{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:54:55Z","timestamp":1792036495266,"version":"4.4.0"},"reference-count":155,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2017,10,5]],"date-time":"2017-10-05T00:00:00Z","timestamp":1507161600000},"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>The progressive loss of immunological memory during aging correlates with a reduced proliferative capacity and shortened telomeres of T cells. Growing evidence suggests that this phenotype is recapitulated during chronic viral infection. The antigenic volume imposed by persistent and latent viruses exposes the immune system to unique challenges that lead to host T-cell exhaustion, characterized by impaired T-cell functions. These dysfunctional memory T cells lack telomerase, the protein capable of extending and stabilizing chromosome ends, imposing constraints on telomere dynamics. A deleterious consequence of this excessive telomere shortening is the premature induction of replicative senescence of viral-specific CD8+ memory T cells. While senescent cells are unable to expand, they can survive for extended periods of time and are more resistant to apoptotic signals. This review takes a closer look at T-cell exhaustion in chronic viruses known to cause human disease: Epstein\u2013Barr virus (EBV), Hepatitis B\/C\/D virus (HBV\/HCV\/HDV), human herpesvirus 8 (HHV-8), human immunodeficiency virus (HIV), human T-cell leukemia virus type I (HTLV-I), human papillomavirus (HPV), herpes simplex virus-1\/2(HSV-1\/2), and Varicella\u2013Zoster virus (VZV). Current literature linking T-cell exhaustion with critical telomere lengths and immune senescence are discussed. The concept that enduring antigen stimulation leads to T-cell exhaustion that favors telomere attrition and a cell fate marked by enhanced T-cell senescence appears to be a common endpoint to chronic viral infections.<\/jats:p>","DOI":"10.3390\/v9100289","type":"journal-article","created":{"date-parts":[[2017,10,5]],"date-time":"2017-10-05T12:38:32Z","timestamp":1507207112000},"page":"289","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":137,"title":["Telomere Dynamics in Immune Senescence and Exhaustion Triggered by Chronic Viral Infection"],"prefix":"10.3390","volume":"9","author":[{"given":"Marcia","family":"Bellon","sequence":"first","affiliation":[{"name":"Department of Pathology, Center for Viral Pathogenesis, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5927-2869","authenticated-orcid":false,"given":"Christophe","family":"Nicot","sequence":"additional","affiliation":[{"name":"Department of Pathology, Center for Viral Pathogenesis, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,10,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.cell.2009.06.036","article-title":"Redefining chronic viral infection","volume":"138","author":"Virgin","year":"2009","journal-title":"Cell"},{"key":"ref_2","unstructured":"Baron, S. (1996). Persistent Viral Infections. Medical Microbiology, University of Texas Medical Branch at Galveston. [4th ed.]."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.virol.2014.12.033","article-title":"T cell exhaustion during persistent viral infections","volume":"479\u2013480","author":"Kahan","year":"2015","journal-title":"Virology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1152\/advan.00066.2013","article-title":"T cell responses: Naive to memory and everything in between","volume":"37","author":"Pennock","year":"2013","journal-title":"Adv. Physiol. Educ."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1084\/jem.20020066","article-title":"Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells","volume":"195","author":"Tan","year":"2002","journal-title":"J. Exp. Med."},{"key":"ref_6","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_7","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_8","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/nbt0898-743","article-title":"Telomere length dynamics in human lymphocyte subpopulations measured by flow cytometry","volume":"16","author":"Rufer","year":"1998","journal-title":"Nat. Biotechnol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4521","DOI":"10.4049\/jimmunol.162.8.4521","article-title":"Virus-induced CD8+ T cell clonal expansion is associated with telomerase up-regulation and telomere length preservation: A mechanism for rescue from replicative senescence","volume":"162","author":"Maini","year":"1999","journal-title":"J. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"147","DOI":"10.4049\/jimmunol.170.1.147","article-title":"Induction of telomerase activity and maintenance of telomere length in virus-specific effector and memory CD8+ T cells","volume":"170","author":"Hathcock","year":"2003","journal-title":"J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1182\/blood.V97.3.700","article-title":"The flow cytometric analysis of telomere length in antigen-specific CD8+ T cells during acute Epstein-Barr virus infection","volume":"97","author":"Plunkett","year":"2001","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1097\/00042560-199912150-00004","article-title":"Telomere loss in peripheral blood mononuclear cells may be moderately accelerated during highly active antiretroviral therapy (HAART)","volume":"22","author":"Hotchkiss","year":"1999","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1126\/science.7605428","article-title":"Specific association of human telomerase activity with immortal cells and cancer","volume":"266","author":"Kim","year":"1994","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1158\/1541-7786.MCR-04-0194","article-title":"The loss of a single telomere can result in instability of multiple chromosomes in a human tumor cell line","volume":"3","author":"Sabatier","year":"2005","journal-title":"Mol. Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/S0092-8674(01)00504-9","article-title":"The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability","volume":"107","author":"Hemann","year":"2001","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1016\/S0960-9822(03)00542-6","article-title":"DNA damage foci at dysfunctional telomeres","volume":"13","author":"Takai","year":"2003","journal-title":"Curr. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"11091","DOI":"10.1073\/pnas.92.24.11091","article-title":"Human naive and memory T lymphocytes differ in telomeric length and replicative potential","volume":"92","author":"Weng","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"407","DOI":"10.2217\/imt.10.107","article-title":"Telomerase and primary T cells: Biology and immortalization for adoptive immunotherapy","volume":"3","author":"Barsov","year":"2011","journal-title":"Immunotherapy"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.mad.2007.11.005","article-title":"Telomere and adaptive immunity","volume":"129","author":"Weng","year":"2008","journal-title":"Mech. Ageing Dev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1006\/clim.2002.5271","article-title":"Divergent telomerase and CD28 expression patterns in human CD4 and CD8 T cells following repeated encounters with the same antigenic stimulus","volume":"105","author":"Valenzuela","year":"2002","journal-title":"Clin. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"589","DOI":"10.2174\/138920212803759749","article-title":"Molecular mechanisms involved in the aging of the T-cell immune response","volume":"13","year":"2012","journal-title":"Curr. Genom."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4838","DOI":"10.4049\/jimmunol.167.9.4838","article-title":"Viral infections induce abundant numbers of senescent CD8 T cells","volume":"167","author":"Voehringer","year":"2001","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1007\/s00262-004-0508-x","article-title":"Replicative senescence of CD8 T cells: Potential effects on cancer immune surveillance and immunotherapy","volume":"53","author":"Effros","year":"2004","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4239","DOI":"10.4049\/jimmunol.165.8.4239","article-title":"Immortalization of human CD8+ T cell clones by ectopic expression of telomerase reverse transcriptase","volume":"165","author":"Hooijberg","year":"2000","journal-title":"J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1006\/clim.2000.4894","article-title":"The increase of IFN-\u03b3 production through aging correlates with the expanded CD8(+high)CD28(\u2212)CD57(+) subpopulation","volume":"96","author":"Bandres","year":"2000","journal-title":"Clin. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1046\/j.1365-2567.1999.00901.x","article-title":"Large clonal expansions of human virus-specific memory cytotoxic T lymphocytes within the CD57+ CD28\u2212 CD8+ T-cell population","volume":"98","author":"Weekes","year":"1999","journal-title":"Immunology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/j.1365-2567.2011.03470.x","article-title":"CD8+ CD28\u2212 and CD8+ CD57+ T cells and their role in health and disease","volume":"134","author":"Strioga","year":"2011","journal-title":"Immunology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3865","DOI":"10.1182\/blood-2010-04-282301","article-title":"CD57 defines a functionally distinct population of mature NK cells in the human CD56dimCD16+ NK-cell subset","volume":"116","author":"Milush","year":"2010","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7710","DOI":"10.4049\/jimmunol.178.12.7710","article-title":"The loss of telomerase activity in highly differentiated CD8+CD28\u2212CD27\u2212 T cells is associated with decreased Akt (Ser473) phosphorylation","volume":"178","author":"Plunkett","year":"2007","journal-title":"J. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6619","DOI":"10.1182\/blood-2009-01-199588","article-title":"KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells","volume":"113","author":"Henson","year":"2009","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1002\/cyto.a.22351","article-title":"From \u201ctruly naive\u201d to \u201cexhausted senescent\u201d T cells: When markers predict functionality","volume":"85","author":"Larbi","year":"2014","journal-title":"Cytom. A"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6303","DOI":"10.4049\/jimmunol.173.10.6303","article-title":"Genetic manipulation of telomerase in HIV-specific CD8+ T cells: Enhanced antiviral functions accompany the increased proliferative potential and telomere length stabilization","volume":"173","author":"Dagarag","year":"2004","journal-title":"J. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"8140","DOI":"10.1128\/JVI.74.17.8140-8150.2000","article-title":"Functional heterogeneity and high frequencies of cytomegalovirus-specific CD8(+) T lymphocytes in healthy seropositive donors","volume":"74","author":"Gillespie","year":"2000","journal-title":"J. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/nm0402-379","article-title":"Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections","volume":"8","author":"Appay","year":"2002","journal-title":"Nat. