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Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Functional cure rates in chronic hepatitis B (CHB) remain below 10% after long-term nucleos(t)ide analogue (NA) therapy, and PD-1\/PD-L1 blockade achieves HBsAg clearance in approximately 30% of selected patients with low baseline HBsAg (\u2264100 IU\/mL). This shortfall reflects an oversimplified view of T-cell exhaustion that neglects nonredundant checkpoints operating in parallel with PD-1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main arguments<\/jats:title>\n                    <jats:p>We synthesize emerging evidence (2019\u20132025) to position the B and T lymphocyte attenuator (BTLA)\/herpesvirus entry mediator (HVEM) axis as an emerging candidate hub for layered therapeutic strategies in HBV infection. BTLA preferentially recruits SHP-1 (versus PD-1-predominant SHP-2) and signals via PI3K\u2013AKT to sustain terminal exhaustion independently of PD-1 status. BTLA preferentially recruits SHP-1 (Src homology region 2 domain-containing phosphatase-1) [versus PD-1-predominant SHP-2 (Src homology region 2 domain-containing phosphatase-2)] and signals via PI3K\u2013AKT to constrain TPEX proliferation and effector differentiation independently of PD-1 status. In CHB, BTLA is upregulated on peripheral and intrahepatic CD4+ and CD8+ T cells, correlating with ALT\/AST and histologic activity; however, this correlation should be interpreted cautiously, as elevated liver enzymes primarily reflect immune-mediated hepatocellular injury during active inflammation rather than purely antiviral immune dysfunction. In HBV-related acute-on-chronic liver failure (HBV-ACLF), CD4+ T-cell BTLA expression independently predicts 90-day mortality and secondary infections. Soluble BTLA has emerged as a candidate minimally invasive biomarker for risk stratification in resource-limited settings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Under low antigen load following long-term NA suppression (HBsAg &amp;lt;100 IU\/mL), biomarker-guided combination therapy targeting BTLA\/HVEM alongside PD-1 may expand functional cure rates beyond the ceiling of single-checkpoint blockade. We outline an adaptive Phase I trial concept with predefined stratification thresholds to enable reproducible translation in HBV-endemic regions.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1882879","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T05:30:51Z","timestamp":1786339851000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The BTLA\/HVEM axis as a key regulator for stratified functional cure in chronic hepatitis B"],"prefix":"10.3389","volume":"17","author":[{"given":"Yuzhen","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Infection Disease, Fujian Provincial Specialty Center for Liver Cirrhosis, Clinical Medical Research Center for Bacterial and Fungal Infectious Diseases of Fujian province, Fujian Medical University Affiliated First Quanzhou hospital","place":["Quanzhou, Fujian, 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Infection Disease, Fujian Provincial Specialty Center for Liver Cirrhosis, Clinical Medical Research Center for Bacterial and Fungal Infectious Diseases of Fujian province, Fujian Medical University Affiliated First Quanzhou hospital","place":["Quanzhou, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueping","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Infection Disease, Fujian Provincial Specialty Center for Liver Cirrhosis, Clinical Medical Research Center for Bacterial and Fungal Infectious Diseases of Fujian province, Fujian Medical University Affiliated First Quanzhou hospital","place":["Quanzhou, Fujian, China"]},{"name":"Key Laboratory of Screening and Control of Infectious Diseases (Quanzhou Medical College), Fujian Provincial University","place":["Quanzhou, Fujian, 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