{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T01:18:21Z","timestamp":1790731101588,"version":"4.1.0"},"reference-count":134,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2019,1,27]],"date-time":"2019-01-27T00:00:00Z","timestamp":1548547200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Virology has played an essential role in deciphering many immunological phenomena, thus shaping our current understanding of the immune system. Animal models of viral infection and human viral infections were both important tools for immunological discoveries. This review discusses two immunological breakthroughs originally identified with the help of the lymphocytic choriomeningitis virus (LCMV) model; immunological restriction by major histocompatibility complex and immunotherapy using checkpoint blockade. In addition, we discuss related discoveries such as development of tetramers, viral escape mutation, and the phenomenon of T-cell exhaustion.<\/jats:p>","DOI":"10.3390\/v11020106","type":"journal-article","created":{"date-parts":[[2019,1,29]],"date-time":"2019-01-29T03:40:55Z","timestamp":1548733255000},"page":"106","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Viruses Teaching Immunology: Role of LCMV Model and Human Viral Infections in Immunological Discoveries"],"prefix":"10.3390","volume":"11","author":[{"given":"Mohamed S.","family":"Abdel-Hakeem","sequence":"first","affiliation":[{"name":"Penn Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Kasr El-Aini, Cairo 11562, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,1,27]]},"reference":[{"key":"ref_1","first-page":"21","article-title":"Edward jenner and the history of smallpox and vaccination","volume":"18","author":"Riedel","year":"2005","journal-title":"Proc. (Bayl. Univ. Med. Cent.)"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"68","DOI":"10.3389\/fimmu.2012.00068","article-title":"Louis pasteur, the father of immunology?","volume":"3","author":"Smith","year":"2012","journal-title":"Front. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/346629a0","article-title":"Viral escape by selection of cytotoxic t cell-resistant virus variants in vivo","volume":"346","author":"Pircher","year":"1990","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"13239","DOI":"10.1128\/JVI.79.21.13239-13249.2005","article-title":"Selective escape from CD8+ T-cell responses represents a major driving force of human immunodeficiency virus type 1 (HIV-1) sequence diversity and reveals constraints on HIV-1 evolution","volume":"79","author":"Allen","year":"2005","journal-title":"J. Virol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1084\/jem.20041006","article-title":"CD8 epitope escape and reversion in acute HCV infection","volume":"200","author":"Timm","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/ni.2035","article-title":"T cell exhaustion","volume":"12","author":"Wherry","year":"2011","journal-title":"Nat. Immunol."},{"key":"ref_7","unstructured":"Baron, S. (1996). Structure and classification of viruses. Medical Microbiology, University of Texas Medical Branch at Galveston. [4th ed.]."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev-pathol-012615-044107","article-title":"An odyssey to viral pathogenesis","volume":"11","author":"Oldstone","year":"2016","journal-title":"Annu. Rev. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2650","DOI":"10.3390\/v4112650","article-title":"Role of lymphocytic choriomeningitis virus (LCMV) in understanding viral immunology: Past, present and future","volume":"4","author":"Zhou","year":"2012","journal-title":"Viruses"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/248701a0","article-title":"Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system","volume":"248","author":"Zinkernagel","year":"1974","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1084\/jem.141.2.502","article-title":"H-2 compatibility is required for T-cell-mediated lysis of target cells infected with lymphocytic choriomeningitis virus","volume":"141","author":"Doherty","year":"1975","journal-title":"J. Exp. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1126\/science.274.5284.94","article-title":"Phenotypic analysis of antigen-specific T lymphocytes","volume":"274","author":"Altman","year":"1996","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2709","DOI":"10.1073\/pnas.050567397","article-title":"HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors","volume":"97","author":"Migueles","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","first-page":"89","article-title":"Progression of HIV to AIDS: A protective role for hla-b27?","volume":"6","year":"2004","journal-title":"AIDS Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1002\/hep.21049","article-title":"Dominant influence of an HLA-B27 restricted CD8+ T cell response in mediating HCV clearance and