Impact of hypoxia on hepatitis B virus replication

Frampton, Nicholas Ross (2018). Impact of hypoxia on hepatitis B virus replication. University of Birmingham. Ph.D.

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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.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: Institute of Immunology and Immunotherapy
Funders: European Commission
Subjects: Q Science > QR Microbiology > QR355 Virology


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