FAM151A inhibits hepatitis B virus by modulating cccDNA transcriptional activity

Hepatitis B virus (HBV) remains a major global public health challenge. Current therapeutic strategies against HBV have limited efficacy, primarily due to the persistence of covalently closed circular DNA (cccDNA) that resists eradication. Family with sequence similarity 151 member A (FAM151A), a member of the FAM151 protein family, is poorly characterized, and its potential antiviral effects have not been previously investigated. In this study, three experimental models were employed to evaluate the antiviral effects of FAM151A, including the HBV1.3 plasmid transfection cell model, AAV1.2-HBV mouse model, and HBV-infected cell culture systems. HBV replication markers were measured to determine which replication stage was affected by FAM151A. Luciferase reporter assays and Chromatin immunoprecipitation were employed to investigate the effects on HBV covalently closed circular DNA (cccDNA). As a result, in both in vivo and in vitro models, FAM151A inhibited HBV replication. Results from in vitro experiments showed that FAM151A inhibited cccDNA transcriptional activity without altering its abundance. Mechanistically, FAM151A regulates HBV promoter activity through post-transcriptional modifications of cccDNA and regulation of host transcription factors involved in HBV RNA synthesis. Overall, this study reveals a previously unrecognized role of FAM151A in modulating cccDNA transcriptional activity. These findings provide important insights into the role of FAM151A in the host defense against HBV.