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/s11357-009-9100-9","article-title":"KLRG1\u2014More than a marker for T cell senescence","volume":"31","author":"Henson","year":"2009","journal-title":"Age"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2408","DOI":"10.1093\/nar\/gkl303","article-title":"Telomeres, chromosome instability and cancer","volume":"34","author":"Bailey","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1002\/hep.20847","article-title":"Telomere shortening correlates with increasing aneuploidy of chromosome 8 in human hepatocellular carcinoma","volume":"42","author":"Plentz","year":"2005","journal-title":"Hepatology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1038\/nri1440","article-title":"Will telomere erosion lead to a loss of T-cell memory?","volume":"4","author":"Akbar","year":"2004","journal-title":"Nat. Rev. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.1182\/blood-2002-07-2103","article-title":"Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells","volume":"101","author":"Brenchley","year":"2003","journal-title":"Blood"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/0047-6374(93)90121-7","article-title":"The in vitro senescence of human T lymphocytes: Failure to divide is not associated with a loss of cytolytic activity or memory T cell phenotype","volume":"67","author":"Perillo","year":"1993","journal-title":"Mech. Ageing Dev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/S0531-5565(99)00033-9","article-title":"Resistance to apoptosis in human CD8+ T cells that reach replicative senescence after multiple rounds of antigen-specific proliferation","volume":"34","author":"Spaulding","year":"1999","journal-title":"Exp. Gerontol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6301","DOI":"10.4049\/jimmunol.165.11.6301","article-title":"Clonality and longevity of CD4+CD28null T cells are associated with defects in apoptotic pathways","volume":"165","author":"Vallejo","year":"2000","journal-title":"J. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.4049\/jimmunol.171.3.1172","article-title":"Constitutive caspase activation and impaired death-inducing signaling complex formation in CD95-resistant, long-term activated, antigen-specific T cells","volume":"171","author":"Strauss","year":"2003","journal-title":"J. Immunol."},{"key":"ref_44","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_45","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1038\/362758a0","article-title":"Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells","volume":"362","author":"Moskophidis","year":"1993","journal-title":"Nature"},{"key":"ref_46","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_47","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1182\/blood-2002-03-0791","article-title":"Most antiviral CD8 T cells during chronic viral infection do not express high levels of perforin and are not directly cytotoxic","volume":"101","author":"Zhang","year":"2003","journal-title":"Blood"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2527","DOI":"10.1128\/JVI.73.3.2527-2536.1999","article-title":"A role for perforin in downregulating T-cell responses during chronic viral infection","volume":"73","author":"Matloubian","year":"1999","journal-title":"J. Virol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1111\/j.1365-2567.2010.03255.x","article-title":"T-cell exhaustion: Characteristics, causes and conversion","volume":"129","author":"Yi","year":"2010","journal-title":"Immunology"},{"key":"ref_50","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_51","doi-asserted-by":"crossref","first-page":"E2480","DOI":"10.1073\/pnas.1305394110","article-title":"Strength of PD-1 signaling differentially affects T-cell effector functions","volume":"110","author":"Wei","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"6104","DOI":"10.4049\/jimmunol.1201617","article-title":"Programmed death-1 shapes memory phenotype CD8 T cell subsets in a cell-intrinsic manner","volume":"190","author":"Charlton","year":"2013","journal-title":"J. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1111\/imr.12520","article-title":"Tim-3 and its role in regulating anti-tumor immunity","volume":"276","author":"Das","year":"2017","journal-title":"Immunol. Rev."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.immuni.2014.01.005","article-title":"Molecular and transcriptional basis of CD4(+) T cell dysfunction during chronic infection","volume":"40","author":"Crawford","year":"2014","journal-title":"Immunity"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"5801","DOI":"10.4049\/jimmunol.1401936","article-title":"PD-1 upregulated on regulatory T cells during chronic virus infection enhances the suppression of CD8+ T cell immune response via the interaction with PD-L1 expressed on CD8+ T cells","volume":"194","author":"Park","year":"2015","journal-title":"J. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1084\/jem.192.2.303","article-title":"Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4","volume":"192","author":"Takahashi","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12964-016-0160-z","article-title":"T cell exhaustion: From pathophysiological basics to tumor immunotherapy","volume":"15","author":"Catakovic","year":"2017","journal-title":"Cell Commun. Signal."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1146\/annurev-med-042909-093756","article-title":"HIV infection, inflammation, immunosenescence, and aging","volume":"62","author":"Deeks","year":"2011","journal-title":"Annu. Rev. