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A new hepatitis B study reveals how viruses adapt to low-oxygen environments, such as those found deep within the liver, opening up possible new therapeutic targets for liver pathogens. NDM researchers have identified hypoxia-inducible factors (HIFs) playing an important role in the regulation of editing of viral RNAs in low oxygen conditions.

The study on hypoxic modulation of m6A-RNA (effect of hypoxia on cellular RNA modification levels) allows for changes in the m6A modification to regulate stem cell pluripotency during embryonic development that might be a solution. This study was published in PLOS Pathogens.

Chronic hepatitis B (CHB) is one of the world’s most economically important diseases, with 2 billion people exposed to the virus during their lifetime resulting in a global burden of over 290 million infections.

Hepatitis B virus (HBV) replicates in the liver and chronic infection can result in progressive liver disease, cirrhosis and liver cancer. At present, there are no curative treatments due to the persistence of HBV DNA and a dysfunctional viral-specific immune response. Understanding the pathways that influence viral gene expression will illuminate new therapeutic approaches.

Oxygen is essential to all living things and its availability varies in different tissues. The liver experiences a range of oxygen from 3-8% between the different areas. Cells adjust to low oxygen with the help of special factors called hypoxia-inducible factors (HIFs). When oxygen is abundant, HIFα subunits get degraded, however, under low oxygen conditions, HIFs help control many cell activities.

This study investigates the role of methyl-N6-adenosine (m6A) modifications of HBV RNAs under hepatic oxygen levels and uncovers a new role for HIFs to regulate m6A-modified viral RNAs, impacting their stability and abundance in infected cells. These observations highlight a role for HIFs in regulating the editing of viral RNAs that may provide new therapeutic targets and be widely applicable to other liver tropic pathogens.

Professor Jane McKeating, Chair of Molecular Virology in the Nuffield Department of Medicine, said: ‘It’s fascinating to see how viruses adapt to their environment and reveal their ‘Achilles’ heel’ for the potential discovery of new antiviral agents. The University of Oxford’s research on the hypoxic modulation of m6A-RNA - effect of hypoxia on cellular RNA modification levels, may provide a mechanism for altered gene expression in liver cancer.’

 Supporting these numerous other studies showed that hypoxic modulation of m6A-RNA is dependent on both the tissue and cell type.

Read the full paper here: