MRC AMED - INTERFERON STIMULATED DEFENCES THAT TARGET HEPATITIS B VIRUS (HBV) AND HEPATITIS D VIRUS (HDV)

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Context: Chronic infection with hepatitis B virus (HBV) is a leading cause of liver cirrhosis and hepatocellular carcinoma worldwide. Hepatitis D virus (HDV) can only complete its lifecycle in HBV-infected cells. Thus, HDV is only observed in HBV-infected individuals and this HBV and HDV coinfection worsens HBV-related pathogenesis. Although most people suppress HBV without any clinical intervention, around 10% of people will become chronically infected 'carriers' and the resulting disease burden is a major global health problem (causing ~0.9 million deaths every year). Type I interferons have become a standard treatment for chronic HBV infection. However, the response rate can be as low as 30%, and there is a need to better-understand why some individuals respond to IFN therapies and some do not.Aims: Interferons stimulate the upregulation of hundreds of genes and exactly how this suppresses HBV/HDV, and which IFN-stimulated genes (ISGs) determine the clinical outcome of interferon therapy, is largely unknown. We propose to identify and characterize the interferon-stimulated defences that underlie the ability of type I interferons to promote the suppression of HBV/HDV. Approach: To uncover the individual host genes that mediate the suppression of HBV and HDV, we will carry out screens that simultaneously measure the ability of hundreds of individual ISGs to inhibit HBV and HDV. Our research team consists of experts at propagating HBV and HDV (from the National Institute of Infectious Diseases (NIID), Tokyo, Japan) and specialists at conducting ISG screens (based at the MRC University of Glasgow Centre for Virus Research (CVR) in Glasgow, UK). This combined expertise should facilitate the rapid identification of genes that inhibit HBV and HDV. Following these screens, we propose to focus on one or two of the identified antiviral factors, selected due to the potency of inhibition in natural settings. We will then execute a variety of molecular virology experiments to reveal the molecular details of how the identified factors block HBV/HDV.We hypothesize that variation in the sequence or amount of the defences that block HBV/HDV helps determine how successful interferon therapies are. Moreover, we believe that variation in our defences influences susceptibility to HDV coinfection. Thus, we plan to examine the levels and sequences of the identified defences, in patients that do and do not respond to interferon therapy. Similarly, we will compare the sequences and levels of defences in patients with and without HDV coinfection. In this way, we aim to reveal the contribution that individual defences make in suppressing HBV and/or HDV. Applications and benefits: Within the timeframe of this award, we plan to shed light on an important area of HBV biology and unlock new avenues of research in this field. In the longer term, our research defining how IFNs inhibit HBV and HDV could inform the design of novel prognostic tests and devices. Eventually (over many years), it is hoped that understanding our natural antiviral defences will lead to these defences being harnessed or mimicked in novel antiviral therapies.