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"20697","DOI":"10.7448\/IAS.19.1.20697","article-title":"Elevation and persistence of CD8 T-cells in HIV infection: The Achilles heel in the ART era","volume":"19","author":"Cao","year":"2016","journal-title":"J. Int. AIDS Soc."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s11904-008-0003-7","article-title":"T-cell exhaustion in HIV infection","volume":"5","author":"Halwani","year":"2008","journal-title":"Curr. HIV\/AIDS Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3873","DOI":"10.4049\/jimmunol.1402176","article-title":"The upregulation of LAG-3 on T cells defines a subpopulation with functional exhaustion and correlates with disease progression in HIV-infected subjects","volume":"194","author":"Tian","year":"2015","journal-title":"J. Immunol."},{"key":"ref_62","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_63","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1084\/jem.20061496","article-title":"PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection","volume":"203","author":"Petrovas","year":"2006","journal-title":"J. Exp. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e99","DOI":"10.1038\/cddis.2010.77","article-title":"Mechanisms of HIV-associated lymphocyte apoptosis: 2010","volume":"1","author":"Cummins","year":"2010","journal-title":"Cell Death Dis."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"4541","DOI":"10.1128\/JVI.78.9.4541-4551.2004","article-title":"Apoptosis of bystander T cells induced by human immunodeficiency virus type 1 with increased envelope\/receptor affinity and coreceptor binding site exposure","volume":"78","author":"Holm","year":"2004","journal-title":"J. Virol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1038\/nm1482","article-title":"Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction","volume":"12","author":"Trautmann","year":"2006","journal-title":"Nat. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1097\/COH.0000000000000086","article-title":"CD8 T cell persistence in treated HIV infection","volume":"9","author":"Mudd","year":"2014","journal-title":"Curr. Opin. HIV AIDS"},{"key":"ref_68","first-page":"221","article-title":"The spectrum of HBV\/HCV coinfection: Epidemiology, clinical characteristics, viralinteractions and management","volume":"28","author":"Konstantinou","year":"2015","journal-title":"Ann. Gastroenterol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3587","DOI":"10.4049\/jimmunol.156.10.3587","article-title":"Shortened telomeres in clonally expanded CD28-CD8+ T cells imply a replicative history that is distinct from their CD28+CD8+ counterparts","volume":"156","author":"Monteiro","year":"1996","journal-title":"J. Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1097\/QAD.0000000000001093","article-title":"Premature aging and immune senescence in HIV-infected children","volume":"30","author":"Gianesin","year":"2016","journal-title":"AIDS"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1084\/jem.185.7.1381","article-title":"Telomere length, telomerase activity, and replicative potential in HIV infection: Analysis of CD4+ and CD8+ T cells from HIV-discordant monozygotic twins","volume":"185","author":"Palmer","year":"1997","journal-title":"J. Exp. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3679","DOI":"10.1182\/blood-2008-01-135442","article-title":"Telomerase activity of HIV-1-specific CD8+ T cells: Constitutive up-regulation in controllers and selective increase by blockade of PD ligand 1 in progressors","volume":"112","author":"Lichterfeld","year":"2008","journal-title":"Blood"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2586","DOI":"10.2741\/3874","article-title":"Genomic instability caused by hepatitis B virus: Into the hepatoma inferno","volume":"16","author":"Hsieh","year":"2011","journal-title":"Front. Biosci. (Landmark Ed.)"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1080\/07357900701561024","article-title":"Telomere length in hepatocellular carcinoma and paired adjacent non-tumor tissues by quantitative PCR","volume":"25","author":"Zhang","year":"2007","journal-title":"Cancer Investig."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/S0165-4608(96)00329-9","article-title":"Progressive telomere shortening and telomerase reactivation during hepatocellular carcinogenesis","volume":"93","author":"Miura","year":"1997","journal-title":"Cancer Genet. Cytogenet."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1002\/eji.200424898","article-title":"Ultra-sensitive class I tetramer analysis reveals previously undetectable populations of antiviral CD8+ T cells","volume":"34","author":"Barnes","year":"2004","journal-title":"Eur. J. Immunol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1111\/j.1365-2893.2005.00550.x","article-title":"Telomerase reverse transcriptase mRNA expression in peripheral lymphocytes of patients with chronic HBV and HCV infections","volume":"12","author":"Satra","year":"2005","journal-title":"J. Viral Hepat."