{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T19:28:57Z","timestamp":1790278137494,"version":"4.1.0"},"reference-count":73,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T00:00:00Z","timestamp":1622764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/L006588\/1"],"award-info":[{"award-number":["MR\/L006588\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>T cell dysfunction occurs early following HIV infection, impacting the emergence of non-AIDS morbidities and limiting curative efforts. ART initiated during primary HIV infection (PHI) can reverse this dysfunction, but the extent of recovery is unknown. We studied 66 HIV-infected individuals treated from early PHI with up to three years of ART. Compared with HIV-uninfected controls, CD4 and CD8 T cells from early HIV infection were characterised by T cell activation and increased expression of the immune checkpoint receptors (ICRs) PD1, Tim-3 and TIGIT. Three years of ART lead to partial \u2013 but not complete \u2013 normalisation of ICR expression, the dynamics of which varied for individual ICRs. For HIV-specific cells, epigenetic profiling of tetramer-sorted CD8 T cells revealed that epigenetic features of exhaustion typically seen in chronic HIV infection were already present early in PHI, and that ART initiation during PHI resulted in only a partial shift of the epigenome to one with more favourable memory characteristics. These findings suggest that although ART initiation during PHI results in significant immune reconstitution, there may be only partial resolution of HIV-related phenotypic and epigenetic changes.<\/jats:p>","DOI":"10.3389\/fimmu.2021.647688","type":"journal-article","created":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T08:27:05Z","timestamp":1622795225000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":32,"title":["Epigenetic Features of HIV-Induced T-Cell Exhaustion Persist Despite Early Antiretroviral Therapy"],"prefix":"10.3389","volume":"12","author":[{"given":"Genevieve E.","family":"Martin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debattama R.","family":"Sen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Pace","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Robinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jodi","family":"Meyerowitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Adland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Thornhill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathew","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ane","family":"Ogbe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Parolini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Olejniczak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panagiota","family":"Zacharopoulou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian B.","family":"Willberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nneka","family":"Nwokolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Fox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Fidler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Nicholas","family":"Haining","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Frater","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1038\/nri.2017.112","article-title":"Immune Checkpoint Blockade in Infectious Diseases","volume":"18","author":"Wykes","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3018(18)30039-0","article-title":"Barriers and Strategies to Achieve a Cure for HIV","volume":"5","author":"Pitman","year":"2018","journal-title":"Lancet HIV"},{"key":"B3","doi-asserted-by":"publisher","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":"B4","doi-asserted-by":"publisher","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":"B5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005661","article-title":"Exhaustion of Activated CD8 T Cells Predicts Disease Progression in Primary Hiv-1 Infection","volume":"12","author":"Hoffmann","year":"2016","journal-title":"PloS Pathog"},{"key":"B6","doi-asserted-by":"publisher","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":"B7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005349","article-title":"TIGIT Marks Exhausted T Cells, Correlates With Disease Progression, and Serves as a Target for Immune Restoration in HIV and","volume":"12","author":"Chew","year":"2016","journal-title":"PloS Pathog"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1086\/428777","article-title":"Effect of Treatment, During Primary Infection, on Establishment and Clearance of Cellular Reservoirs of HIV-1","volume":"191","author":"Strain","year":"2005","journal-title":"J Infect Dis"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cix1068","article-title":"Long-Term Therapeutic Impact of the Timing of Antiretroviral Therapy in Patients Diagnosed With Primary Human Immunodeficiency Virus Type 1 Infection","volume":"66","author":"Novelli","year":"2018","journal-title":"Clin Infect Dis"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jit311","article-title":"Antiretroviral Therapy Initiated Within 6 Months of HIV Infection is Associated With Lower T-cell Activation and Smaller HIV Reservoir Size","volume":"208","author":"Jain","year":"2013","journal-title":"J\u00a0Infect Dis"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3851\/IMP1776","article-title":"Effect of Early Antiretroviral Therapy During Primary HIV-1 Infection on Cell-Associated HIV-1 DNA and Plasma HIV-1 