{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T07:36:27Z","timestamp":1790753787362,"version":"4.1.0"},"reference-count":125,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T00:00:00Z","timestamp":1677628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81991491, 32070940, 82272144"],"award-info":[{"award-number":["81991491, 32070940, 82272144"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2021M700115"],"award-info":[{"award-number":["2021M700115"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["20720220006"],"award-info":[{"award-number":["20720220006"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Chronic hepatitis B virus (HBV) infection continues to be a significant public health challenge, and more than 250 million people around world are infected with HBV. The clearance of HBV with virus-specific CD8 T cells is critical for a functional cure. However, na\u00efve HBV-specific CD8 T cells are heavily hindered during the priming process, and this phenomenon is closely related to abnormal cell and signal interactions in the complex immune microenvironment. Here, we briefly summarize the recent progress in understanding the abnormal priming of HBV-specific CD8 T cells and some corresponding immunotherapies to facilitate their functional recovery, which provides a novel perspective for the design and development of immunotherapy for chronic HBV infection (CHB). Finally, we also highlight the balance between viral clearance and pathological liver injury induced by CD8 T-cell activation that should be carefully considered during drug development.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1106700","type":"journal-article","created":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T05:14:20Z","timestamp":1677647660000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Abnormally primed CD8 T cells: The Achilles\u2019 heel of CHB"],"prefix":"10.3389","volume":"14","author":[{"given":"Xiaoqing","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichao","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningshao","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxin","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-019-0196-9","article-title":"Restoring, releasing or replacing adaptive immunity in chronic hepatitis b","volume":"16","author":"Maini","year":"2019","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21896","article-title":"Hepatitis b virus infection initiates with a large surface protein-dependent binding to heparan sulfate proteoglycans","volume":"46","author":"Schulze","year":"2007","journal-title":"Hepatology"},{"key":"B3","doi-asserted-by":"publisher","first-page":"e00049","DOI":"10.7554\/eLife.00049","article-title":"Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis b and d virus","volume":"1","author":"Yan","year":"2012","journal-title":"Elife"},{"key":"B4","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1128\/mmbr.64.1.51-68.2000","article-title":"Hepatitis b virus biology","volume":"64","author":"Seeger","year":"2000","journal-title":"Microbiol Mol Biol Rev"},{"key":"B5","doi-asserted-by":"publisher","first-page":"eaan0241","DOI":"10.1126\/scitranslmed.aan0241","article-title":"RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis b virus DNA is a source of HBsAg","volume":"9","author":"Wooddell","year":"2017","journal-title":"Sci Transl Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(87)90614-7","article-title":"Natural history of acute hepatitis b surface antigen-positive hepatitis in Greek adults","volume":"92","author":"Tassopoulos","year":"1987","journal-title":"Gastroenterology"},{"key":"B7","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.jhep.2015.01.018","article-title":"Strategies to control hepatitis b: Public policy, epidemiology, vaccine and drugs","volume":"62","author":"Locarnini","year":"2015","journal-title":"J Hepatol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"18035","DOI":"10.1038\/nrdp.2018.35","article-title":"Hepatitis b virus infection","volume":"4","author":"Yuen","year":"2018","journal-title":"Nat Rev Dis Primers"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(19)30119-0","article-title":"A global scientific strategy to cure hepatitis b","volume":"4","author":"Revill","year":"2019","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1038\/s41577-021-00549-4","article-title":"Immunobiology and pathogenesis of hepatitis b virus infection","volume":"22","author":"Iannacone","year":"2022","journal-title":"Nat Rev Immunol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1146\/annurev.pathol.1.110304.100230","article-title":"Immunobiology and pathogenesis of viral hepatitis","volume":"1","author":"Guidotti","year":"2006","journal-title":"Annu Rev Pathology-Mechanisms Dis"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20162115","article-title":"IL-2(high) tissue-resident T cells in the human liver: Sentinels for hepatotropic infection","volume":"214","author":"Pallett","year":"2017","journal-title":"J