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

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.

The hypothesis underlying this proposal is that there are specific interferon-induced defences that target hepatitis B virus (HBV) and hepatitis D virus (HDV) that have not yet been identified. These unidentified interferon-stimulated genes (ISGs) could play an important role in the success of interferon therapies, help define the species tropism of HBV and HDV, influence the incidence of HDV coinfection and contribute to the natural suppression of HBV/HDV (which occurs in most infected patients).

To identify the ISGs that target HBV and/or HDV, we will screen over 1000 ISGs, to identify inhibitory genes, using a series of cell-culture models of HBV/HDV infection and replication. We have substantial expertise concerning the development and use of HBV/HDV infection and replication models and have used arrayed ISG-expression screening to identify ISGs targeting retroviruses, bunyaviruses and vesiculoviruses, leaving us well placed to identify and characterise ISGs inhibiting HBV/HDV.

By analogy to retroviruses, we predict that anti-HBV/HDV effectors may show species dependent patterns of activity. To address this possibility, we propose to initially screen ISGs from humans and mammalian species. Moreover, we will also examine multiple mammalian orthologues of the human effectors we identify. It is possible that ISGs play an underappreciated role in defining the species-tropism of HBV/HDV.

Using existing samples and data, we also plan to examine SNPs and expression levels of the identified ISGs, in patients that do and do not respond to interferon therapies. In addition, we will consider the role that expression level and polymorphism might play in the incidence of HBV coinfection.

Our overall goal is to generate and disseminate knowledge about the genome-encoded antiviral defences that target HBV/HDV. This will stimulate future research in this area, and in the longer term, inform the design of prognostic/intervention strategies targeting HBV and HDV.

Impacts - We will produce outputs of both immediate and longer-term value to diverse beneficiaries in the UK, Japan and beyond.

In academia, there will be an immediate benefit through the generation and dissemination (through high-impact publication) of new knowledge about how hepatitis viruses interact with host defences, inspiring further research, potentially for many years.

For healthcare professionals, knowledge generated could be useful for predicting the clinical outcome of IFN therapy in HBV infections and HBV/HDV coinfections. IFN therapies cause significant adverse effects. The examination of ISG expression levels or the SNPs in patients may help predict the clinical outcome of IFN therapy. Moreover, such genetic examination could also identify healthcare professionals at higher risk of infection with HBV and HDV.

For the pharmaceutical/biotechnology sector, our research could be of longer-term benefit as it may aid the development of novel prognostic devices, antiviral treatments and biotechnologies. The sum of these impacts will be of value to wider society as they will not only improve our understanding of HBV/HDV pathogenesis, but could potentially stimulate the development of interventions that improve human health, which, in turn, will have economic benefits.

Exploitation potential - As described above, the main areas of exploitation include:
The development of prognostic tests/devices indicating susceptibility to infection or clinical outcome of IFN therapy. In the much longer term, it is possible that the antiviral defences identified in this proposal could be harnessed or mimicked in therapeutic interventions.