Impact of hypoxia on hepatitis B virus replication

[摘要] Hepatitis B virus (HBV) is one of the world’s unconquered diseases, with 370 million chronically infected globally. HBV replicates in hepatocytes within the liver that exist under a range of oxygen tensions from 11% in the peri-portal area to 3% in the peri-central lobules. HBV transgenic mice show a zonal pattern of' viral antigen with expression in the peri-central areas supporting a hypothesis that low oxygen regulates HBV replication. We investigated this hypothesis using a recently developed in vitro model system that supports HBV replication. We demonstrate that low oxygen significantly increases covalently closed circular viral DNA (cccDNA), viral promoter activity and pre-genomic RNA (pgRNA) level, consistent with low oxygen boosting viral transcription. Hypoxia inducible factors (HIFs) regulate cellular responses to low oxygen and we investigated a role for HIF-1\(\alpha\) or HIF-2\(\alpha\) on viral transcription. A combination of HIF inhibitors and silencing of HIF-l\(\alpha\) and HIF-2\(\alpha\) ablated the effect of low oxygen on cccDNA and pgRNA, suggesting a role in regulating HBV transcription. This study highlights a new role for hepatic oxygen levels to regulate multiple steps in the HBV life cycle and this may impact on future treatments for viral associated pathologies.

[发布机构] University:University of Birmingham;Department:Institute of Immunology and Immunotherapy

[关键词] Q Science;QR Microbiology;QR355 Virology