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Feng, W., Yu, D., Li, B., Luo, O.Y., Xu, T., Cao, Y., and Ding, Y. (2017). Paired assessment of liver telomere lengths in hepatocellular cancer is a reliable predictor of disease persistence. Biosci. Rep., 37.","DOI":"10.1042\/BSR20160621"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.jhep.2010.03.005","article-title":"CD4+ T-lymphocyte telomere length is related to fibrosis stage, clinical outcome and treatment response in chronic hepatitis C virus infection","volume":"53","author":"Hoare","year":"2010","journal-title":"J. Hepatol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1016\/j.ejca.2012.02.066","article-title":"Relative telomere length: A novel non-invasive biomarker for the risk of non-cirrhotic hepatocellular carcinoma in patients with chronic hepatitis B infection","volume":"48","author":"Fu","year":"2012","journal-title":"Eur. J. Cancer"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s12979-016-0065-0","article-title":"HCV monoinfection and HIV\/HCV coinfection enhance T-cell immune senescence in injecting drug users early during infection","volume":"13","author":"Grady","year":"2016","journal-title":"Immun. Ageing"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1038\/nm.4275","article-title":"Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B","volume":"23","author":"Fisicaro","year":"2017","journal-title":"Nat. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/1423-0127-18-41","article-title":"Thymic function and T cell parameters in a natural human experimental model of seasonal infectious diseases and nutritional burden","volume":"18","author":"Ngom","year":"2011","journal-title":"J. Biomed. Sci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1016\/j.jhep.2012.12.009","article-title":"gamma-H2AX+CD8+ T lymphocytes cannot respond to IFN-\u03b1, IL-2 or IL-6 in chronic hepatitis C virus infection","volume":"58","author":"Hoare","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"8218","DOI":"10.4049\/jimmunol.175.12.8218","article-title":"Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion","volume":"175","author":"Fletcher","year":"2005","journal-title":"J. Immunol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1084\/jem.20040178","article-title":"Telomere erosion in memory T cells induced by telomerase inhibition at the site of antigenic challenge in vivo","volume":"199","author":"Reed","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"3532","DOI":"10.1128\/JVI.80.7.3532-3540.2006","article-title":"Expression of the interleukin-7 receptor alpha chain (CD127) on virus-specific CD8+ T cells identifies functionally and phenotypically defined memory T cells during acute resolving hepatitis B virus infection","volume":"80","author":"Boettler","year":"2006","journal-title":"J. Virol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"972","DOI":"10.4103\/0971-5916.92645","article-title":"Loss of CD127 & increased immunosenescence of T cell subsets in HIV infected individuals","volume":"134","author":"Mojumdar","year":"2011","journal-title":"Indian J. Med. Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"9122","DOI":"10.1128\/JVI.00639-09","article-title":"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","volume":"83","author":"Palmer","year":"2009","journal-title":"J. Virol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"6697","DOI":"10.4049\/jimmunol.0800997","article-title":"Chronic antigen stimulation alone is sufficient to drive CD8+ T cell exhaustion","volume":"182","author":"Bucks","year":"2009","journal-title":"J. Immunol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1093\/jnci\/djm269","article-title":"Regulation of telomerase and telomeres: Human tumor viruses take control","volume":"100","author":"Bellon","year":"2008","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1111\/j.1365-2249.1994.tb06618.x","article-title":"Cytokine production in varicella zoster virus-stimulated limiting dilution lymphocyte cultures","volume":"98","author":"Zhang","year":"1994","journal-title":"Clin. Exp. Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s13365-014-0237-7","article-title":"T cells increase before zoster and PD-1 expression increases at the time of zoster in immunosuppressed nonhuman primates latently infected with simian varicella virus","volume":"20","author":"James","year":"2014","journal-title":"J. Neurovirol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"4184","DOI":"10.1128\/JVI.02290-10","article-title":"The role of LAT in increased CD8+ T cell exhaustion in trigeminal ganglia of mice latently infected with herpes simplex virus 1","volume":"85","author":"Allen","year":"2011","journal-title":"J. Virol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/1742-4933-10-37","article-title":"Telomere length dynamics in human memory T cells specific for viruses causing acute or latent infections","volume":"10","author":"Woda","year":"2013","journal-title":"Immun. Ageing"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1128\/CMR.00063-09","article-title":"Epidemiology, treatment, and prevention of human T-cell leukemia virus type 1-associated diseases","volume":"23","author":"Goncalves","year":"2010","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2294","DOI":"10.1086\/420832","article-title":"Human T cell lymphotropic virus (HTLV) type-1-specific CD8+ T cells: Frequency and immunodominance hierarchy","volume":"189","author":"Goon","year":"2004","journal-title":"J. Infect. Dis."