Exp Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.967055","article-title":"Tissue-resident memory T cells in chronic liver diseases: Phenotype, development and function","volume":"13","author":"Li","year":"2022","journal-title":"Front Immunol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"2457","DOI":"10.3390\/cells9112457","article-title":"Tissue-resident memory T cells in the liver-unique characteristics of local specialists","volume":"9","author":"Bartsch","year":"2020","journal-title":"Cells"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1825","DOI":"10.1016\/j.immuni.2021.06.013","article-title":"Nonterminally exhausted tumour-resident memory HBV-specific T cell responses correlate with relapse-free survival in hepatocellular carcinoma","volume":"54","author":"Cheng","year":"2021","journal-title":"Immunity"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20170842","article-title":"Tissue-resident T cells in hepatitis b: A new target for cure","volume":"214","author":"Bolte","year":"2017","journal-title":"J Exp Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2016.07.011","article-title":"Determinants of hepatic effector CD8(+) T-cell dynamics","volume":"66","author":"Benechet","year":"2017","journal-title":"J Hepatol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1016\/j.cell.2015.03.005","article-title":"Immunosurveillance of the liver by intravascular effector CD8(+) T cells","volume":"161","author":"Guidotti","year":"2015","journal-title":"Cell"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/srep07341","article-title":"In vivo flow mapping in complex vessel networks by single image correlation","volume":"4","author":"Sironi","year":"2014","journal-title":"Sci Rep"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21378","article-title":"T Lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells","volume":"44","author":"Warren","year":"2006","journal-title":"Hepatology"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1159\/000512729","article-title":"Antigen-presenting cells: Potential of proven und new players in immune therapies","volume":"47","author":"Eiz-Vesper","year":"2020","journal-title":"Transfus Med Haemother"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20092136","article-title":"Antigen-specific clonal expansion and cytolytic effector function of CD8+ T lymphocytes depend on the transcription factor Bcl11b","volume":"207","author":"Zhang","year":"2010","journal-title":"J Exp Med"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-065x.2003.00009.x","article-title":"T-Cell anergy and costimulation","volume":"192","author":"Appleman","year":"2003","journal-title":"Immunol Rev"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.11.003","article-title":"Neonatal fc receptor expression in dendritic cells mediates protective immunity against colorectal cancer","volume":"39","author":"Baker","year":"2013","journal-title":"Immunity"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinre.2019.07.016","article-title":"Quantative HBsAg level correlates dendritic cells maturation in chronic hepatitis b patients","volume":"44","author":"Li","year":"2020","journal-title":"Clinics Res Hepatol Gastroenterol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30080","article-title":"Outcome of antiviral immunity in the liver is shaped by the level of antigen expressed in infected hepatocytes","volume":"68","author":"Manske","year":"2018","journal-title":"Hepatology"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.3390\/cells10051114","article-title":"CD4(+) T cells in chronic hepatitis b and T-Cell-Directed immunotherapy","volume":"10","author":"Buschow","year":"2021","journal-title":"Cells"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1111\/imm.12400","article-title":"Amphiregulin promotes the immunosuppressive activity of intrahepatic CD4(+) regulatory T cells to impair CD8(+) T-cell immunity against hepatitis b virus infection","volume":"144","author":"Dai","year":"2015","journal-title":"Immunology"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32331","article-title":"Diverse facets of MDSC in different phases of chronic HBV infection: Impact on HBV-specific T-cell response and homing","volume":"76","author":"Pal","year":"2022","journal-title":"Hepatology"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2015.11.050","article-title":"Hepatitis b virus\u2013specific and global T-cell dysfunction in chronic hepatitis b","volume":"150","author":"Park","year":"2016","journal-title":"Gastroenterology"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.07.014","article-title":"Early inhibition of hepatocyte innate responses by hepatitis b virus","volume":"63","author":"Luangsay","year":"2015","journal-title":"J Hepatol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2010.12.042","article-title":"The hepatitis b e antigen (HBeAg) targets and suppresses activation of the toll-like receptor signalling pathway","volume":"55","author":"Lang","year":"2011","journal-title":"J