Bim-mediated attrition of virus-specific CD8 T cells in chronic HBV infection

Lead Research Organisation: University College London
Department Name: Immunology and Molecular Pathology

Abstract

Hepatitis B virus remains one of the top ten killers in the world today, causing around a million deaths every year from chronic liver disease, leading to liver failure and liver cancer. There is a vaccine to prevent spread, but this is of no use to the 400 million people estimated to already be chronically infected. There are now a number of drugs available to treat hepatitis B infection but these typically only suppress the virus rather than clear it; when the patient stops the treatment the virus level comes back up.
The goal of the work proposed here is to allow us to develop a type of treatment supplement to boost immune control, such that costly and potentially toxic antiviral drugs would only need to be given for a short period. We will address this by parallel experiments using both a mouse model and also cells studied directly from patients, including those on the latest treatments available for hepatitis B virus infection. We have identified a critical defect in T cells (a key type of killer immune cell), which could account for their failure to control hepatitis B virus in patients with chronic infection. We have found that their T cells are triggered to commit suicide when they encounter hepatitis B virus; too few of these cells then survive to control the infection. This proposal aims to work out what drives this cell suicide and whether it can be safely blocked to allow a recovery of T cells. This could then switch the immune response back to the successful type seen in people who manage to control this infection naturally without requiring drug treatment.

Technical Summary

Persistent infection with hepatitis B virus (HBV) continues to account for more than a million deaths a year worldwide from liver cirrhosis and hepatocellular carcinoma. Existing therapies usually suppress rather than cure infection, necessitating long-term maintenance use of drugs with ongoing limitations of cost, viral resistance and toxicity. There is therefore a pressing need to complement antiviral therapy with a targeted immunotherapeutic approach aiming to restore effective immune control of HBV and achieve sustained off-treatment responses.
CD8 T cells are known to be critical to the control of HBV and are markedly depleted in patients with persistent infection. We have identified a dysregulated apoptotic pathway in these cells that contributes to their attrition. The pro-apoptotic protein Bim (Bcl-2-interacting mediator) was found to be upregulated in HBV-specific CD8 T cells in patients with chronic compared to resolved HBV infection; downstream inhibition of this pathway rescued HBV-specific CD8 directly ex vivo (Lopes et al JCI May 2008). We hypothesise that blocking Bim-mediated apoptosis will allow successful reconstitution of HBV-specific CD8 T cells able to control infection.
The underlying mechanism responsible for the induction of Bim in HBV-specific CD8 may be related to excessive TCR triggering, to presentation of antigen by infected hepatocytes, or to cross-presentation of HBV antigens. We will investigate in vitro the contribution of each of these processes to triggering this pro-apoptotic pathway in HBV-specific CD8. We will also address the role of aberrant 41BB signalling and any potential to counteract Bim-mediated apoptosis by correcting this. We will use this experimental set-up to explore the potential to block the induction of Bim using immunosuppressive or non-immunosuppressive cyclophilin inhibitors.
To determine the contribution of Bim-mediated apoptosis to loss of the HBV-specific response in vivo, we will use transgenic mice that replicate HBV at high levels in the liver. When HBV-specific CD8 are infused into these mice they are known to undergo premature death; we will investigate whether this is mediated through the Bim pathway using Bim knockout mice.
Finally we will examine whether current treatment regimes for chronic HBV infection have any impact on Bim-mediated apoptosis of HBV-specific CD8.
By identifying underlying triggers and testing the potential of blocking approaches in vitro and in vivo, this work will inform future targeted therapeutic interventions to re-programme the pro-apoptotic defect of HBV-specific CD8 T cells.

Publications

10 25 50

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Burton AR (2018) Circulating and intrahepatic antiviral B cells are defective in hepatitis B. in The Journal of clinical investigation

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Das A (2012) IL-10-producing regulatory B cells in the pathogenesis of chronic hepatitis B virus infection. in Journal of immunology (Baltimore, Md. : 1950)

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Heiberg IL (2015) Defective natural killer cell anti-viral capacity in paediatric HBV infection. in Clinical and experimental immunology

 
Description Clinical Research Training Fellowship
Amount £236,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 03/2010 
End 02/2013
 
Description Clinician Scientist Starter Grant
Amount £30,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2011 
End 12/2012
 
Description EASL Entry level fellowship
Amount £52,000 (GBP)
Organisation European Association for the Study of the Liver (EASL) 
Sector Learned Society
Country European Union (EU)
Start 04/2009 
End 03/2011
 
Description Fast Track grant
Amount £50,000 (GBP)
Organisation University College London Hospital 
Department University College London Hospitals Charity (UCLH)
Sector Charity/Non Profit
Country United Kingdom
Start 04/2013 
End 03/2014
 
Description MRC Clinical Research Training Fellowship
Amount £245,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2009 
End 08/2012
 
Description MRC/A*Star Singapore joint initiative
Amount £300,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2011 
End 12/2012
 
Description Senior Investigator Award
Amount £1,400,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2014 
End 12/2019
 
Description Supervisor on Clinical Research traning Fellowship
Amount $82,000 (AUD)
Organisation National Health and Medical Research Council 
Sector Public
Country Australia
Start 07/2012 
End 06/2015
 
Description UCLH Clinical Research and Development Committee (CRDC) Clinician Scientist Fellowship
Amount £60,000 (GBP)
Organisation University College London Hospitals NHS Foundation Trust 
Sector Public
Country United Kingdom
Start 03/2009 
End 02/2010
 
Title Bim knockout in HBV transgenic 
Description New animal model/reagent available: Bim knockout HBV-specific CD8 in HBV transgenic mouse 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact NEw scientific findings, not yet published 
 
Description Collaboration with Barts and the London 
Organisation Queen Mary University of London
Department Barts and The London School of Medicine and Dentistry
Country United Kingdom 
Sector Academic/University 
PI Contribution Analysis of intrahepatic NK cells
Collaborator Contribution Provision of liver biopsy material for analysis of intrahepatic lymphocytes
Impact Peppa et al PLoS Pathogens 2010
Start Year 2010
 
Description Investigating immunosensececence of T cells in viral hepatitis 
Organisation University of Cambridge
Department School of Clinical Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Expertise in methodology for analysis of replicative senescence of T cells
Collaborator Contribution Collaboration on investigating senescent immune responses in livers of HBV patients
Impact Publication by Hoare et al, J Hepatol 2010
Start Year 2007
 
Description Redirecting the specificity of T cells in HBV 
Organisation Agency for Science, Technology and Research (A*STAR)
Country Singapore 
Sector Public 
PI Contribution Collaborating on investigating ways of overcoming T cell tolerance in HBV
Collaborator Contribution Expertise and new reagents to examine T cell tolerance in HBV
Impact Joint grant MRC/A* Star funding
 
Description Role of Bim in HBV transgenic mice 
Organisation San Raffaele Hospital
Department San Raffaele Scientific Institute (SRSI)
Country Italy 
Sector Academic/University 
PI Contribution Original work in humans pointing to the importanc eof this pathway. Co-designed the experiments and co-supervising the work.
Collaborator Contribution Confirming the role of the pro-apoptotic moleucule Bim in limiting survival of CD8 T cells in the setting of HBV replication using T cells from Bim knockout mice transferred to HBV transgenic mice.
Impact New animal model/reagent available: Bim knockout HBV-specific CD8 in HBV transgenic mouse NEw scientific findings, not yet published
Start Year 2009