{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T16:38:54Z","timestamp":1768322334512,"version":"3.49.0"},"reference-count":111,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,9,18]],"date-time":"2021-09-18T00:00:00Z","timestamp":1631923200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT-173467"],"award-info":[{"award-number":["PJT-173467"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["U01AI131313, R01AI136533 and U19AI159819"],"award-info":[{"award-number":["U01AI131313, R01AI136533 and U19AI159819"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Over the past decade, tremendous progress has been made in systems biology-based approaches to studying immunity to viral infections and responses to vaccines. These approaches that integrate multiple facets of the immune response, including transcriptomics, serology and immune functions, are now being applied to understand correlates of protective immunity against hepatitis C virus (HCV) infection and to inform vaccine development. This review focuses on recent progress in understanding immunity to HCV using systems biology, specifically transcriptomic and epigenetic studies. It also examines proposed strategies moving forward towards an integrated systems immunology approach for predicting and evaluating the efficacy of the next generation of HCV vaccines.<\/jats:p>","DOI":"10.3390\/v13091871","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T22:35:20Z","timestamp":1632263720000},"page":"1871","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Towards a Systems Immunology Approach to Understanding Correlates of Protective Immunity against HCV"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8817-8238","authenticated-orcid":false,"given":"Naglaa H.","family":"Shoukry","sequence":"first","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al (CRCHUM), Tour Viger, Local R09.414, 900 Rue St-Denis, Montr\u00e9al, QC H2X 0A9, Canada"},{"name":"D\u00e9partement de M\u00e9decine, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, QC H2X 0A9, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,18]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (WHO) (2021, September 12). Hepatitis C Fact Sheet. 27 July 2021. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/hepatitis-c."},{"key":"ref_2","unstructured":"World Health Organization (WHO) (2016). Global Health Sector Strategy on Viral Hepatitis. 2016\u20132021, World Health Organization (WHO)."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S87","DOI":"10.1016\/j.jhep.2015.02.006","article-title":"From non-A, non-B hepatitis to hepatitis C virus cure","volume":"62","author":"Pawlotsky","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Scott, N., Wilson, D.P., Thompson, A.J., Barnes, E., El-Sayed, M., Benzaken, A.S., Drummer, H.E., and Hellard, M.E. (2019). The case for a universal hepatitis C vaccine to achieve hepatitis C elimination. BMC Med., 17.","DOI":"10.1186\/s12916-019-1411-9"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1093\/cid\/ciaa253","article-title":"Reinfection following successful direct-acting antiviral therapy for hepatitis C infection among people who inject drugs","volume":"72","author":"Cunningham","year":"2021","journal-title":"Clin. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1056\/NEJMoa2023345","article-title":"Randomized Trial of a Vaccine Regimen to Prevent Chronic HCV Infection","volume":"384","author":"Page","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"20140146","DOI":"10.1098\/rstb.2014.0146","article-title":"Vaccinology in the era of high-throughput biology","volume":"370","author":"Nakaya","year":"2015","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.immuni.2012.12.008","article-title":"Systems scale interactive exploration reveals quantitative and qualitative differences in response to influenza and pneumococcal vaccines","volume":"38","author":"Obermoser","year":"2013","journal-title":"Immunity"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Chaussabel, D., Pascual, V., and Banchereau, J. (2010). Assessing the human immune system through blood transcriptomics. BMC Biol., 8.","DOI":"10.1186\/1741-7007-8-84"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/ni.1688","article-title":"Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans","volume":"10","author":"Querec","year":"2009","journal-title":"Nat. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3119","DOI":"10.1084\/jem.20082292","article-title":"Yellow fever vaccine induces integrated multilineage and polyfunctional immune responses","volume":"205","author":"Gaucher","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/ni.2789","article-title":"Molecular signatures of antibody responses derived from a systems biology study of five human vaccines","volume":"15","author":"Li","year":"2014","journal-title":"Nat. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1016\/j.immuni.2015.11.012","article-title":"Systems Analysis of Immunity to Influenza Vaccination across Multiple Years and in Diverse Populations Reveals Shared Molecular Signatures","volume":"43","author":"Nakaya","year":"2015","journal-title":"Immunity"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.cell.2014.03.031","article-title":"Global analyses of human immune variation reveal baseline predictors of postvaccination responses","volume":"157","author":"Tsang","year":"2014","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10369","DOI":"10.1038\/ncomms10369","article-title":"Pre-vaccination inflammation and B-cell signalling predict age-related hyporesponse to hepatitis B vaccination","volume":"7","author":"Fourati","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.chom.2014.06.001","article-title":"Dengue virus infection induces expansion of a CD14(+)CD16(+) monocyte population that stimulates plasmablast differentiation","volume":"16","author":"Kwissa","year":"2014","journal-title":"Cell Host Microbe"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"eaay4014","DOI":"10.1126\/science.aay4014","article-title":"The science and medicine of human immunology","volume":"369","author":"Pulendran","year":"2020","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3225","DOI":"10.1128\/jvi.66.5.3225-3229.1992","article-title":"Hepatitis C virus (HCV) circulates as a population of different but closely related genomes: Quasispecies nature of HCV genome distribution","volume":"66","author":"Martell","year":"1992","journal-title":"J. Virol."},{"key":"ref_19","first-page":"1631","article-title":"Replication of hepatitis C virus","volume":"81","author":"Bartenschlager","year":"2000","journal-title":"J. Gen. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"15131","DOI":"10.1128\/JVI.79.24.15131-15141.2005","article-title":"Effect of bottlenecking on evolution of the nonstructural protein 3 gene of hepatitis C virus during sexually transmitted acute resolving infection","volume":"79","author":"Quer","year":"2005","journal-title":"J. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1016\/j.meegid.2009.07.011","article-title":"The quasispecies nature and biological implications of the hepatitis C virus","volume":"9","author":"Fishman","year":"2009","journal-title":"Infect. Genet. Evol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/nrgastro.2015.36","article-title":"Mixed HCV infection and reinfection in people who inject drugs\u2014Impact on therapy","volume":"12","author":"Cunningham","year":"2015","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-1-59745-372-1_1","article-title":"DNA microarrays: An introduction to the technology","volume":"509","author":"Bilitewski","year":"2009","journal-title":"Methods Mol. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nrg2484","article-title":"RNA-Seq: A revolutionary tool for transcriptomics","volume":"10","author":"Wang","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Tomlinson, J.E., Wolfisberg, R., Fahn\u00f8e, U., Patel, R.S., Trivedi, S., Kumar, A., Sharma, H., Nielsen, L., McDonough, S.P., and Bukh, J. (2021). Pathogenesis, MicroRNA-122 Gene-Regulation, and Protective Immune Responses After Acute Equine Hepacivirus Infection. Hepatology.","DOI":"10.1002\/hep.31802"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/nbt.1621","article-title":"Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation","volume":"28","author":"Trapnell","year":"2010","journal-title":"Nat. Biotechnol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e112","DOI":"10.1093\/nar\/gkq041","article-title":"Prediction of alternative isoforms from exon expression levels in RNA-Seq experiments","volume":"38","author":"Richard","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e106","DOI":"10.1093\/nar\/gkp507","article-title":"Detection of single nucleotide variations in expressed exons of the human genome using RNA-Seq","volume":"37","author":"Chepelev","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/978-1-61779-018-8_6","article-title":"Identifying mRNA editing deaminase targets by RNA-Seq","volume":"718","author":"Rosenberg","year":"2011","journal-title":"Methods Mol. Biol"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1038\/nsmb.1975","article-title":"Transcriptome-wide sequencing reveals numerous APOBEC1 mRNA-editing targets in transcript 3\u2019 UTRs","volume":"18","author":"Rosenberg","year":"2011","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1038\/nbt.2122","article-title":"Comprehensive analysis of RNA-Seq data reveals extensive RNA editing in a human transcriptome","volume":"30","author":"Peng","year":"2012","journal-title":"Nat. Biotechnol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/nmeth.3337","article-title":"Robust enumeration of cell subsets from tissue expression profiles","volume":"12","author":"Newman","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4383","DOI":"10.1038\/s41467-018-06318-7","article-title":"Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations","volume":"9","author":"MacParland","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1038\/s41586-019-1631-3","article-title":"Resolving