Hepatol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.02415-06","article-title":"The level of viral antigen presented by hepatocytes influences CD8 T-cell function","volume":"81","author":"Gehring","year":"2007","journal-title":"J Virol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21482","article-title":"Regulation of toll-like receptor-2 expression in chronic hepatitis b by the precore protein","volume":"45","author":"Visvanathan","year":"2007","journal-title":"Hepatology"},{"key":"B35","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1002\/hep.30637","article-title":"Characteristics of impaired dendritic cell function in patients with hepatitis b virus infection","volume":"70","author":"Yonejima","year":"2019","journal-title":"Hepatology"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V98.6.1872","article-title":"Efficient identification of HLA-A*2402-restricted cytomegalovirus-specific CD8(+) T-cell epitopes by a computer algorithm and an enzyme-linked immunospot assay","volume":"98","author":"Kuzushima","year":"2001","journal-title":"Blood"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-004-6249-y","article-title":"Decreased frequency and function of circulating plasmocytoid dendritic cells (pDC) in hepatitis b virus infected humans","volume":"24","author":"Duan","year":"2004","journal-title":"J Clin Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.11.2.169","article-title":"Impaired function of antigen-presenting dendritic cells in patients with chronic hepatitis b: Localization of HBV DNA and HBV RNA in blood DC by in situ hybridization","volume":"11","author":"Arima","year":"2003","journal-title":"Int J Mol Med"},{"key":"B39","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1111\/liv.13475","article-title":"Immune correlates of hepatitis b surface antigen spontaneous seroconversion in hepatitis b e antigen negative chronic hepatitis b patients","volume":"38","author":"Vyas","year":"2018","journal-title":"Liver Int"},{"key":"B40","doi-asserted-by":"publisher","first-page":"141965","DOI":"10.1172\/jci141965","article-title":"SIGLEC-3 (CD33) serves as an immune checkpoint receptor for HBV infection","volume":"131","author":"Tsai","year":"2021","journal-title":"J Clin Invest"},{"key":"B41","doi-asserted-by":"publisher","first-page":"e1003490","DOI":"10.1371\/journal.ppat.1003490","article-title":"CD40 activation rescues antiviral CD8(+) T cells from PD-1-Mediated exhaustion","volume":"9","author":"Isogawa","year":"2013","journal-title":"PloS Pathog"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1620-6","article-title":"Dynamics and genomic landscape of CD8(+) T cells undergoing hepatic priming","volume":"574","author":"Benechet","year":"2019","journal-title":"Nature"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.092675799","article-title":"IL-15 mimics T-cell receptor crosslinking in the induction of cellular proliferation, gene expression, and cytotoxicity in CD8+ memory T cells","volume":"99","author":"Liu","year":"2002","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2556","article-title":"Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T-cell differentiation","volume":"14","author":"Sinclair","year":"2013","journal-title":"Nat Immunol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1158\/2326-6066.CIR-15-0178","article-title":"Molecular programming of tumour-infiltrating CD8+ T cells and IL15 resistance","volume":"4","author":"Doedens","year":"2016","journal-title":"Cancer Immunol Res"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2018.11.002","article-title":"HBV antigen and DNA loss from mouse serum is associated with novel vaccine-induced HBV surface antigen-specific cell-mediated immunity and cytokine production","volume":"161","author":"Chuai","year":"2019","journal-title":"Antiviral Res"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.11","article-title":"Liver macrophages in tissue homeostasis and disease","volume":"17","author":"Krenkel","year":"2017","journal-title":"Nat Rev Immunol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.021908.132629","article-title":"The liver as a lymphoid organ","volume":"27","author":"Crispe","year":"2009","journal-title":"Annu Rev Immunol"},{"key":"B49","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1080\/01926230590522365","article-title":"Liver immunobiology","volume":"33","author":"Parker","year":"2005","journal-title":"Toxicologic Pathol"},{"key":"B50","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1038\/ni.2691","article-title":"Immune surveillance by the liver","volume":"14","author":"Jenne","year":"2013","journal-title":"Nat Immunol"},{"key":"B51","doi-asserted-by":"publisher","first-page":"2089","DOI":"10.1016\/j.immuni.2021.05.005","article-title":"Identification of a kupffer cell subset capable of reverting the T-cell dysfunction induced by hepatocellular priming","volume":"54","author":"De Simone","year":"2021","journal-title":"Immunity"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.08.006","article-title":"A subset of kupffer cells regulates metabolism