evolution","volume":"43","author":"McKiernan","year":"2006","journal-title":"Hepatology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1053\/j.gastro.2010.09.042","article-title":"Spontaneous control of HCV is associated with expression of HLA-B 57 and preservation of targeted epitopes","volume":"140","author":"Kim","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1126\/science.271.5256.1734","article-title":"Enhancement of antitumor immunity by CTLA-4 blockade","volume":"271","author":"Leach","year":"1996","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nature04444","article-title":"Restoring function in exhausted CD8 T cells during chronic viral infection","volume":"439","author":"Barber","year":"2006","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1038\/nrd.2018.167","article-title":"Trends in the global immuno-oncology landscape","volume":"17","author":"Tang","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1038\/nrd.2018.210","article-title":"Trial watch: The clinical trial landscape for PD1\/PDL1 immune checkpoint inhibitors","volume":"17","author":"Tang","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4911","DOI":"10.1128\/JVI.77.8.4911-4927.2003","article-title":"Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment","volume":"77","author":"Wherry","year":"2003","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.immuni.2007.09.006","article-title":"Molecular signature of CD8+ T cell exhaustion during chronic viral infection","volume":"27","author":"Wherry","year":"2007","journal-title":"Immunity"},{"key":"ref_23","unstructured":"Charles, A., and Janeway, J. (2001). Paul Travers, Mark Walport, and Mark J Shlomchik. Immunobiology: The Immune System in Health and Disease, Garland Science. [5th ed.]."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"J.Moticka, E. (2015). Activation of t lymphocytes and mhc restriction. A Historical Perspective on Evidence-Based Immunology, Elsevier.","DOI":"10.1016\/B978-0-12-398381-7.00020-4"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1038\/nri2368","article-title":"The known unknowns of antigen processing and presentation","volume":"8","author":"Vyas","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1038\/nri3084","article-title":"Towards a systems understanding of MHC class I and MHC class II antigen presentation","volume":"11","author":"Neefjes","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1001\/jama.1934.02750360007004","article-title":"Etiology of the 1933 epidemic of encephalitis","volume":"103","author":"Muckenfuss","year":"1934","journal-title":"JAMA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1084\/jem.63.4.533","article-title":"An epidemic in a mouse colony due to the virus of acute lymphocytic choriomeningitis","volume":"63","author":"Traub","year":"1936","journal-title":"J. Exp. Med."},{"key":"ref_29","first-page":"1635","article-title":"Arenaviridae: The viruses and their replication","volume":"Volume 2","author":"David","year":"2001","journal-title":"Fields Virology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1084\/jem.114.4.415","article-title":"Demonstration of mouse isoantigens at the cellular level by the fluorescent antibody technique","volume":"114","author":"Moller","year":"1961","journal-title":"J. Exp. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1084\/jem.134.2.495","article-title":"Receptors on immunocompetent cells. Ii. Specificity and nature of receptors on dinitrophenylated guinea pig albumin- 125 I-binding lymphocytes of normal guinea pigs","volume":"134","author":"Davie","year":"1971","journal-title":"J. Exp. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1084\/jem.137.4.1024","article-title":"Monospecificity of bone marrow-derived lymphocytes","volume":"137","author":"Raff","year":"1973","journal-title":"J. Exp. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1084\/jem.134.4.1005","article-title":"Surface immunoglobulins on thymus and thymus-derived lymphoid cells","volume":"134","author":"Bankhurst","year":"1971","journal-title":"J. Exp. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1084\/jem.134.3.618","article-title":"Immunoglobulins on the surface of thymus-derived cells engaged in the initiation of a humoral immune response","volume":"134","author":"Lesley","year":"1971","journal-title":"J. Exp. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1002\/ijc.2910100318","article-title":"Cell-mediated reaction against tumors induced by oncornaviruses. I. Kinetics and specificity of the immune response in murine sarcoma virus (MSV)-induced tumors and transplanted lymphomas","volume":"10","author":"Leclerc","year":"1972","journal-title":"Int. J. