The immunoecology of occult hepatitis B virus infection: genetic remodeling and the immune-mediated microcosm

Occult hepatitis B infection (OBI) is characterized by the persistence of replication-competent hepatitis B virus (HBV) DNA in the absence of detectable hepatitis B surface antigen (HBsAg). Although typically clinically silent, OBI remains associated with transfusion-transmitted infection, viral reactivation during immunosuppression, and an increased risk of hepatocellular carcinoma (HCC). The mechanisms underlying this persistent low-replicative state remain incompletely understood. In this review, we summarize current evidence supporting the concept that OBI is maintained through dynamic interactions among viral genetic adaptation, host genetic and epigenetic regulation, and the intrahepatic immune microenvironment. Building upon these observations, we propose the immune-mediated microcosm as a conceptual framework describing how these processes may interact to sustain long-term immune equilibrium. We further discuss emerging evidence for coordinated viral and host genetic remodeling, immunometabolic regulation, and immune checkpoint signaling, while explicitly distinguishing mechanisms supported by direct evidence in OBI from those inferred from chronic hepatitis B, hepatocellular carcinoma, or experimental models. Finally, we examine the implications of this framework for biomarker discovery, risk stratification, and therapeutic development, while emphasizing the current evidential limitations and the need for direct validation in human OBI. Rather than providing a definitive mechanistic model, this framework is intended to facilitate mechanistic investigation, generate experimentally testable hypotheses, and help identify priorities for future research into OBI pathogenesis.