through the expression of CD36","volume":"54","author":"Bleriot","year":"2021","journal-title":"Immunity"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2016.12.015","article-title":"Liver sinusoidal endothelial cell cross-priming is supported by CD4 T-cell-derived IL-2","volume":"66","author":"Wittlich","year":"2017","journal-title":"J Hepatol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1128\/Jvi.00867-09","article-title":"The size of the viral inoculum contributes to the outcome of hepatitis b virus infection","volume":"83","author":"Asabe","year":"2009","journal-title":"J Virol"},{"key":"B55","doi-asserted-by":"publisher","first-page":"e1003208","DOI":"10.1371\/journal.ppat.1003208","article-title":"The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells","volume":"9","author":"Schurich","year":"2013","journal-title":"PloS Pathog"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.08.019","article-title":"Optimal generation of tissue-resident but not circulating memory T cells during viral infection requires crosspriming by DNGR-1(+) dendritic cells","volume":"45","author":"Iborra","year":"2016","journal-title":"Immunity"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(00)80078-1","article-title":"A phase I\/II study of recombinant human interleukin-12 in patients with chronic hepatitis b","volume":"32","author":"Carreno","year":"2000","journal-title":"J Hepatol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20888","article-title":"Lamivudine plus interleukin-12 combination therapy in chronic hepatitis b: Antiviral and immunological activity","volume":"42","author":"Rigopoulou","year":"2005","journal-title":"Hepatology"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1128\/Jvi.71.4.3236-3243.1997","article-title":"Interleukin-12 inhibits hepatitis b virus replication in transgenic mice","volume":"71","author":"Cavanaugh","year":"1997","journal-title":"J Virol"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1128\/Jvi.01597-09","article-title":"Semliki forest virus expressing interleukin-12 induces antiviral and antitumoral responses in woodchucks with chronic viral hepatitis and hepatocellular carcinoma","volume":"83","author":"Rodriguez-Madoz","year":"2009","journal-title":"J Virol"},{"key":"B61","doi-asserted-by":"publisher","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":"B62","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2007.05.016","article-title":"Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T-cell responses","volume":"27","author":"Butte","year":"2007","journal-title":"Immunity"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.21.9543-9553.2005","article-title":"CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms","volume":"25","author":"Parry","year":"2005","journal-title":"Mol Cell Biol"},{"key":"B64","doi-asserted-by":"publisher","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":"B65","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.07.005","article-title":"Restoration of HBV-specific CD8+ T-cell function by PD-1 blockade in inactive carrier patients is linked to T-cell differentiation","volume":"61","author":"Bengsch","year":"2014","journal-title":"J Hepatol"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.3949\/ccjm.76.s3.06","article-title":"Management of hepatitis b in pregnancy: Weighing the options","author":"Tran","year":"2009","journal-title":"Cleve Clin J Med"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.04.008","article-title":"Maternal-derived hepatitis b virus e antigen alters macrophage function in offspring to drive viral persistence after vertical transmission","volume":"44","author":"Tian","year":"2016","journal-title":"Immunity"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abi4670","article-title":"NK cells limit therapeutic vaccine-induced CD8(+)T-cell immunity in a PD-L1-dependent manner","volume":"14","author":"Diniz","year":"2022","journal-title":"Sci Transl Med"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1186\/s12865-019-0309-9","article-title":"CD4(+) T-cell exhaustion revealed by high PD-1 and LAG-3 expression and the loss of helper T-cell function in chronic hepatitis b","volume":"20","author":"Dong","year":"2019","journal-title":"BMC Immunol"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20101235","article-title":"A critical role for regulatory T-cell-mediated control of inflammation in the absence of commensal microbiota","volume":"207","author":"Chinen","year":"2010","journal-title":"J Exp Med"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2012.06.063","article-title":"Regulatory T cells are the most important determinant factor of hepatitis b infection prognosis: A systematic review and meta-analysis","volume":"30","author":"Aalaei-Andabili","year":"2012","journal-title":"Vaccine"},{"key":"B72","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1111\/j.1365-2567.2007.02691.x","article-title":"Circulating CD4+ CD25+ regulatory T cells correlate with chronic hepatitis b