Molecular insights into the mechanisms of occult hepatitis B virus infection

Occult hepatitis B virus Infection (OBI) is a form of hepatitis B virus (HBV) persistence that is not accompanied by the presence of circulating HBsAg. It is generally defined as the presence of replication-competent viral DNA, mostly covalently closed circular DNA (cccDNA), in hepatocytes. Although viral load is low and serum markers are typically undetectable, OBI has clinical significance due to its association with transmission, reactivation under immunosuppression, HCV replicative levels, and the progression of liver fibrosis, cirrhosis, and hepatocellular carcinoma. The presence of cccDNA, a stable episomal minichromosome sustained through epigenetic regulation and immune evasion mechanisms, forms the basis for viral evasion of immune clearance and diagnostic detection. The molecular drivers of OBI involve complex interactions among three key factors: viral genetic mutations (particularly in the S region), epigenetic modifications (including cytosine methylation and histone modifications), and host immune responses that are often weakened or exhausted. This review integrates current knowledge regarding these molecular pathways and their contributions to OBI's persistence, reactivation, and associated diseases. A comprehensive understanding of these mechanisms is essential for improving diagnostic approaches, developing targeted therapies, and ultimately achieving the eradication of HBV in this resistant form of infection.