the fibrotic niche of human liver cirrhosis at single-cell level","volume":"575","author":"Ramachandran","year":"2019","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1016\/j.jhep.2020.06.004","article-title":"Single-cell genomics and spatial transcriptomics: Discovery of novel cell states and cellular interactions in liver physiology and disease biology","volume":"73","author":"Saviano","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"317","DOI":"10.3389\/fgene.2019.00317","article-title":"Single-Cell RNA-Seq Technologies and Related Computational Data Analysis","volume":"10","author":"Chen","year":"2019","journal-title":"Front. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.ejca.2021.03.005","article-title":"Applications of single-cell and bulk RNA sequencing in onco-immunology","volume":"149","author":"Kuksin","year":"2021","journal-title":"Eur. J. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/s13073-017-0467-4","article-title":"A practical guide to single-cell RNA-sequencing for biomedical research and clinical applications","volume":"9","author":"Haque","year":"2017","journal-title":"Genome Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/j.cell.2016.04.019","article-title":"Mass Cytometry: Single Cells, Many Features","volume":"165","author":"Spitzer","year":"2016","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1038\/nmeth.4380","article-title":"Simultaneous epitope and transcriptome measurement in single cells","volume":"14","author":"Stoeckius","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1038\/nbt.3973","article-title":"Multiplexed quantification of proteins and transcripts in single cells","volume":"35","author":"Peterson","year":"2017","journal-title":"Nat. Biotechnol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1038\/nmeth.4488","article-title":"Single-cell RNA-seq\u2014now with protein","volume":"14","author":"Todorovic","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s43556-020-00009-w","article-title":"Profiling chromatin regulatory landscape: Insights into the development of ChIP-seq and ATAC-seq","volume":"1","author":"Ma","year":"2020","journal-title":"Mol. Biomed."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1038\/d41586-021-01396-y","article-title":"Tissues, not blood, are where immune cells function","volume":"593","author":"Farber","year":"2021","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/s41576-021-00370-8","article-title":"Integrating single-cell and spatial transcriptomics to elucidate intercellular tissue dynamics","volume":"22","author":"Longo","year":"2021","journal-title":"Nat. Rev. Genet."},{"key":"ref_46","first-page":"e60740","article-title":"Visualization, Quantification, and Mapping of Immune Cell Populations in the Tumor Microenvironment","volume":"157","author":"Fabre","year":"2020","journal-title":"J. Vis. Exp."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"a036970","DOI":"10.1101\/cshperspect.a036970","article-title":"Animal Models of Hepatitis C Virus Infection","volume":"10","author":"Ploss","year":"2020","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1002\/hep.29494","article-title":"Viral persistence, liver disease, and host response in a hepatitis C-like virus rat model","volume":"68","author":"Trivedi","year":"2018","journal-title":"Hepatology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"15669","DOI":"10.1073\/pnas.202608199","article-title":"Genomic analysis of the host response to hepatitis C virus infection","volume":"99","author":"Su","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"7059","DOI":"10.1128\/JVI.75.15.7059-7066.2001","article-title":"DNA microarray analysis of chimpanzee liver during acute resolving hepatitis C virus infection","volume":"75","author":"Bigger","year":"2001","journal-title":"J. Virol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"15661","DOI":"10.1073\/pnas.202608299","article-title":"Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease","volume":"99","author":"Thimme","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1053\/j.gastro.2012.05.044","article-title":"Interferon-\u03b3-stimulated genes, but not USP18, are expressed in livers of patients with acute hepatitis C","volume":"143","author":"Dill","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Rosenberg, B.R., Depla, M., Freije, C.A., Gaucher, D., Mazouz, S., Boisvert, M., Bedard, N., Bruneau, J., Rice, C.M., and Shoukry, N.H. (2018). Longitudinal transcriptomic characterization of the immune response to acute hepatitis C virus infection in patients with spontaneous viral clearance. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1007290"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1053\/j.gastro.2005.01.059","article-title":"Hepatic Gene Expression Discriminates Responders and Nonresponders in Treatment of Chronic Hepatitis C Viral Infection","volume":"128","author":"Chen","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1089\/jir.2012.0037","article-title":"The blood transcriptional signature of chronic hepatitis C virus is consistent with an ongoing interferon-mediated antiviral response","volume":"33","author":"Bolen","year":"2013","journal-title":"J. Interferon. Cytokine Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"S14","DOI":"10.1016\/j.jhep.2014.06.035","article-title":"Innate and adaptive immune responses in HCV infections","volume":"61","author":"Heim","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"5699","DOI":"10.1038\/ncomms6699","article-title":"Reduced IFNlambda4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes","volume":"5","author":"Bibert","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1002\/hep.25647","article-title":"Dysregulation of innate immunity in HCV genotype 1 IL28B unfavorable genotype patients: Impaired viral kinetics and therapeutic response","volume":"56","author":"Naggie","year":"2012","journal-title":"Hepatology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"628","DOI":"10.3389\/fimmu.2016.00628","article-title":"Type III Interferons in Hepatitis C Virus Infection","volume":"7","author":"Boisvert","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Kemming, J., Thimme, R., and Neumann-Haefelin, C. (2020). Adaptive Immune Response against Hepatitis C Virus. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21165644"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/nri.2016.69","article-title":"Immune responses and immunopathology in acute and chronic viral hepatitis","volume":"16","author":"Shin","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_62","first-page":"274","article-title":"Protective immunity against hepatitis C: Many shades of gray","volume":"5","author":"Shoukry","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1002\/hep.21365","article-title":"Loss of IL-7 receptor alpha-chain (CD127) expression in acute HCV infection associated with viral persistence","volume":"44","author":"Burton","year":"2006","journal-title":"Hepatology"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1128\/JVI.01354-06","article-title":"Analysis of CD127 and KLRG1 expression on hepatitis C virus-specific CD8+ T cells reveals the existence of different memory T-cell subsets in the peripheral blood and liver","volume":"81","author":"Bengsch","year":"2007","journal-title":"J. Virol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"10017","DOI":"10.1128\/JVI.01083-08","article-title":"Early interferon therapy for hepatitis C virus infection rescues polyfunctional, long-lived CD8+ memory T cells","volume":"82","author":"Badr","year":"2008","journal-title":"J. Virol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"4772","DOI":"10.1128\/JVI.03122-12","article-title":"The Frequency of CD127+ HCV-specific T cells but not the Expression of Exhaustion Markers Predict the Outcome of Acute Hepatitis C Virus Infection","volume":"87","author":"Shin","year":"2013","journal-title":"J. Virol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Kared, H., Fabre, T., Bedard, N., Bruneau, J., and Shoukry, N.H. (2013). Galectin-9 and IL-21 mediate cross-regulation between Th17 and Treg cells during acute hepatitis C. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003422"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1084\/jem.20050808","article-title":"Mutational escape from CD8+ T cell immunity: HCV evolution, from chimpanzees to man","volume":"201","author":"Bowen","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4831","DOI":"10.3748\/wjg.v13.i36.4831","article-title":"CD4+ T cell responses in hepatitis C virus infection","volume":"13","author":"Semmo","year":"2007","journal-title":"World J. Gastroenterol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1084\/jem.20100388","article-title":"Broadly directed virus-specific CD4+ T cell responses are primed during acute hepatitis C infection, but rapidly disappear from human blood with viral persistence","volume":"209","author":"Ciuffreda","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Gupta, P.K., Godec, J., Wolski, D., Adland, E., Yates, K., Pauken, K.E., Cosgrove, C., Ledderose, C., Junger, W.G., and Robson, S.C. (2015). CD39 Expression Identifies Terminally Exhausted CD8+ T Cells. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1005177"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/s41586-019-1326-9","article-title":"TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection","volume":"571","author":"Alfei","year":"2019","journal-title":"Nature"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1126\/science.1229620","article-title":"Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection","volume":"338","author":"Paley","year":"2012","journal-title":"Science"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.immuni.2016.07.021","article-title":"T Cell Factor 1-Expressing Memory-like CD8(+) T Cells Sustain the Immune Response to Chronic Viral Infections","volume":"45","author":"Utzschneider","year":"2016","journal-title":"Immunity"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1053\/j.gastro.2014.07.005","article-title":"Signatures of protective memory immune responses during hepatitis C virus reinfection","volume":"147","author":"Bedard","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1128\/JVI.01499-09","article-title":"Hepatitis C virus (HCV) sequence variation induces an HCV-specific T-cell phenotype analogous to spontaneous resolution","volume":"84","author":"Kasprowicz","year":"2010","journal-title":"J. Virol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1084\/jem.191.9.1499","article-title":"Analysis of successful immune responses in persons infected with hepatitis C virus","volume":"191","author":"Lechner","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1084\/jem.194.10.1395","article-title":"Determinants of viral clearance and persistence during acute hepatitis C virus infection","volume":"194","author":"Thimme","year":"2001","journal-title":"J. Exp. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"5692","DOI":"10.1073\/pnas.96.10.5692","article-title":"Quantitative analysis of hepatitis C virus-specific CD8(+) T cells in peripheral blood and liver using peptide-MHC tetramers","volume":"96","author":"He","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1128\/JVI.02021-06","article-title":"Liver-Infiltrating Lymphocytes in Chronic Human Hepatitis C Virus Infection Display an Exhausted Phenotype with High Levels of PD-1 and Low Levels of CD127 Expression","volume":"81","author":"Radziewicz","year":"2007","journal-title":"J. Virol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/j.immuni.2017.09.006","article-title":"Early Transcriptional Divergence Marks Virus-Specific Primary Human CD8(+) T Cells in Chronic versus Acute Infection","volume":"47","author":"Wolski","year":"2017","journal-title":"Immunity"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1016\/j.immuni.2018.04.026","article-title":"Epigenomic-Guided Mass Cytometry Profiling Reveals Disease-Specific Features of Exhausted CD8 T Cells","volume":"48","author":"Bengsch","year":"2018","journal-title":"Immunity"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1038\/s41467-019-14137-7","article-title":"Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection","volume":"11","author":"Barili","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Bengsch, B., Seigel, B., Ruhl, M., Timm, J., Kuntz, M., Blum, H.E., Pircher, H., and Thimme, R. (2010). 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.","DOI":"10.1371\/journal.ppat.1000947"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"15050","DOI":"10.1038\/ncomms15050","article-title":"TCF1(+) hepatitis C virus-specific CD8(+) T cells are maintained after cessation of chronic antigen stimulation","volume":"8","author":"Wieland","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.it.2019.11.004","article-title":"Stem, Effector, and Hybrid States of Memory CD8(+) T Cells","volume":"41","author":"Lugli","year":"2020","journal-title":"Trends Immunol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.jhep.2014.05.043","article-title":"Restoration of HCV-specific CD8+ T cell function by interferon-free therapy","volume":"61","author":"Martin","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Llorens-Revull, M., Costafreda, M.I., Rico, A., Guerrero-Murillo, M., Soria, M.E., P\u00edriz-Ruzo, S., Vargas-Accarino, E., Gabriel-Medina, P., Rodr\u00edguez-Fr\u00edas, F., and Riveiro-Barciela, M. (2021). Partial restoration of immune response in Hepatitis C patients after viral clearance by direct-acting antiviral therapy. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0254243"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/s41590-020-00817-w","article-title":"Memory-like HCV-specific CD8(+) T cells retain a molecular scar after cure of chronic HCV infection","volume":"22","author":"Hensel","year":"2021","journal-title":"Nat. Immunol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1038\/s41590-021-00982-6","article-title":"Differentiation of exhausted CD8(+) T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory","volume":"22","author":"Tonnerre","year":"2021","journal-title":"Nat. Immunol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1038\/s41590-021-00979-1","article-title":"Epigenetic scars of CD8(+) T cell exhaustion persist after cure of chronic infection in humans","volume":"22","author":"Yates","year":"2021","journal-title":"Nat. Immunol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1038\/s41590-021-00975-5","article-title":"Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation","volume":"22","author":"Manne","year":"2021","journal-title":"Nat. Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1002\/hep.27278","article-title":"T-cell immunity and hepatitis C virus reinfection after cure of chronic hepatitis C with an interferon-free antiviral regimen in a chimpanzee","volume":"60","author":"Callendret","year":"2014","journal-title":"Hepatology"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1172\/JCI126277","article-title":"Hepatitis C virus-specific CD4+ T cell phenotype and function in different infection outcomes","volume":"130","author":"Chen","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1172\/JCI133222","article-title":"CD4+ T cell responses in human viral infection: Lessons from hepatitis C","volume":"130","author":"Binder","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1146\/annurev-immunol-031210-101400","article-title":"Follicular helper CD4 T cells (TFH)","volume":"29","author":"Crotty","year":"2011","journal-title":"Annu. Rev. Immunol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1016\/j.immuni.2019.04.011","article-title":"T Follicular Helper Cell Biology: A Decade of Discovery and Diseases","volume":"50","author":"Crotty","year":"2019","journal-title":"Immunity"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1053\/j.gastro.2015.11.005","article-title":"Virus-Specific CD4+ T Cells Have Functional and Phenotypic Characteristics of Follicular T-Helper Cells in Patients With Acute and Chronic HCV Infections","volume":"150","author":"Raziorrouh","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1172\/JCI129642","article-title":"Follicular T helper cells shape the HCV-specific CD4+ T cell repertoire after virus elimination","volume":"130","author":"Smits","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"10149","DOI":"10.1073\/pnas.0403519101","article-title":"Neutralizing antibody response during acute and chronic hepatitis C virus infection","volume":"101","author":"Logvinoff","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1038\/75063","article-title":"Cellular immune responses persist and humoral responses decrease two decades after recovery from a single-source outbreak of hepatitis C","volume":"6","author":"Takaki","year":"2000","journal-title":"Nat. Med."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1016\/j.tim.2018.04.002","article-title":"Can Broadly Neutralizing Monoclonal Antibodies Lead to a Hepatitis C Virus Vaccine?","volume":"26","author":"Kinchen","year":"2018","journal-title":"Trends Microbiol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.coviro.2021.05.002","article-title":"Structural perspectives on HCV humoral immune evasion mechanisms","volume":"49","author":"Sevvana","year":"2021","journal-title":"Curr. Opin. Virol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.3389\/fimmu.2018.01480","article-title":"Hepatitis C Vaccines, Antibodies, and T Cells","volume":"9","author":"Shoukry","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"4848","DOI":"10.4049\/jimmunol.1600763","article-title":"Novel E2 Glycoprotein Tetramer Detects Hepatitis C Virus-Specific Memory B Cells","volume":"197","author":"Boisvert","year":"2016","journal-title":"J. Immunol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"e140590","DOI":"10.1172\/JCI140590","article-title":"Early T follicular helper cell activity accelerates hepatitis C virus-specific B cell expansion","volume":"131","author":"Salinas","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.1016\/j.cell.2021.02.018","article-title":"Time-resolved systems immunology reveals a late juncture linked to fatal COVID-19","volume":"184","author":"Liu","year":"2021","journal-title":"Cell"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Wang, X., Xu, G., Liu, X., Liu, Y., Zhang, S., and Zhang, Z. (2021). Multiomics: Unraveling the panoramic landscapes of SARS-CoV-2 infection. Cell Mol. Immunol., 1\u201312.","DOI":"10.1038\/s41423-021-00754-0"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.virusres.2016.10.014","article-title":"Understanding the complex evolution of rapidly mutating viruses with deep sequencing: Beyond the analysis of viral diversity","volume":"239","author":"Leung","year":"2017","journal-title":"Virus Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1111\/imr.12503","article-title":"Systems serology for evaluation of HIV vaccine trials","volume":"275","author":"Ackerman","year":"2017","journal-title":"Immunol. Rev."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/s41577-021-00522-1","article-title":"The first 12 months of COVID-19: A timeline of immunological insights","volume":"21","author":"Carvalho","year":"2021","journal-title":"Nat. Rev. Immunol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/9\/1871\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:02:03Z","timestamp":1760166123000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/9\/1871"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,18]]},"references-count":111,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["v13091871"],"URL":"https:\/\/doi.org\/10.3390\/v13091871","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,18]]}}}