infection","volume":"123","author":"Peng","year":"2008","journal-title":"Immunology"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20649","article-title":"Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis b virus infection","volume":"41","author":"Stoop","year":"2005","journal-title":"Hepatology"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1111\/jvh.12078","article-title":"Increased regulatory T cells and impaired functions of circulating CD8 T lymphocytes is associated with viral persistence in hepatitis b virus-positive newborns","volume":"20","author":"Shrivastava","year":"2013","journal-title":"J Viral Hepat"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1400849","article-title":"Myeloid-derived suppressor cells regulate immune response in patients with chronic hepatitis b virus infection through PD-1-induced IL-10","volume":"193","author":"Huang","year":"2014","journal-title":"J Immunol"},{"key":"B76","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1038\/nm.3856","article-title":"Metabolic regulation of hepatitis b immunopathology by myeloid-derived suppressor cells","volume":"21","author":"Pallett","year":"2015","journal-title":"Nat Med"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1111\/apt.15226","article-title":"Myeloid-derived suppressor cells induce regulatory T cells in chronically HBV infected patients with high levels of hepatitis b surface antigen and persist after antiviral therapy","volume":"49","author":"Pal","year":"2019","journal-title":"Aliment Pharmacol Ther"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2017-314098","article-title":"Regulatory NK cells mediated between immunosuppressive monocytes and dysfunctional T cells in chronic HBV infection","volume":"67","author":"Li","year":"2018","journal-title":"Gut"},{"key":"B79","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1146\/annurev-med-080119-103356","article-title":"New therapeutics for hepatitis b: The road to cure","volume":"72","author":"Naggie","year":"2021","journal-title":"Annu Rev Med"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2017-315588","article-title":"Poly I:C-based rHBVvac therapeutic vaccine eliminates HBV via generation of HBV-specific CD8(+) effector memory T cells","volume":"68","author":"Zhao","year":"2019","journal-title":"Gut"},{"key":"B81","doi-asserted-by":"publisher","first-page":"70:E50-1","DOI":"10.1016\/S0618-8278(19)30090-8","article-title":"A phase 1b evaluation of HepTcell HBV-specific immunotherapy in nuc-controlled, eAg negative chronic HBV infection","author":"Lim","year":"2019","journal-title":"J Hepatol"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2016.05.016","article-title":"Randomized phase II study of GS-4774 as a therapeutic vaccine in virally suppressed patients with chronic hepatitis b","volume":"65","author":"Lok","year":"2016","journal-title":"J Hepatol"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2021.100361","article-title":"Therapeutic vaccine BRII-179 restores HBV-specific immune responses in patients with chronic HBV in a phase Ib\/IIa study","volume":"3","author":"Ma","year":"2021","journal-title":"JHEP Rep"},{"key":"B84","doi-asserted-by":"publisher","first-page":"184","DOI":"10.3390\/vaccines8020184","article-title":"The design and development of a multi-HBV antigen encoded in chimpanzee adenoviral and modified vaccinia Ankara viral vectors; a novel therapeutic vaccine strategy against HBV","volume":"8","author":"Chinnakannan","year":"2020","journal-title":"Vaccines (Basel)"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32109","article-title":"Efficacy and safety of a nanoparticle therapeutic vaccine in patients with chronic hepatitis b: A randomized clinical trial","volume":"75","author":"Wei","year":"2022","journal-title":"Hepatology"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2013.02.003","article-title":"GS-9620, an oral agonist of toll-like receptor-7, induces prolonged suppression of hepatitis b virus in chronically infected chimpanzees","volume":"144","author":"Lanford","year":"2013","journal-title":"Gastroenterology"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31046-2","article-title":"Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, noncomparative, phase 1\/2 dose escalation and expansion trial","volume":"389","author":"El-Khoueiry","year":"2017","journal-title":"Lancet"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2018.03.027","article-title":"Nonlytic lymphocytes engineered to express virus-specific T-cell receptors limit HBV infection by activating APOBEC3","volume":"155","author":"Koh","year":"2018","journal-title":"Gastroenterology"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2013.04.047","article-title":"T Cells expressing a chimeric antigen receptor that binds hepatitis b virus envelope proteins control virus replication in mice","volume":"145","author":"Krebs","year":"2013","journal-title":"Gastroenterology"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2014.06.039","article-title":"Immunization with adenovirus LIGHT-engineered dendritic