{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:15:46Z","timestamp":1791404146295,"version":"4.3.3"},"reference-count":88,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,21]],"date-time":"2022-03-21T00:00:00Z","timestamp":1647820800000},"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","id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004895","name":"European Social Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004895","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>\n                      During chronic hepatitis C virus (HCV) infection, CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cells become functionally exhausted, undergoing progressive phenotypic changes, i.e., overexpression of \u201cinhibitory\u201d molecules such as PD-1 (programmed cell death protein 1) and\/or Tim-3 (T-cell immunoglobulin and mucin domain-containing molecule-3). The extreme intrahost genetic diversity of HCV is a major mechanism of immune system evasion, facilitating epitope escape. The aim of the present study was to determine whether T-cell exhaustion phenotype in chronic HCV infection is related to the sequence repertoire of NS3 viral immunodominant epitopes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The study population was ninety prospective patients with chronic HCV genotype 1b infection. Populations of peripheral blood CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cells expressing PD-1\/Tim-3 were assessed by multiparametric flow cytometry, including HCV-specific T-cells after magnetic-based enrichment using MHC-pentamer. Autologous epitope sequences were inferred from next-generation sequencing. The correction of sequencing errors and genetic variants reconstruction was performed using Quasirecomb.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      There was an interplay between the analyzed epitopes sequences and exhaustion phenotype of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cells. A predominance of NS3\n                      <jats:sub>1406<\/jats:sub>\n                      epitope sequence, representing neither prototype KLSGLGLNAV nor cross-reactive variants (KLSSLGLNAV, KLSGLGINAV or KLSALGLNAV), was associated with higher percentage of HCV-specific CD8\n                      <jats:sup>+<\/jats:sup>\n                      PD-1\n                      <jats:sup>+<\/jats:sup>\n                      Tim-3\n                      <jats:sup>+<\/jats:sup>\n                      T-cells, P=0.0102. Variability (at least two variants) of NS3\n                      <jats:sub>1406<\/jats:sub>\n                      epitope sequence was associated with increased frequencies of global CD8\n                      <jats:sup>+<\/jats:sup>\n                      PD-1\n                      <jats:sup>+<\/jats:sup>\n                      Tim-3\n                      <jats:sup>+<\/jats:sup>\n                      T-cells (P=0.0197) and lower frequencies of CD8\n                      <jats:sup>+<\/jats:sup>\n                      PD-1\n                      <jats:sup>\u2212<\/jats:sup>\n                      Tim-3\n                      <jats:sup>\u2212<\/jats:sup>\n                      T-cells (P=0.0079). In contrast, infection with NS3\n                      <jats:sub>1073<\/jats:sub>\n                      dominant variant epitope (other than prototype CVNGVCWTV) was associated with lower frequency of global CD8\n                      <jats:sup>+<\/jats:sup>\n                      PD-1\n                      <jats:sup>+<\/jats:sup>\n                      Tim-3\n                      <jats:sup>+<\/jats:sup>\n                      T-cells (P=0.0054).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our results indicate that PD-1\/Tim-3 receptor expression is largely determined by viral epitope sequence and is evident for both HCV-specific and global CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cells, pointing to the importance of evaluating autologous viral epitope sequences in the investigation of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell exhaustion in HCV infection.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2022.832206","type":"journal-article","created":{"date-parts":[[2022,3,21]],"date-time":"2022-03-21T13:04:10Z","timestamp":1647867850000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["CD8+ T-Cell Exhaustion Phenotype in Chronic Hepatitis C Virus Infection Is Associated With Epitope Sequence Variation"],"prefix":"10.3389","volume":"13","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":"Karol","family":"Perlejewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Berak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iwona","family":"Bukowska-O\u015bko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Pollak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Zielenkiewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marek","family":"Radkowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamila","family":"Caraballo 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