RNA","volume":"16","author":"Gianella","year":"2011","journal-title":"Antivir Ther"},{"key":"B12","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1038\/nm.1972","article-title":"HIV Reservoir Size and Persistence are Driven by T Cell Survival and Homeostatic Proliferation","volume":"15","author":"Chomont","year":"2009","journal-title":"Nat Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.7.3382","article-title":"Early Highly Active Antiretroviral Therapy for Acute HIV-1 Infection Preserves Immune Function of CD8+ and CD4+ T Lymphocytes","volume":"97","author":"Oxenius","year":"2000","journal-title":"Proc Natl Acad Sci USA"},{"key":"B14","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1001\/jamainternmed.2014.4010","article-title":"Influence of the Timing of Antiretroviral Therapy on the Potential for Normalization of Immune Status in Human Immunodeficiency Virus 1-Infected Individuals","volume":"175","author":"Okulicz","year":"2015","journal-title":"JAMA Intern Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1086\/315202","article-title":"Effect of Combination Antiretroviral Therapy on T-cell Immunity in Acute Human Immunodeficiency Virus Type 1 Infection","volume":"181","author":"Malhotra","year":"2000","journal-title":"J Infect Dis"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20041270","article-title":"Loss of HIV-1-specific CD8+ T Cell Proliferation After Acute HIV-1 Infection and Restoration by Vaccine-Induced HIV-1-specific CD4+ T Cells","volume":"200","author":"Lichterfeld","year":"2004","journal-title":"J Exp Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/civ809","article-title":"Early Initiation Rather Than Prolonged Duration of Antiretroviral Therapy in HIV Infection Contributes to the Normalization of CD8 T-Cell Counts","volume":"62","author":"Cao","year":"2016","journal-title":"Clin Infect Dis"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.7448\/IAS.17.4.19480","article-title":"Enhanced Normalisation of CD4\/CD8 Ratio With Early Antiretroviral Therapy in Primary HIV Infection","volume":"17","author":"Thornhill","year":"2014","journal-title":"J Int AIDS Soc"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1097\/QAI.0b013e318285cd33","article-title":"Antiretroviral Therapy Initiated During Acute HIV Infection Fails to Prevent Persistent T-Cell Activation","volume":"62","author":"Vinikoor","year":"2013","journal-title":"J Acquir Immune Defic Syndr"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciw683","article-title":"Persistent, Albeit Reduced, Chronic Inflammation in Persons Starting Antiretroviral Therapy in Acute Hiv Infection","volume":"64","author":"Sereti","year":"2017","journal-title":"Clin Infect Dis"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiz030","article-title":"Very Early Initiation of Antiretroviral Therapy During Acute HIV Infection Is Associated With Normalized Levels of Immune Activation Markers in Cerebrospinal Fluid But Not in Plasma","volume":"220","author":"Hellmuth","year":"2019","journal-title":"J Infect Dis"},{"key":"B22","doi-asserted-by":"publisher","first-page":"8495","DOI":"10.1038\/ncomms9495","article-title":"Immunological Biomarkers Predict HIV-1 Viral Rebound After Treatment Interruption","volume":"6","author":"Hurst","year":"2015","journal-title":"Nat Commun"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1089\/aid.2016.0324","article-title":"Early and Delayed Antiretroviral Therapy Results in Comparable Reductions in CD8(+) T Cell Exhaustion Marker Expression","volume":"33","author":"Rutishauser","year":"2017","journal-title":"AIDS Res Hum Retroviruses"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002840","article-title":"CD160 and PD-1 Co-Expression on HIV-specific CD8 T Cells Defines a Subset With Advanced Dysfunction","volume":"8","author":"Peretz","year":"2012","journal-title":"PloS Pathog"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0000000000000314","article-title":"Programmed Death-1 Expression on CD4(+) and CD8(+) T Cells in Treated and Untreated HIV Disease","volume":"28","author":"Cockerham","year":"2014","journal-title":"AIDS"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1200646","article-title":"Programmed Death-1 is a Marker for Abnormal Distribution of Naive\/Memory T Cell Subsets in HIV-1 Infection","volume":"191","author":"Breton","year":"2013","journal-title":"J Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aag1809","article-title":"Delayed Differentiation of Potent Effector CD8+T Cells Reducing Viremia and Reservoir Seeding in Acute HIV Infection","volume":"9","author":"Takata","year":"2017","journal-title":"Sci Trans Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aau0528","article-title":"Augmentation of HIV-Specific T Cell Function by Immediate Treatment of Hyperacute HIV-1 Infection","volume":"11","author":"Ndhlovu","year":"2019","journal-title":"Sci Trans Med"},{"key":"B29","doi-asserted-by":"publisher","first-page":"e100","DOI":"10.1371\/journal.pmed.0050100","article-title":"Antigen Load and Viral Sequence Diversification Determine the Functional Profile of HIV-1\u2013Specific CD8+ T Cells","volume":"5","author":"Streeck","year":"2008","journal-title":"PloS Med"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005805","article-title":"Temporal Dynamics of CD8+ T Cell Effector Responses During Primary HIV Infection","volume":"12","author":"Demers","year":"2016","journal-title":"PloS