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1093\/jnci\/51.5.1497","article-title":"In vitro cytotoxicity studies of murine sarcoma virus-induced immunity in mice","volume":"51","author":"Lavrin","year":"1973","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1084\/jem.138.5.1194","article-title":"Function of macrophages in antigen recognition by guinea pig T lymphocytes. I. Requirement for histocompatible macrophages and lymphocytes","volume":"138","author":"Rosenthal","year":"1973","journal-title":"J. Exp. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1084\/jem.138.5.1213","article-title":"Function of macrophages in antigen recognition by guinea pig T lymphocytes. II. Role of the macrophage in the regulation of genetic control of the immune response","volume":"138","author":"Shevach","year":"1973","journal-title":"J. Exp. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1002\/eji.1830040802","article-title":"Cell-mediated cytotoxicity to trinitrophenyl-modified syngeneic lymphocytes","volume":"4","author":"Shearer","year":"1974","journal-title":"Eur. J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.4049\/jimmunol.112.4.1548","article-title":"Specificity and development of cytotoxic thymus-derived lymphocytes in lymphocytic choriomeningitis","volume":"112","author":"Doherty","year":"1974","journal-title":"J. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/251547a0","article-title":"Immunological surveillance against altered self components by sensitised T lymphocytes in lymphocytic choriomeningitis","volume":"251","author":"Zinkernagel","year":"1974","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1084\/jem.141.6.1427","article-title":"H-2 compatability requirement for T-cell-mediated lysis of target cells infected with lymphocytic choriomeningitis virus. Different cytotoxic T-cell specificities are associated with structures coded for in H-2K or H-2D","volume":"141","author":"Zinkernagel","year":"1975","journal-title":"J. Exp. Med."},{"key":"ref_43","first-page":"499","article-title":"Studies on the genetic and antigenic basis of tumour transplantation. Linkage between a histocompatibility gene and \u2018fused\u2019 in mice","volume":"135","author":"Gorer","year":"1948","journal-title":"Proc. R. Soc. Lond."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1084\/jem.137.5.1201","article-title":"Histocompatibility-linked genetic control of disease susceptibility. Murine lymphocytic choriomeningitis virus infection","volume":"137","author":"Oldstone","year":"1973","journal-title":"J. Exp. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1084\/jem.138.5.1266","article-title":"Cytotoxic thymus-derived lymphocytes in cerebrospinal fluid of mice with lymphocytic choriomeningitis","volume":"138","author":"Zinkernagel","year":"1973","journal-title":"J. Exp. Med."},{"key":"ref_46","first-page":"89","article-title":"T-cell-mediated immunopathology in viral infections","volume":"19","author":"Doherty","year":"1974","journal-title":"Transplant. Rev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/S0167-5699(97)80008-4","article-title":"The discovery of mhc restriction","volume":"18","author":"Zinkernagel","year":"1997","journal-title":"Immunol. Today"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"940","DOI":"10.4049\/jimmunol.109.5.940","article-title":"H-2 dependence of co-operation between T and B cells in vivo","volume":"109","author":"Kindred","year":"1972","journal-title":"J. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1084\/jem.137.6.1405","article-title":"Cell interactions between histoincompatible T and B lymphocytes. II. Failure of physiologic cooperative interactions between T and B lymphocytes from allogeneic donor strains in humoral response to hapten-protein conjugates","volume":"137","author":"Katz","year":"1973","journal-title":"J. Exp. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2624","DOI":"10.1073\/pnas.70.9.2624","article-title":"Cell interactions between histoincompatible T and B lymphocytes. The H-2 gene complex determines successful physiologic lymphocyte interactions","volume":"70","author":"Katz","year":"1973","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"460","DOI":"10.4049\/jimmunol.91.4.460","article-title":"The pathogenesis of lymphocytic choriomeningitis in mice: The effects of different inoculation routes and the footpad response","volume":"91","author":"Hotchin","year":"1963","journal-title":"J. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/0042-6822(63)90191-0","article-title":"Increased susceptibility of mice to lymphocytic choriomeningitis virus after peripheral inoculation","volume":"21","author":"Seamer","year":"1963","journal-title":"Virology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1017\/S002217240004167X","article-title":"Dose-response relationships of lymphocytic choriomeningitis viruses in mice and L cell tube cultures","volume":"67","year":"1969","journal-title":"J. Hyg. (Lond.)"},{"key":"ref_54","first-page":"303","article-title":"Lymphocytic choriomeningitis in the mouse. 3. Comparative titrations of virus strains in inbred mice","volume":"28","year":"1969","journal-title":"Arch. Gesamte. Virusforsch."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1099\/0022-1317-5-1-63","article-title":"A persistent and inapparent infection of l cells with the virus of lymphocytic choriomeningitis","volume":"5","author":"Slenczka","year":"1969","journal-title":"J. Gen. Virol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1038\/329506a0","article-title":"Structure of the human class I histocompatibility antigen, HLA-A2","volume":"329","author":"Bjorkman","year":"1987","journal-title":"Nature"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/364033a0","article-title":"Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1","volume":"364","author":"Brown","year":"1993","journal-title":"Nature"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2293","DOI":"10.4049\/jimmunol.129.5.2293","article-title":"Tumor-specific antigen of murine T-lymphoma defined with monoclonal antibody","volume":"129","author":"Allison","year":"1982","journal-title":"J. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1084\/jem.157.2.705","article-title":"Clonotypic structures involved in antigen-specific human T cell function. Relationship to the t3 molecular complex","volume":"157","author":"Meuer","year":"1983","journal-title":"J. Exp. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1084\/jem.157.4.1149","article-title":"The major histocompatibility complex-restricted antigen receptor on T cells. I. Isolation with a monoclonal antibody","volume":"157","author":"Haskins","year":"1983","journal-title":"J. Exp. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/308149a0","article-title":"Isolation of cDNA clones encoding T cell-specific membrane-associated proteins","volume":"308","author":"Hedrick","year":"1984","journal-title":"Nature"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/308145a0","article-title":"A human T cell-specific cDNA clone encodes a protein having extensive homology to immunoglobulin chains","volume":"308","author":"Yanagi","year":"1984","journal-title":"Nature"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1038\/309757a0","article-title":"Complete primary structure of a heterodimeric T-cell receptor deduced from cDNA sequences","volume":"309","author":"Saito","year":"1984","journal-title":"Nature"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/nrg3114","article-title":"Human genetic susceptibility to infectious disease","volume":"13","author":"Chapman","year":"2012","journal-title":"Nat. Rev. Genet."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1038\/nbt.2593","article-title":"Combinatorial tetramer staining and mass cytometry analysis facilitate T-cell epitope mapping and characterization","volume":"31","author":"Newell","year":"2013","journal-title":"Nat. Biotechnol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1111\/cei.12339","article-title":"Comparison of peptide-major histocompatibility complex tetramers and dextramers for the identification of antigen-specific T cells","volume":"177","author":"Dolton","year":"2014","journal-title":"Clin. Exp. Immunol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1055\/s-2007-1007262","article-title":"Genetic heterogeneity of hepatitis c virus: Quasispecies and genotypes","volume":"15","author":"Bukh","year":"1995","journal-title":"Semin. Liver Dis."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.antiviral.2005.12.001","article-title":"A target on the move: Innate and adaptive immune escape strategies of hepatitis C virus","volume":"69","author":"Thimme","year":"2006","journal-title":"Antiviral Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1084\/jem.20050121","article-title":"Cellular immune selection with hepatitis C virus persistence in humans","volume":"201","author":"Cox","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/35030124","article-title":"Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia","volume":"407","author":"Allen","year":"2000","journal-title":"Nature"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"7069","DOI":"10.1128\/JVI.78.13.7069-7078.2004","article-title":"Selection, transmission, and reversion of an antigen-processing cytotoxic T-lymphocyte escape mutation in human immunodeficiency virus type 1 infection","volume":"78","author":"Allen","year":"2004","journal-title":"J. Virol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev.biochem.67.1.1","article-title":"HIV-1: Fifteen proteins and an RNA","volume":"67","author":"Frankel","year":"1998","journal-title":"Annu. Rev. Biochem."},{"key":"ref_73","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_74","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/S2055-6640(20)30490-8","article-title":"HIV persistence in the setting of antiretroviral therapy: When, where and how does HIV hide?","volume":"1","author":"Kulpa","year":"2015","journal-title":"J. Virus Erad."