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1002\/ana.10065","article-title":"Increased HTLV-I proviral load and preferential expansion of HTLV-I Tax-specific CD8+ T cells in cerebrospinal fluid from patients with HAM\/TSP","volume":"50","author":"Nagai","year":"2001","journal-title":"Ann. Neurol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/leu.2008.272","article-title":"PD-1\/PD-L1 expression in human T-cell leukemia virus type 1 carriers and adult T-cell leukemia\/lymphoma patients","volume":"23","author":"Kozako","year":"2009","journal-title":"Leukemia"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"5718","DOI":"10.4049\/jimmunol.177.8.5718","article-title":"Reduced frequency, diversity, and function of human T cell leukemia virus type 1-specific CD8+ T cell in adult T cell leukemia patients","volume":"177","author":"Kozako","year":"2006","journal-title":"J. Immunol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/1742-4690-8-100","article-title":"Functional impairment of Tax-specific but not cytomegalovirus-specific CD8+ T lymphocytes in a minor population of asymptomatic human T-cell leukemia virus type 1-carriers","volume":"8","author":"Takamori","year":"2011","journal-title":"Retrovirology"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2411","DOI":"10.1182\/blood-2008-02-140335","article-title":"Impaired function of human T-lymphotropic virus type 1 (HTLV-1)-specific CD8+ T cells in HTLV-1-associated neurologic disease","volume":"112","author":"Sabouri","year":"2008","journal-title":"Blood"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1093\/infdis\/jiq153","article-title":"Reduced Tim-3 expression on human T-lymphotropic virus type I (HTLV-I) Tax-specific cytotoxic T lymphocytes in HTLV-I infection","volume":"203","author":"Abdelbary","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Ezinne, C.C., Yoshimitsu, M., White, Y., and Arima, N. (2014). HTLV-1 specific CD8+ T cell function augmented by blockade of 2B4\/CD48 interaction in HTLV-1 infection. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0087631"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Yasuma, K., Yasunaga, J., Takemoto, K., Sugata, K., Mitobe, Y., Takenouchi, N., Nakagawa, M., Suzuki, Y., and Matsuoka, M. (2016). HTLV-1 bZIP Factor Impairs Anti-viral Immunity by Inducing Co-inhibitory Molecule, T Cell Immunoglobulin and ITIM Domain (TIGIT). PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005372"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Ndhlovu, L.C., Leal, F.E., Hasenkrug, A.M., Jha, A.R., Carvalho, K.I., Eccles-James, I.G., Bruno, F.R., Vieira, R.G., York, V.A., and Chew, G.M. (2011). HTLV-1 tax specific CD8+ T cells express low levels of Tim-3 in HTLV-1 infection: Implications for progression to neurological complications. PLoS Negl. Trop. Dis., 5.","DOI":"10.1371\/journal.pntd.0001030"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1016\/j.humimm.2011.07.308","article-title":"Programmed death-1 (PD-1)\/PD-1 ligand pathway-mediated immune responses against human T-lymphotropic virus type 1 (HTLV-1) in HTLV-1-associated myelopathy\/tropical spastic paraparesis and carriers with autoimmune disorders","volume":"72","author":"Kozako","year":"2011","journal-title":"Hum. Immunol."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Enose-Akahata, Y., Matsuura, E., Oh, U., and Jacobson, S. (2009). High expression of CD244 and SAP regulated CD8 T cell responses of patients with HTLV-I associated neurologic disease. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000682"},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Santos, S.B., Porto, A.F., Muniz, A.L., de Jesus, A.R., Magalhaes, E., Melo, A., Dutra, W.O., Gollob, K.J., and Carvalho, E.M. (2004). Exacerbated inflammatory cellular immune response characteristics of HAM\/TSP is observed in a large proportion of HTLV-I asymptomatic carriers. BMC Infect. Dis., 4.","DOI":"10.1186\/1471-2334-4-7"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.jneuroim.2006.03.013","article-title":"Memory lineage relationships in HTLV-1-specific CD8+ cytotoxic T cells","volume":"176","author":"Graber","year":"2006","journal-title":"J. Neuroimmunol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2090","DOI":"10.1002\/ijc.22026","article-title":"Increased expression of telomere length regulating factors TRF1, TRF2 and TIN2 in patients with adult T-cell leukemia","volume":"119","author":"Bellon","year":"2006","journal-title":"Int. J. Cancer"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1038\/sj.onc.1210718","article-title":"Telomere attrition induces a DNA double-strand break damage signal that reactivates p53 transcription in HTLV-I leukemic cells","volume":"27","author":"Datta","year":"2008","journal-title":"Oncogene"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"2763","DOI":"10.1084\/jem.20081398","article-title":"Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection","volume":"205","author":"Jones","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Quan, L., Chen, X., Liu, A., Zhang, Y., Guo, X., Yan, S., and Liu, Y. (2015). PD-1 Blockade Can Restore Functions of T-Cells in Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma In Vitro. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0136476"},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Larsen, M., Sauce, D., Deback, C., Arnaud, L., Mathian, A., Miyara, M., Boutolleau, D., Parizot, C., Dorgham, K., and Papagno, L. (2011). Exhausted cytotoxic control of Epstein-Barr virus in human lupus. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1002328"},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Loebel, M., Strohschein, K., Giannini, C., Koelsch, U., Bauer, S., Doebis, C., Thomas, S., Unterwalder, N., von Baehr, V., and Reinke, P. (2014). Deficient EBV-specific B- and T-cell response in patients with chronic fatigue syndrome. