells are maintained after cessation of chronic antigen stimulation. Nat. Commun. 8, 15050. https:\/\/doi.org\/10.1038\/ncomms15050 (2017).","journal-title":"Nat. Commun."},{"key":"73137_CR49","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.1093\/infdis\/jiz291","volume":"220","author":"JW Han","year":"2019","unstructured":"Han, J. W. et al. Dynamic changes in ex vivo T-cell function after viral clearance in chronic HCV infection. J. Infect. Dis. 220, 1290\u20131301. https:\/\/doi.org\/10.1093\/infdis\/jiz291 (2019).","journal-title":"J. Infect. Dis."},{"key":"73137_CR50","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1172\/JCI129642","volume":"130","author":"M Smits","year":"2020","unstructured":"Smits, M. et al. Follicular T helper cells shape the HCV-specific CD4+ T cell repertoire after virus elimination. J. Clin. Investig. 130, 998\u20131009. https:\/\/doi.org\/10.1172\/JCI129642 (2020).","journal-title":"J. Clin. Investig."},{"key":"73137_CR51","doi-asserted-by":"publisher","first-page":"3637","DOI":"10.4049\/jimmunol.180.6.3637","volume":"180","author":"L Golden-Mason","year":"2008","unstructured":"Golden-Mason, L., Klarquist, J., Wahed, A. S. & Rosen, H. R. Cutting edge: programmed death-1 expression is increased on immunocytes in chronic hepatitis C virus and predicts failure of response to antiviral therapy: race-dependent differences. J. Immunol. 180, 3637\u20133641 (2008).","journal-title":"J. Immunol."},{"key":"73137_CR52","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1016\/j.jhep.2014.05.043","volume":"61","author":"B Martin","year":"2014","unstructured":"Martin, B. et al. Restoration of HCV-specific CD8+ T cell function by interferon-free therapy. J. Hepatol. 61, 538\u2013543. https:\/\/doi.org\/10.1016\/j.jhep.2014.05.043 (2014).","journal-title":"J. Hepatol."},{"key":"73137_CR53","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1111\/jvh.12465","volume":"22","author":"MA Burchill","year":"2015","unstructured":"Burchill, M. A., Golden-Mason, L., Wind-Rotolo, M. & Rosen, H. R. Memory re-differentiation and reduced lymphocyte activation in chronic HCV-infected patients receiving direct-acting antivirals. J. Viral Hepat. 22, 983\u2013991. https:\/\/doi.org\/10.1111\/jvh.12465 (2015).","journal-title":"J. Viral Hepat."},{"key":"73137_CR54","doi-asserted-by":"publisher","first-page":"e0171217","DOI":"10.1371\/journal.pone.0171217","volume":"12","author":"C Zhang","year":"2017","unstructured":"Zhang, C. et al. Comprehensive mapping of antigen specific T cell responses in hepatitis C virus infected patients with or without spontaneous viral clearance. PLoS ONE 12, e0171217. https:\/\/doi.org\/10.1371\/journal.pone.0171217 (2017).","journal-title":"PLoS ONE"},{"key":"73137_CR55","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31060","author":"MG Ghany","year":"2019","unstructured":"Ghany, M. G. et al. Update: AASLD-IDSA recommendations for testing, managing, and treating hepatitis C virus infection. Hepatology https:\/\/doi.org\/10.1002\/hep.31060 (2019).","journal-title":"Hepatology"},{"key":"73137_CR56","doi-asserted-by":"publisher","first-page":"1743","DOI":"10.1093\/cid\/civ170","volume":"60","author":"S Sidharthan","year":"2015","unstructured":"Sidharthan, S. et al. Utility of hepatitis C viral load monitoring on direct-acting antiviral therapy. Clin. Infect. Dis. 60, 1743\u20131751. https:\/\/doi.org\/10.1093\/cid\/civ170 (2015).","journal-title":"Clin. Infect. Dis."},{"key":"73137_CR57","doi-asserted-by":"publisher","first-page":"35410","DOI":"10.1038\/srep35410","volume":"6","author":"G Cloherty","year":"2016","unstructured":"Cloherty, G. et al. Hepatitis C RNA assay differences in results: potential implications for shortened therapy and determination of sustained virologic response. Sci. Rep. 6, 35410. https:\/\/doi.org\/10.1038\/srep35410 (2016).","journal-title":"Sci. Rep."