Abstract
Abstract Approximately 300 million people globally suffer from chronic hepatitis B (CHB), leading to complications like hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. Despite a significant reduction in new HBV infections through vaccination, a definitive CHB cure remains elusive. Current treatments rely on antiviral nucleos(t)ide analogues, often failing to induce crucial anti-HBsAg antibody (HBsAb) production. Our prior study unveiled myeloid CD33 (Siglec-3) as an immune checkpoint receptor for HBV, contributing to HBV-induced tolerance. Blocking CD33 with anti-hCD33 mAb enhances antigen-presenting molecule expression and activation markers in dendritic cells, restoring TLR7 agonist-induced cytokine production in CHB patient PBMCs. We recently identified a novel CD19+ B cell population expressing abundant CD33 in CHB patient PBMCs (5-20% of CD19+ B cells), contrasting with rare detection in healthy donors (0.5-3%). Anti-hCD33 mAb treatment induces HBsAb production in PBMCs and CD19+ B cells. Furthermore, establishing a CHB mouse model via pAAV-HBV-1.2 hydrodynamic injection in human CD33 transgenic mice (hCD33 Tg) demonstrated prolonged HBsAg persistence compared to wild-type mice, suggesting human CD33 impedes HBV clearance. Remarkably, anti-hCD33 mAb administration accelerates HBsAg clearance in hCD33 Tg mice, highlighting CD33 as a promising CHB therapeutic target, with anti-hCD33 mAb potential to reactivate host immunity for HBV clearance in CHB patients.
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