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0085387"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"e126","DOI":"10.1038\/cti.2016.87","article-title":"Defective T-cell control of Epstein-Barr virus infection in multiple sclerosis","volume":"6","author":"Pender","year":"2017","journal-title":"Clin. Transl. Immunol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1158\/1078-0432.CCR-11-1942","article-title":"Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: Implications for targeted therapy","volume":"18","author":"Green","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"4831","DOI":"10.4049\/jimmunol.165.9.4831","article-title":"Changing patterns of dominant TCR usage with maturation of an EBV-specific cytotoxic T cell response","volume":"165","author":"Annels","year":"2000","journal-title":"J. Immunol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1182\/blood.V98.1.146","article-title":"Dysfunctional Epstein-Barr virus (EBV)-specific CD8+ T lymphocytes and increased EBV load in HIV-1 infected individuals progressing to AIDS-related non-Hodgkin lymphoma","volume":"98","author":"Hovenkamp","year":"2001","journal-title":"Blood"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1086\/592170","article-title":"Progressive telomere shortening of Epstein-Barr virus-specific memory T cells during HIV infection: Contributor to exhaustion?","volume":"198","author":"Nanlohy","year":"2008","journal-title":"J. Infect. Dis."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/j.mad.2005.03.006","article-title":"The impact of telomere erosion on memory CD8+ T cells in patients with X-linked lymphoproliferative syndrome","volume":"126","author":"Plunkett","year":"2005","journal-title":"Mech. Ageing Dev."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1086\/507648","article-title":"Low T cell responses to human herpesvirus 8 in patients with AIDS-related and classic Kaposi sarcoma","volume":"194","author":"Guihot","year":"2006","journal-title":"J. Infect. Dis."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"72961","DOI":"10.18632\/oncotarget.12150","article-title":"PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma","volume":"7","author":"Lambert","year":"2016","journal-title":"Oncotarget"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"3462","DOI":"10.1158\/1078-0432.CCR-13-0855","article-title":"PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies","volume":"19","author":"Chen","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1097\/QAD.0b013e3283601144","article-title":"Immunosenescence is associated with presence of Kaposi\u2019s sarcoma in antiretroviral treated HIV infection","volume":"27","author":"Unemori","year":"2013","journal-title":"AIDS"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"8623","DOI":"10.1073\/pnas.0809818106","article-title":"High antigen levels are the cause of T cell exhaustion during chronic viral infection","volume":"106","author":"Mueller","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"4928","DOI":"10.1128\/JVI.77.8.4928-4937.2003","article-title":"A synthetic E7 gene of human papillomavirus type 16 that yields enhanced expression of the protein in mammalian cells and is useful for DNA immunization studies","volume":"77","author":"Juarez","year":"2003","journal-title":"J. Virol."},{"key":"ref_129","first-page":"365","article-title":"Use of fluorogenic histocompatibility leukocyte antigen-A*0201\/HPV 16 E7 peptide complexes to isolate rare human cytotoxic T-lymphocyte-recognizing endogenous human papillomavirus antigens","volume":"60","author":"Youde","year":"2000","journal-title":"Cancer Res."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"5464","DOI":"10.1128\/JVI.77.9.5464-5474.2003","article-title":"Human papillomavirus type 16 E7 peptide-directed CD8+ T cells from patients with cervical cancer are cross-reactive with the coronavirus NS2 protein","volume":"77","author":"Nilges","year":"2003","journal-title":"J. Virol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1002\/ijc.2910560303","article-title":"Analysis of HLA-DR expression on keratinocytes in cervical neoplasia","volume":"56","author":"Coleman","year":"1994","journal-title":"Int. J. Cancer"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"172ra120","DOI":"10.1126\/scitranslmed.3004888","article-title":"Mucosal imprinting of vaccine-induced CD8(+) T cells is crucial to inhibit the growth of mucosal tumors","volume":"5","author":"Sandoval","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1111\/imm.12101","article-title":"Increased expression of programmed death (PD)-1 and its ligand PD-L1 correlates with impaired cell-mediated immunity in high-risk human papillomavirus-related cervical intraepithelial neoplasia","volume":"139","author":"Yang","year":"2013","journal-title":"Immunology"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"6633","DOI":"10.4049\/jimmunol.1004181","article-title":"Papillomavirus-specific CD4+ T cells exhibit reduced STAT-5 signaling and altered cytokine profiles in patients with recurrent respiratory papillomatosis","volume":"186","author":"James","year":"2011","journal-title":"J. Immunol."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/cgt.2015.40","article-title":"An HPV-E6\/E7 immunotherapy plus PD-1 checkpoint inhibition results in tumor regression and reduction in PD-L1 expression","volume":"22","author":"Rice","year":"2015","journal-title":"Cancer Gene Ther."