},{"key":"73137_CR58","doi-asserted-by":"publisher","first-page":"9122","DOI":"10.1128\/JVI.00639-09","volume":"83","author":"L Golden-Mason","year":"2009","unstructured":"Golden-Mason, L. et al. Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells. J. Virol. 83, 9122\u20139130. https:\/\/doi.org\/10.1128\/JVI.00639-09 (2009).","journal-title":"J. Virol."},{"key":"73137_CR59","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1016\/j.jhep.2005.05.024","volume":"43","author":"KH Tang","year":"2005","unstructured":"Tang, K. H. et al. Relationship between early HCV kinetics and T-cell reactivity in chronic hepatitis C genotype 1 during peginterferon and ribavirin therapy. J. Hepatol. 43, 776\u2013782. https:\/\/doi.org\/10.1016\/j.jhep.2005.05.024 (2005).","journal-title":"J. Hepatol."},{"key":"73137_CR60","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.4049\/jimmunol.161.4.1947","volume":"161","author":"T Luft","year":"1998","unstructured":"Luft, T. et al. Type I IFNs enhance the terminal differentiation of dendritic cells. J. Immunol. 161, 1947\u20131953 (1998).","journal-title":"J. Immunol."},{"key":"73137_CR61","doi-asserted-by":"publisher","first-page":"2992","DOI":"10.1073\/pnas.0408824102","volume":"102","author":"K Li","year":"2005","unstructured":"Li, K. et al. Immune evasion by hepatitis C virus NS3\/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proc. Natl. Acad. Sci. USA 102, 2992\u20132997. https:\/\/doi.org\/10.1073\/pnas.0408824102 (2005).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"73137_CR62","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/1471-2172-9-28","volume":"9","author":"L Barrett","year":"2008","unstructured":"Barrett, L. et al. Enhanced IL-10 production in response to hepatitis C virus proteins by peripheral blood mononuclear cells from human immunodeficiency virus-monoinfected individuals. BMC Immunol. 9, 28. https:\/\/doi.org\/10.1186\/1471-2172-9-28 (2008).","journal-title":"BMC Immunol."},{"key":"73137_CR63","doi-asserted-by":"publisher","first-page":"e1000947","DOI":"10.1371\/journal.ppat.1000947","volume":"6","author":"B Bengsch","year":"2010","unstructured":"Bengsch, B. et al. Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8+ T cells is linked to antigen recognition and T cell differentiation. PLoS Pathog 6, e1000947. https:\/\/doi.org\/10.1371\/journal.ppat.1000947 (2010).","journal-title":"PLoS Pathog"},{"key":"73137_CR64","doi-asserted-by":"publisher","first-page":"2281","DOI":"10.1084\/jem.20061496","volume":"203","author":"C Petrovas","year":"2006","unstructured":"Petrovas, C. et al. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J Exp Med 203, 2281\u20132292. https:\/\/doi.org\/10.1084\/jem.20061496 (2006).","journal-title":"J Exp Med"},{"key":"73137_CR65","doi-asserted-by":"publisher","first-page":"2763","DOI":"10.1084\/jem.20081398","volume":"205","author":"RB Jones","year":"2008","unstructured":"Jones, R. B. et al. Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J. Exp. Med. 205, 2763\u20132779. https:\/\/doi.org\/10.1084\/jem.20081398 (2008).","journal-title":"J. Exp. Med."},{"key":"73137_CR66","doi-asserted-by":"publisher","first-page":"1926","DOI":"10.3389\/fimmu.2019.01926","volume":"10","author":"A Vranjkovic","year":"2019","unstructured":"Vranjkovic, A. et al. Direct-acting antiviral treatment of HCV infection does not resolve the dysfunction of circulating CD8(+) T-cells in advanced liver disease. Front. Immunol. 10, 1926. https:\/\/doi.org\/10.3389\/fimmu.2019.01926 (2019).","journal-title":"Front. Immunol."},{"key":"73137_CR67","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1016\/j.jhep.2019.06.025","volume":"71","author":"A Aregay","year":"2019","unstructured":"Aregay, A. et al. Elimination of hepatitis C virus has limited impact on the functional and mitochondrial impairment of HCV-specific CD8+ T cell responses. J. Hepatol. 71, 889\u2013899. https:\/\/doi.org\/10.1016\/j.jhep.2019.06.025 (2019).","journal-title":"J. Hepatol."