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"11094","DOI":"10.1128\/JVI.00912-06","article-title":"Evidence of viral adaptation to HLA class I-restricted immune pressure in chronic hepatitis C virus infection","volume":"80","author":"Gaudieri","year":"2006","journal-title":"J. Virol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1136\/gut.2005.072231","article-title":"Relation between viral fitness and immune escape within the hepatitis C virus protease","volume":"55","author":"Soderholm","year":"2006","journal-title":"Gut"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"11658","DOI":"10.1128\/JVI.00995-07","article-title":"Viral sequence evolution in acute hepatitis C virus infection","volume":"81","author":"Kuntzen","year":"2007","journal-title":"J. Virol"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1084\/jem.20040511","article-title":"Determinants of human immunodeficiency virus type 1 escape from the primary CD8+ cytotoxic T lymphocyte response","volume":"200","author":"Jones","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1084\/jem.20042284","article-title":"Immune evasion versus recovery after acute hepatitis C virus infection from a shared source","volume":"201","author":"Tester","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_80","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_81","doi-asserted-by":"crossref","first-page":"10429","DOI":"10.1128\/JVI.01094-10","article-title":"Comparison of immune restoration in early versus late alpha interferon therapy against hepatitis C virus","volume":"84","author":"Bedard","year":"2010","journal-title":"J. Virol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1084\/jem.193.3.375","article-title":"Clustered mutations in HIV-1 gag are consistently required for escape from HLA-b27-restricted cytotoxic T lymphocyte responses","volume":"193","author":"Kelleher","year":"2001","journal-title":"J. Exp. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2581","DOI":"10.1097\/00002030-200312050-00005","article-title":"Influence of HLA-B57 on clinical presentation and viral control during acute HIV-1 infection","volume":"17","author":"Altfeld","year":"2003","journal-title":"AIDS"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1002\/hep.23275","article-title":"Protective effect of human leukocyte antigen B27 in hepatitis C virus infection requires the presence of a genotype-specific immunodominant CD8+ T-cell epitope","volume":"51","author":"Timm","year":"2010","journal-title":"Hepatology"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1002\/hep.24541","article-title":"Human leukocyte antigen B27 selects for rare escape mutations that significantly impair hepatitis C virus replication and require compensatory mutations","volume":"54","author":"Kuntzen","year":"2011","journal-title":"Hepatology"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1084\/jem.160.2.521","article-title":"Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence","volume":"160","author":"Ahmed","year":"1984","journal-title":"J. Exp. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"8056","DOI":"10.1128\/jvi.68.12.8056-8063.1994","article-title":"Cd4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection","volume":"68","author":"Matloubian","year":"1994","journal-title":"J. Virol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/0042-6822(88)90566-1","article-title":"Virus-lymphocyte interactions. Iv. Molecular characterization of LCMV armstrong (CTL+) small genomic segment and that of its variant, Clone 13 (CTL-)","volume":"164","author":"Salvato","year":"1988","journal-title":"Virology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1084\/jem.172.4.1043","article-title":"Genetic basis of viral persistence: Single amino acid change in the viral glycoprotein affects ability of lymphocytic choriomeningitis virus to persist in adult mice","volume":"172","author":"Matloubian","year":"1990","journal-title":"J. Exp. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2969","DOI":"10.1073\/pnas.1019304108","article-title":"Point mutation in the glycoprotein of lymphocytic choriomeningitis virus is necessary for receptor binding, dendritic cell infection, and long-term persistence","volume":"108","author":"Sullivan","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"16004","DOI":"10.1073\/pnas.0407192101","article-title":"Antigen-independent memory CD8 T cells do not develop during chronic viral infection","volume":"101","author":"Wherry","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/ni.1679","article-title":"Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection","volume":"10","author":"Blackburn","year":"2009","journal-title":"Nat. Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1016\/j.immuni.2012.08.021","article-title":"Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory","volume":"37","author":"Doering","year":"2012","journal-title":"Immunity"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1126\/science.aaf2807","article-title":"Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade","volume":"354","author":"Pauken","year":"2016","journal-title":"Science"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1084\/jem.188.12.2205","article-title":"Viral immune evasion due to persistence of activated T cells without effector function","volume":"188","author":"Zajac","year":"1998","journal-title":"J. Exp. Med."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1126\/science.aar6711","article-title":"Car T cell immunotherapy for human cancer","volume":"359","author":"June","year":"2018","journal-title":"Science"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1038\/s41568-018-0009-4","article-title":"Oncolytic viruses as engineering platforms for combination immunotherapy","volume":"18","author":"Pettigrew","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Schumacher, T.N., Scheper, W., and Kvistborg, P. (2018). Cancer neoantigens. Annu. Rev. Immunol.","DOI":"10.1146\/annurev-immunol-042617-053402"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/nature23003","article-title":"Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer","volume":"547","author":"Sahin","year":"2017","journal-title":"Nature"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/s13046-018-0751-1","article-title":"The perfect personalized cancer therapy: Cancer vaccines against neoantigens","volume":"37","author":"Aurisicchio","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1126\/science.aar4060","article-title":"Cancer immunotherapy using checkpoint blockade","volume":"359","author":"Ribas","year":"2018","journal-title":"Science"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1056\/NEJMoa1302369","article-title":"Nivolumab plus ipilimumab in advanced melanoma","volume":"369","author":"Wolchok","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.ccell.2015.03.001","article-title":"Immune checkpoint blockade: A common denominator approach to cancer therapy","volume":"27","author":"Topalian","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1016\/j.immuni.2016.04.022","article-title":"Costimulatory and coinhibitory receptor pathways in infectious disease","volume":"44","author":"Attanasio","year":"2016","journal-title":"Immunity"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/328267a0","article-title":"A new member of the immunoglobulin superfamily--CTLA-4","volume":"328","author":"Brunet","year":"1987","journal-title":"Nature"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1084\/jem.182.2.459","article-title":"CD28 and CTLA-4 have opposing effects on the response of t cells to stimulation","volume":"182","author":"Krummel","year":"1995","journal-title":"J. Exp. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"477","DOI":"10.4049\/jimmunol.170.1.477","article-title":"Ablation of CD8 and CD4 T cell responses by high viral loads","volume":"170","author":"Fuller","year":"2003","journal-title":"J. Immunol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1084\/jem.20061937","article-title":"Viral antigen and extensive division maintain virus-specific CD8 t cells during chronic infection","volume":"204","author":"Shin","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1126\/science.aae0491","article-title":"The epigenetic landscape of T cell exhaustion","volume":"354","author":"Sen","year":"2016","journal-title":"Science"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.it.2015.02.008","article-title":"Overcoming T cell exhaustion in infection and cancer","volume":"36","author":"Pauken","year":"2015","journal-title":"Trends Immunol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1126\/science.aaf1292","article-title":"T cell costimulatory receptor CD28 is a primary target for pd-1-mediated inhibition","volume":"355","author":"Hui","year":"2017","journal-title":"Science"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1126\/science.aaf0683","article-title":"Rescue of exhausted CD8 T cells by PD-1-targeted therapies is cd28-dependent","volume":"355","author":"Kamphorst","year":"2017","journal-title":"Science"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1146\/annurev.immunol.26.021607.090331","article-title":"PD-1 and its ligands in tolerance and immunity","volume":"26","author":"Keir","year":"2008","journal-title":"Annu. Rev. Immunol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/nri3862","article-title":"Molecular and cellular insights into T cell exhaustion","volume":"15","author":"Wherry","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1111\/j.0105-2896.2006.00382.x","article-title":"Signals required for programming effector and memory development by CD8+ T cells","volume":"211","author":"Mescher","year":"2006","journal-title":"Immunol. Rev."