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1158\/0008-5472.CAN-12-2606","article-title":"PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer","volume":"73","author":"Badoual","year":"2013","journal-title":"Cancer Res."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"5559","DOI":"10.1128\/JVI.75.12.5559-5566.2001","article-title":"Telomerase activation by human papillomavirus type 16 E6 protein: Induction of human telomerase reverse transcriptase expression through Myc and GC-rich Sp1 binding sites","volume":"75","author":"Oh","year":"2001","journal-title":"J. Virol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/j.virol.2008.02.025","article-title":"HPV E7 contributes to the telomerase activity of immortalized and tumorigenic cells and augments E6-induced hTERT promoter function","volume":"375","author":"Liu","year":"2008","journal-title":"Virology"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"3561","DOI":"10.1038\/sj.onc.1207388","article-title":"Telomere erosion and chromosomal instability in cells expressing the HPV oncogene 16E6","volume":"23","author":"Sundsvold","year":"2004","journal-title":"Oncogene"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"7441","DOI":"10.1038\/sj.onc.1207527","article-title":"Telomere attrition predominantly occurs in precursor lesions during in vivo carcinogenic process of the uterine cervix","volume":"23","author":"Zhang","year":"2004","journal-title":"Oncogene"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"5996","DOI":"10.1158\/0008-5472.CAN-13-0881","article-title":"Telomere length in peripheral blood lymphocytes contributes to the development of HPV-associated oropharyngeal carcinoma","volume":"73","author":"Zhang","year":"2013","journal-title":"Cancer Res."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.canep.2014.07.010","article-title":"Combined effects of leukocyte telomere length, p53 polymorphism and human papillomavirus infection on esophageal squamous cell carcinoma in a Han Chinese population","volume":"38","author":"Yu","year":"2014","journal-title":"Cancer Epidemiol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1093\/jnci\/djg011","article-title":"Telomere dysfunction: A potential cancer predisposition factor","volume":"95","author":"Wu","year":"2003","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_144","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_145","doi-asserted-by":"crossref","first-page":"5439","DOI":"10.4049\/jimmunol.180.8.5439","article-title":"Immune activation driven by CTLA-4 blockade augments viral replication at mucosal sites in simian immunodeficiency virus infection","volume":"180","author":"Cecchinato","year":"2008","journal-title":"J. Immunol."},{"key":"ref_146","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_147","doi-asserted-by":"crossref","unstructured":"Tzeng, H.T., Tsai, H.F., Liao, H.J., Lin, Y.J., Chen, L., Chen, P.J., and Hsu, P.N. (2012). PD-1 blockage reverses immune dysfunction and hepatitis B viral persistence in a mouse animal model. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0039179"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"193","DOI":"10.2146\/ajhp140768","article-title":"Pembrolizumab and nivolumab: PD-1 inhibitors for advanced melanoma","volume":"73","author":"Ivashko","year":"2016","journal-title":"Am. J. Health Syst. Pharm."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/S1470-2045(17)30104-3","article-title":"Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): A multicentre, single-arm, phase 2 study","volume":"18","author":"Morris","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_150","doi-asserted-by":"crossref","unstructured":"Ma, S.D., Xu, X., Jones, R., Delecluse, H.J., Zumwalde, N.A., Sharma, A., Gumperz, J.E., and Kenney, S.C. (2016). PD-1\/CTLA-4 blockade inhibits Epstein-Barr virus-induced lymphoma growth in a cord blood humanized-mouse model. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005642"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"10501","DOI":"10.1038\/ncomms10501","article-title":"Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints","volume":"7","author":"Koyama","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1016\/j.immuni.2016.04.015","article-title":"PSGL-1 is an immune checkpoint regulator that promotes T cell exhaustion","volume":"44","author":"Tinoco","year":"2016","journal-title":"Immunity"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1053\/j.seminhematol.2013.03.030","article-title":"Telomere dynamics in mice and humans","volume":"50","author":"Calado","year":"2013","journal-title":"Semin. Hematol."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.lfs.2015.10.025","article-title":"Men and mice: Relating their ages","volume":"152","author":"Dutta","year":"2016","journal-title":"Life Sci."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"15525","DOI":"10.1073\/pnas.1521629112","article-title":"The discovery of HTLV-1, the first pathogenic human retrovirus","volume":"112","author":"Coffin","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/9\/10\/289\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:46:38Z","timestamp":1760208398000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/9\/10\/289"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,10,5]]},"references-count":155,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2017,10]]}},"alternative-id":["v9100289"],"URL":"https:\/\/doi.org\/10.3390\/v9100289","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,10,5]]}}}