Understanding HBV immunopathogenesis to inform future immune-based therapies

Chronic hepatitis B virus (HBV) infection remains a major cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide, with more than 250 million people living with chronic infection despite effective prophylactic vaccination. While current treatments provide durable suppression of viral replication and reduce liver-related complications, they rarely achieve functional cure, defined as sustained hepatitis B surface antigen (HBsAg) loss after treatment cessation. Viral persistence is maintained by intrahepatic covalently closed circular DNA and HBV DNA integration, which sustain antigen production and contribute to immune dysfunction. This review summarizes current understanding of HBV immunopathogenesis across acute resolution and chronicity, emphasizing the compartmentalized and tolerogenic liver microenvironment, impaired innate sensing, and progressive dysfunction of HBV-specific B- and T-cell responses, including exhaustion phenotypes shaped by antigen specificity and intrahepatic priming. We also discuss immune correlates associated with functional cure, including partial restoration of polyfunctional HBV-specific T cells and intrahepatic immune remodeling. Finally, we discuss human clinical trials of immune-based therapies highlighting emerging combination strategies designed to couple antigen reduction with immune restauration, defined as the recovery of functional HBV-specific antiviral responses. Collectively, preclinical and clinical data suggest that achieving durable off-treatment control will likely require approaches that address both viral replication, antigen burden and HBV-specific immune responses.