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.coi.2010.02.013","article-title":"Inflammatory cytokines as a third signal for T cell activation","volume":"22","author":"Curtsinger","year":"2010","journal-title":"Curr. Opin. Immunol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1038\/356607a0","article-title":"Cd28-mediated signalling co-stimulates murine t cells and prevents induction of anergy in T-cell clones","volume":"356","author":"Harding","year":"1992","journal-title":"Nature"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"6586","DOI":"10.1073\/pnas.90.14.6586","article-title":"Human t-cell clonal anergy is induced by antigen presentation in the absence of B7 costimulation","volume":"90","author":"Gimmi","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1126\/science.1235214","article-title":"Persistent LCMV infection is controlled by blockade of type I interferon signaling","volume":"340","author":"Teijaro","year":"2013","journal-title":"Science"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1126\/science.1235208","article-title":"Blockade of chronic type I interferon signaling to control persistent LCMV infection","volume":"340","author":"Wilson","year":"2013","journal-title":"Science"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.immuni.2009.06.015","article-title":"Cell-intrinsic transforming growth factor-beta signaling mediates virus-specific CD8+ T cell deletion and viral persistence in vivo","volume":"31","author":"Tinoco","year":"2009","journal-title":"Immunity"},{"key":"ref_122","first-page":"39","article-title":"The role of Il-10 in regulating immunity to persistent viral infections","volume":"350","author":"Wilson","year":"2011","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1038\/nature07662","article-title":"Enhancing SIV-specific immunity in vivo by PD-1 blockade","volume":"458","author":"Velu","year":"2009","journal-title":"Nature"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"211","DOI":"10.4049\/jimmunol.1201108","article-title":"In vivo blockade of the pd-1 receptor suppresses HIV-1 viral loads and improves CD4+ T cell levels in humanized mice","volume":"190","author":"Palmer","year":"2013","journal-title":"J. Immunol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1038\/nature05115","article-title":"PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression","volume":"443","author":"Day","year":"2006","journal-title":"Nature"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"4215","DOI":"10.1128\/JVI.02844-06","article-title":"Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection","volume":"81","author":"Boni","year":"2007","journal-title":"J. Virol."},{"key":"ref_127","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_128","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1182\/blood-2008-09-179697","article-title":"Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and disease progression","volume":"114","author":"Mumprecht","year":"2009","journal-title":"Blood"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.immuni.2016.07.011","article-title":"Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis","volume":"45","author":"Schietinger","year":"2016","journal-title":"Immunity"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1182\/blood-2008-12-195792","article-title":"Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired","volume":"114","author":"Ahmadzadeh","year":"2009","journal-title":"Blood"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/cmi.2010.28","article-title":"Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer","volume":"7","author":"Zhang","year":"2010","journal-title":"Cell Mol. Immunol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"2280","DOI":"10.1182\/blood-2006-04-015164","article-title":"Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen-specific cd8+ t-cell function in hodgkin lymphoma patients","volume":"108","author":"Gandhi","year":"2006","journal-title":"Blood"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"7875","DOI":"10.1073\/pnas.1003345107","article-title":"Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer","volume":"107","author":"Matsuzaki","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1182\/blood-2012-09-457531","article-title":"T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production","volume":"121","author":"Riches","year":"2013","journal-title":"Blood"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/11\/2\/106\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:28:56Z","timestamp":1760185736000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/11\/2\/106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,27]]},"references-count":134,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2019,2]]}},"alternative-id":["v11020106"],"URL":"https:\/\/doi.org\/10.3390\/v11020106","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,1,27]]}}}