Abstract
Background & AimsHypoxia inducible factors (HIFs) are a hallmark of inflammation and are key regulators of hepatic immunity and metabolism, yet their role in HBV replication is poorly defined. HBV replicates in hepatocytes within the liver, a naturally hypoxic organ, however most studies of viral replication are performed under conditions of atmospheric oxygen, where HIFs are inactive. We therefore investigated the role of HIFs in regulating HBV replication.MethodsUsing cell culture, animal models, human tissue and pharmacological agents inhibiting the HIF-prolyl hydroxylases, we investigated the impact of hypoxia on the HBV life cycle.ResultsCulturing liver cell-based model systems under low oxygen uncovered a new role for HIFs in binding HBV DNA and activating the basal core promoter, leading to increased pre-genomic RNA and de novo HBV particle secretion. The presence of hypoxia responsive elements among all primate members of the hepadnaviridae highlights an evolutionary conserved role for HIFs in regulating this virus family.ConclusionsIdentifying a role for this conserved oxygen sensor in regulating HBV transcription suggests that this virus has evolved to exploit the HIF signaling pathway to persist in the low oxygen environment of the liver. Our studies show the importance of considering oxygen availability when studying HBV-host interactions and provide innovative routes to better understand and target chronic HBV infection.Lay summaryViral replication in host cells is defined by the cellular microenvironment and one key factor is local oxygen tension. Hepatitis B virus (HBV) replicates in the liver, a naturally hypoxic organ. Hypoxia inducible factors (HIFs) are the major sensors of low oxygen; herein, we identify a new role for these factors in regulating HBV replication, revealing new therapeutic targets.
Highlights
Hepatitis B virus (HBV) is a global health problem, with more than 250 million people chronically infected and at least 880,000 deaths/year from HBV-related liver diseases such as cirrhosis and hepatocellular carcinoma (HCC) (WHO, Global hepatitis Report 2017)
Hypoxia inducible factors activate the HBV basal core promoter To investigate a role for HIFs in the HBV life cycle, we first assessed whether the viral genome encodes hypoxic responsive element (HRE)
Since HIFa isoform expression can vary between cell types we show that FG-4592 induced HIF-1a and HIF-2a expression in HepG2 cells derived from a human HCC (Fig. 1B)
Summary
HBV is a global health problem, with more than 250 million people chronically infected and at least 880,000 deaths/year from HBV-related liver diseases such as cirrhosis and hepatocellular carcinoma (HCC) (WHO, Global hepatitis Report 2017). Chronic infection is associated with a blunted host innate immune response, high viral antigen expression and exhausted antiviral T cell responses that fail to control HBV replication.[1] In most cases, treatment may be life-long and patients with a functional cure may still develop liver cancer.[2] Effective antiviral drugs have revolutionized treatments for hepatitis C virus and there is a growing impetus to identify curative therapies for HBV.[3]. Results: Culturing liver cell-based model systems under low oxygen uncovered a new role for HIFs in binding HBV DNA and activating the basal core promoter, leading to increased pregenomic RNA and de novo HBV particle secretion. Lay summary: Viral replication in host cells is defined by the cellular microenvironment and one key factor is local oxygen
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