},{"key":"73137_CR68","doi-asserted-by":"publisher","first-page":"1451","DOI":"10.1002\/hep4.1258","volume":"2","author":"S Shrivastava","year":"2018","unstructured":"Shrivastava, S. et al. Multitarget direct-acting antiviral therapy is associated with superior immunologic recovery in patients coinfected with human immunodeficiency virus and hepatitis C virus. Hepatol. Commun. 2, 1451\u20131466. https:\/\/doi.org\/10.1002\/hep4.1258 (2018).","journal-title":"Hepatol. Commun."},{"key":"73137_CR69","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1186\/s12948-017-0077-0","volume":"15","author":"MT Ventura","year":"2017","unstructured":"Ventura, M. T., Casciaro, M., Gangemi, S. & Buquicchio, R. Immunosenescence in aging: between immune cells depletion and cytokines up-regulation. Clin. Mol. Allergy 15, 21. https:\/\/doi.org\/10.1186\/s12948-017-0077-0 (2017).","journal-title":"Clin. Mol. Allergy"},{"key":"73137_CR70","doi-asserted-by":"publisher","first-page":"1782","DOI":"10.4049\/jimmunol.1601166","volume":"198","author":"S Ghosh","year":"2017","unstructured":"Ghosh, S. & Klein, R. S. Sex drives dimorphic immune responses to viral infections. J. Immunol. 198, 1782\u20131790. https:\/\/doi.org\/10.4049\/jimmunol.1601166 (2017).","journal-title":"J. Immunol."},{"key":"73137_CR71","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1016\/j.humimm.2011.05.025","volume":"72","author":"S Ferrando-Martinez","year":"2011","unstructured":"Ferrando-Martinez, S., Leal, M., Gonzalez-Escribano, M. F., Vega, Y. & Ruiz-Mateos, E. Simplified sequence-specific oligonucleotide-based polymerase chain reaction protocol to characterize human major histocompatibility complex A*02 and A*24 specificities. Hum. Immunol. 72, 869\u2013871. https:\/\/doi.org\/10.1016\/j.humimm.2011.05.025 (2011).","journal-title":"Hum. Immunol."},{"key":"73137_CR72","doi-asserted-by":"publisher","first-page":"5232","DOI":"10.1128\/JVI.00093-11","volume":"85","author":"J Schmidt","year":"2011","unstructured":"Schmidt, J. et al. Immunodominance of HLA-A2-restricted hepatitis C virus-specific CD8+ T cell responses is linked to naive-precursor frequency. J. Virol. 85, 5232\u20135236. https:\/\/doi.org\/10.1128\/JVI.00093-11 (2011).","journal-title":"J. Virol."},{"key":"73137_CR73","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1128\/JVI.02242-14","volume":"89","author":"K Nitschke","year":"2015","unstructured":"Nitschke, K. et al. Tetramer enrichment reveals the presence of phenotypically diverse hepatitis C virus-specific CD8+ T cells in chronic infection. J. Virol. 89, 25\u201334. https:\/\/doi.org\/10.1128\/JVI.02242-14 (2015).","journal-title":"J. Virol."},{"key":"73137_CR74","doi-asserted-by":"publisher","first-page":"3718","DOI":"10.1182\/blood-2009-10-251124","volume":"115","author":"C Alanio","year":"2010","unstructured":"Alanio, C., Lemaitre, F., Law, H. K., Hasan, M. & Albert, M. L. Enumeration of human antigen-specific naive CD8+ T cells reveals conserved precursor frequencies. Blood 115, 3718\u20133725. https:\/\/doi.org\/10.1182\/blood-2009-10-251124 (2010).","journal-title":"Blood"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-73137-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-73137-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-73137-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,8]],"date-time":"2023-10-08T16:12:23Z","timestamp":1696781543000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-73137-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,29]]},"references-count":74,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["73137"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-73137-6","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,29]]},"assertion":[{"value":"21 February 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 August 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 September 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"16060"}}