cells induces potent T-cell responses and therapeutic immunity in HBV transgenic mice","volume":"32","author":"Jiang","year":"2014","journal-title":"Vaccine"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.06.028","article-title":"Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis b: A pilot study","volume":"71","author":"Gane","year":"2019","journal-title":"J Hepatol"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2019.03.044","article-title":"Combined GS-4774 and tenofovir therapy can improve HBV-specific T-cell responses in patients with chronic hepatitis","volume":"157","author":"Boni","year":"2019","journal-title":"Gastroenterology"},{"key":"B93","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1038\/s41392-021-00776-0","article-title":"Restoration of HBV-specific CD8(+) T-cell responses by sequential low-dose IL-2 treatment in nonresponder patients after IFN-\u03b1 therapy","volume":"6","author":"Wang","year":"2021","journal-title":"Signal Transduct Target Ther"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2019.1689081","article-title":"A dendritic cell-targeted chimeric hepatitis b virus immunotherapeutic vaccine induces both cellular and humorall immune responses in vivo","volume":"16","author":"George","year":"2020","journal-title":"Hum Vaccin Immunother"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2015.64","article-title":"Overcoming HBV immune tolerance to eliminate HBsAg-positive hepatocytes via preadministration of GM-CSF as a novel adjuvant for a hepatitis b vaccine in HBV transgenic mice","volume":"13","author":"Wang","year":"2016","journal-title":"Cell Mol Immunol"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm6715a5","article-title":"Recommendations of the advisory committee on immunization practices for use of a hepatitis b vaccine with a novel adjuvant","volume":"67","author":"Schillie","year":"2018","journal-title":"MMWR Morb Mortal Wkly Rep"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2021.120674","article-title":"Engineered therapeutic nanovaccine against chronic hepatitis b virus infection","volume":"269","author":"Qiao","year":"2021","journal-title":"Biomaterials"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-019-0037-0","article-title":"Therapeutic strategies for hepatitis b virus infection: Towards a cure","volume":"18","author":"Fanning","year":"2019","journal-title":"Nat Rev Drug Discovery"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.965018","article-title":"Toll-like receptor-mediated innate immunity orchestrates adaptive immune responses in HBV infection","volume":"13","author":"Du","year":"2022","journal-title":"Front Immunol"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12791","article-title":"A single and multiple ascending dose study of toll-like receptor 7 agonist (RO7020531) in Chinese healthy volunteers","volume":"13","author":"Luk","year":"2020","journal-title":"Clin Transl Sci"},{"key":"B101","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1002\/hep.31695","article-title":"Therapeutic potential of TLR8 agonist GS-9688 (Selgantolimod) in chronic hepatitis b: Remodelling of antiviral and regulatory mediators","volume":"74","author":"Amin","year":"2021","journal-title":"Hepatology"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1111\/jvh.12942","article-title":"Safety and efficacy of vesatolimod (GS-9620) in patients with chronic hepatitis b who are not currently on antiviral treatment","volume":"25","author":"Agarwal","year":"2018","journal-title":"J Viral Hepat"},{"key":"B103","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1186\/s12985-022-01785-3","article-title":"HBx inhibits DNA sensing signalling pathway via ubiquitination and autophagy of cGAS","volume":"19","author":"Chen","year":"2022","journal-title":"Virol J"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.2c00424","article-title":"Synthetic stimulator of interferon genes (STING) agonists induce a cytokine-mediated anti-hepatitis b virus response in nonparenchymal liver cells","volume":"9","author":"Pimkova Polidarova","year":"2022","journal-title":"ACS Infect Dis"},{"key":"B105","doi-asserted-by":"publisher","first-page":"2119","DOI":"10.1038\/s41467-017-02304-7","article-title":"Hepatitis b virus persistence in mice reveals IL-21 and IL-33 as regulators of viral clearance","volume":"8","author":"Shen","year":"2017","journal-title":"Nat Commun"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.7150\/thno.35331","article-title":"IL-21-based therapies induce clearance of hepatitis b virus persistence in mouse models","volume":"9","author":"Shen","year":"2019","journal-title":"Theranostics"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-04-495531","article-title":"Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes","volume":"122","author":"Abate-Daga","year":"2013","journal-title":"Blood"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1172\/jci121957","article-title":"PD-1 blockade partially recovers dysfunctional virus-specific b cells in chronic hepatitis b