Pathog"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiz563","article-title":"Levels of Human Immunodeficiency Virus DNA Are Determined Before ART Initiation and Linked to CD8 T-Cell Activation and Memory Expansion","volume":"221","author":"Martin","year":"2020","journal-title":"J\u00a0Infect Dis"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1126\/science.1229620","article-title":"Progenitor and Terminal Subsets of CD8+ T Cells Cooperate to Contain Chronic Viral Infection","volume":"338","author":"Paley","year":"2012","journal-title":"Science"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2046","article-title":"Transcription Factor T-bet Represses Expression of the Inhibitory Receptor PD-1 and Sustains Virus-Specific CD8+ T Cell Responses During Chronic Infection","volume":"12","author":"Kao","year":"2011","journal-title":"Nat Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00217","article-title":"Characterization of T-bet and Eomes in Peripheral Human Immune Cells","volume":"5","author":"Knox","year":"2014","journal-title":"Front Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004251","article-title":"T-Bet and Eomes are Differentially Linked to the Exhausted Phenotype of CD8+ T Cells in HIV Infection","volume":"10","author":"Buggert","year":"2014","journal-title":"PloS Pathog"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr597","article-title":"MissForest\u2013non-parametric Missing Value Imputation for Mixed-Type Data","volume":"28","author":"Stekhoven","year":"2012","journal-title":"Bioinformatics"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1002\/0471142727.mb2129s109","article-title":"ATAC-Seq: A Method for Assaying Chromatin Accessibility Genome-Wide","volume":"109","author":"Buenrostro","year":"2015","journal-title":"Curr Protoc Mol Biol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2688","article-title":"Transposition of Native Chromatin for Fast and Sensitive Epigenomic Profiling of Open Chromatin, DNA-binding Proteins and Nucleosome Position","volume":"10","author":"Buenrostro","year":"2013","journal-title":"Nat Methods"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1110039","article-title":"Short-Course Antiretroviral Therapy in Primary HIV Infection","volume":"368","author":"Fidler","year":"2013","journal-title":"N Engl J Med"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1126\/science.aae0491","article-title":"The Epigenetic Landscape of T Cell Exhaustion","volume":"354","author":"Sen","year":"2016","journal-title":"Science"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.03.035","article-title":"Master Transcription Factors and Mediator Establish Super-Enhancers At Key Cell Identity Genes","volume":"153","author":"Whyte","year":"2013","journal-title":"Cell"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.09.053","article-title":"Super-Enhancers in the Control of Cell Identity and Disease","volume":"155","author":"Hnisz","year":"2013","journal-title":"Cell"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jir046","article-title":"Genome-Wide Association Study Implicates PARD3B-Based AIDS Restriction","volume":"203","author":"Troyer","year":"2011","journal-title":"J Infect Dis"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/srep10879","article-title":"Genome-Wide Association Studies of HIV-1 Host Control in Ethnically Diverse Chinese Populations","volume":"5","author":"Wei","year":"2015","journal-title":"Sci Rep"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1900422","article-title":"Terminal Effector Cd8 T Cells Defined by an IKZF2+IL-7R\u2013 Transcriptional Signature Express Fc\u03b3RIIIA, Expand in HIV Infection, and Mediate Potent HIV-Specific Antibody-Dependent Cellular Cytotoxicity","volume":"203","author":"Naluyima","year":"2019","journal-title":"J Immunol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1325-x","article-title":"TOX Transcriptionally and Epigenetically Programs CD8(+) T Cell Exhaustion","volume":"571","author":"Khan","year":"2019","journal-title":"Nature"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1126\/science.1254194","article-title":"Specific HIV Integration Sites are Linked to Clonal Expansion and Persistence of Infected Cells","volume":"345","author":"Maldarelli","year":"2014","journal-title":"Science"},{"key":"B48","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1038\/s41467-017-00609-1","article-title":"HIV-1-mediated Insertional Activation of STAT5B and BACH2 Trigger Viral Reservoir in T Regulatory Cells","volume":"8","author":"Cesana","year":"2017","journal-title":"Nat Commun"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-11-317297","article-title":"Surface Expression Patterns of Negative Regulatory Molecules Identify Determinants of Virus-Specific CD8+ T-Cell Exhaustion in HIV Infection","volume":"117","author":"Yamamoto","year":"2011","journal-title":"Blood"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/srep40354","article-title":"Perturbed CD8+ T Cell TIGIT\/CD226\/PVR Axis Despite Early Initiation of Antiretroviral Treatment in HIV Infected Individuals","volume":"7","author":"Tauriainen","year":"2017","journal-title":"Sci Rep"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0b013e3282eee548","article-title":"PD-1 Expression on Human CD8 T Cells Depends on Both State of Differentiation and Activation Status","volume":"21","author":"Sauce","year":"2007","journal-title":"AIDS"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005761","article-title":"CD4+ T Cells Expressing PD-1, TIGIT and LAG-3 Contribute to HIV Persistence During ART","volume":"12","author":"Fromentin","year":"2016","journal-title":"PloS Pathog"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.142640","article-title":"HIV-Specific T Cell Responses Reflect Substantive In Vivo Interactions With Antigen Despite Long-Term Therapy","volume":"6","author":"Stevenson","year":"2021","journal-title":"JCI Insight"},{"key":"B54","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1056\/NEJMoa1506816","article-title":"Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection","volume":"373","year":"2015","journal-title":"New Engl J Med"},{"key":"B55","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1007\/s11904-013-0190-8","article-title":"Inflammatory Co-Morbidities in HIV+ Individuals: Learning Lessons From Healthy Ageing","volume":"11","author":"Hearps","year":"2014","journal-title":"Curr HIV\/AIDS Rep"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-09-044826","article-title":"PD-1 Up-Regulation is Correlated With HIV-specific Memory CD8+ T-Cell Exhaustion in Typical Progressors But Not in Long-Term Nonprogressors","volume":"109","author":"Zhang","year":"2007","journal-title":"Blood"},{"key":"B57","doi-asserted-by":"publisher","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\u00a0Exp Med"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.21723","article-title":"Impact of Changes in Antigen Level on CD38\/PD-1 Co-Expression on HIV-specific CD8 T Cells in Chronic, Untreated HIV-1 Infection","volume":"82","author":"Vollbrecht","year":"2010","journal-title":"J Med Virol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0782-y","article-title":"CTLA-4 and PD-1 Dual Blockade Induces SIV Reactivation Without Control of Rebound After Antiretroviral Therapy Interruption","volume":"26","author":"Harper","year":"2020","journal-title":"Nat Med"},{"key":"B60","doi-asserted-by":"publisher","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":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.07.008","article-title":"Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 are an Early Driver of CD8+ T Cell Exhaustion","volume":"45","author":"Bengsch","year":"2016","journal-title":"Immunity"},{"key":"B62","doi-asserted-by":"publisher","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":"B63","doi-asserted-by":"publisher","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":"B64","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1203161","article-title":"Cutting Edge: Prolonged Exposure to HIV Reinforces a Poised Epigenetic Program for PD-1 Expression in Virus-Specific CD8 T Cells","volume":"191","author":"Youngblood","year":"2013","journal-title":"J Immunol (Baltimore Md 1950)"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1038\/nature25461","article-title":"Enhancer Redundancy Provides Phenotypic Robustness in Mammalian Development","volume":"554","author":"Osterwalder","year":"2018","journal-title":"Nature"},{"key":"B66","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1016\/j.immuni.2018.04.026","article-title":"Epigenomic-Guided Mass Cytometry Profiling Reveals Disease-Specific Features of Exhausted CD8 T Cells","volume":"48","author":"Bengsch","year":"2018","journal-title":"Immunity"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1038\/ni845","article-title":"HIV-Specific CD8+ T Cell Proliferation is Coupled to Perforin Expression and is Maintained in Nonprogressors","volume":"3","author":"Migueles","year":"2002","journal-title":"Nat Immunol"},{"key":"B68","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1084\/jem.192.1.63","article-title":"HIV-Specific CD8(+) T Cells Produce Antiviral Cytokines But are Impaired in Cytolytic Function","volume":"192","author":"Appay","year":"2000","journal-title":"J Exp Med"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02014-05","article-title":"Passive Sexual Transmission of Human Immunodeficiency Virus Type 1 Variants and Adaptation in New Hosts","volume":"80","author":"Frater","year":"2006","journal-title":"J Virol"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01545-08","article-title":"Hla-Associated Clinical Progression Correlates With Epitope Reversion Rates in Early Human Immunodeficiency Virus Infection","volume":"83","author":"Duda","year":"2009","journal-title":"J Virol"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0001678","article-title":"One-Pot, Mix-and-Read Peptide-MHC Tetramers","volume":"3","author":"Leisner","year":"2008","journal-title":"PloS One"},{"key":"B72","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/nature11247","article-title":"An Integrated Encyclopedia of DNA Elements in the Human Genome","volume":"489","year":"2012","journal-title":"Nature"},{"key":"B73","doi-asserted-by":"crossref","DOI":"10.1126\/science.aav1898","article-title":"The Chromatin Accessibility Landscape of Primary Human Cancers","volume":"362","author":"Corces","year":"2018","journal-title":"Science"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.647688\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T08:27:09Z","timestamp":1622795229000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.647688\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,4]]},"references-count":73,"alternative-id":["10.3389\/fimmu.2021.647688"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.647688","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,4]]},"article-number":"647688"}}