infection","volume":"128","author":"Salimzadeh","year":"2018","journal-title":"J Clin Invest"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00849","article-title":"Pathogenetic mechanisms of T-cell dysfunction in chronic HBV infection and related therapeutic approaches","volume":"11","author":"Fisicaro","year":"2020","journal-title":"Front Immunol"},{"key":"B110","doi-asserted-by":"publisher","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":"B111","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.10.034","article-title":"Functional reconstitution of HBV-specific CD8 T cells by in vitro polyphenol treatment in chronic hepatitis b","volume":"74","author":"Acerbi","year":"2021","journal-title":"J Hepatol"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1501362","article-title":"Polarization of monocytic myeloid-derived suppressor cells by hepatitis b surface antigen is mediated via ERK\/IL-6\/STAT3 signalling feedback and restrains the activation of T cells in chronic hepatitis b virus infection","volume":"195","author":"Fang","year":"2015","journal-title":"J Immunol"},{"key":"B113","doi-asserted-by":"publisher","first-page":"e20211838","DOI":"10.1084\/jem.20211838","article-title":"Monocytic MDSCs homing to thymus contribute to age-related CD8+ T-cell tolerance of HBV","volume":"219","author":"Fang","year":"2022","journal-title":"J Exp Med"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1128\/Jvi.76.17.8609-8620.2002","article-title":"Immunogenicity and tolerogenicity of hepatitis b virus structural and nonstructural proteins: Implications for immunotherapy of persistent viral infections","volume":"76","author":"Kakimi","year":"2002","journal-title":"J Virol"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1016\/0168-8278(95)80226-6","article-title":"Histological grading and staging of chronic hepatitis","volume":"22","author":"Ishak","year":"1995","journal-title":"J Hepatol"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2014-308964","article-title":"Prolonged suppression of HBV in mice by a novel antibody that targets a unique epitope on hepatitis b surface antigen","volume":"65","author":"Zhang","year":"2016","journal-title":"Gut"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2018-317725","article-title":"A unique b-cell epitope-based particulate vaccine shows effective suppression of hepatitis b surface antigen in mice","volume":"69","author":"Zhang","year":"2020","journal-title":"Gut"},{"key":"B118","doi-asserted-by":"publisher","first-page":"S49","DOI":"10.1038\/d41586-022-00813-0","article-title":"Developing a cure for chronic hepatitis b requires a fresh approach","volume":"603","author":"Guidotti","year":"2022","journal-title":"nature"},{"key":"B119","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.coviro.2018.04.003","article-title":"Overcoming immune tolerance in chronic hepatitis b by therapeutic vaccination","volume":"30","author":"Dembek","year":"2018","journal-title":"Curr Opin Virol"},{"key":"B120","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.04.019","article-title":"Effects of hepatitis b surface antigen on virus-specific and global T cells in patients with chronic hepatitis b virus infection","volume":"159","author":"Le Bert","year":"2020","journal-title":"Gastroenterology"},{"key":"B121","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2021-324646","article-title":"Impact of HBsAg and HBcrAg levels on phenotype and function of HBV-specific T cells in patients with chronic hepatitis b virus infection","volume":"71","author":"Aliabadi","year":"2021","journal-title":"Gut"},{"key":"B122","doi-asserted-by":"publisher","first-page":"e20200298","DOI":"10.1084\/jem.20200298","article-title":"Serum HBsAg clearance has minimal impact on CD8+ T-cell responses in mouse models of HBV infection","volume":"217","author":"Fumagalli","year":"2020","journal-title":"J Exp Med"},{"key":"B123","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2016.01.026","article-title":"Adaptive immunity in HBV infection","volume":"64","author":"Bertoletti","year":"2016","journal-title":"J Hepatol"},{"key":"B124","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2019.05.039","article-title":"When (and when not) to treat patients with HBV infection","volume":"17","author":"Fricker","year":"2019","journal-title":"Clin Gastroenterol Hepatol"},{"key":"B125","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2018.3795","article-title":"Chronic hepatitis b infection: A review","volume":"319","author":"Tang","year":"2018","journal-title":"Jama"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1106700\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T05:14:24Z","timestamp":1677647664000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1106700\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,1]]},"references-count":125,"alternative-id":["10.3389\/fimmu.2023.1106700"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1106700","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,1]]},"article-number":"1106700"}}