Cellular immunity to herpesvirus infection : studies with Epstein-Barr virus and human cytomegalovirus

Lead Research Organisation: University of Birmingham
Department Name: Clinical and Experimental Medicine

Abstract

Epstein-Barr virus (EBV) and Cytomegalovirus (CMV) are common infections that most of us carry for life with no ill effect. But in people whose immune systems are suppressed, especially patients receiving bone marrow transplants after radiation treatment for leukaemia, these virus infections get out of control and become life-threatening. This reflects the important role that our immune system, especially that part of the immune system involving a type of white blood cell called a T cell, normally plays in controlling virus infections. We are studying the way human T cells normally control EBV and CMV infections, what parts of the virus are the main targets for T cell attack, and how the efficiency of T cell control and the choice of virus targets might change from the time immediately after infection, when the immune response first develops, to a point several years later when the virus is kept under control by long-lived ?memory? T cells. We are also developing new ways to isolate the important T cells from the blood of bone marrow donors, then to give them to the bone marrow recipients and in that way protect these patients from virus disease in the first few dangerous months after the transplant.

Technical Summary

Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are common human herpesviruses, sometimes causing symptomatic primary infections but then persisting for life as apparently harmless passengers. Host T cell surveillance is critical for asymptomatic virus carriage, however, and T cell-immunocompromised patients reveal the full pathogenic effects of uncontrolled infection. These viruses therefore serve both as model agents to study the human T cell response to infection and as important pathogens in their own right. The Programme will focus on:
(i) Primary CD8+ T cell responses and the development of memory: we shall continue to follow primary EBV infections prospectively, studying the selection of particular epitope-specificities and T cell receptor (TCR) clonotypes from primary CD8+ T cell responses into memory, and initiate parallel studies on primary CMV infections in transplant recipients. We shall also explore the potential of two new model systems to examine epitope selection and TCR usage in primary responses to EBV.
(ii) CD8 immunodominance among viral antigens and immunoevasion : we shall extend work on the marked hierarchy of CD8 immunodominance among EBV lytic cycle antigens, and link this to mechanistic studies on a unique early lytic cycle protein which we find impairs antigen presentation to CD8+ T cells. We shall pursue our identification of new targets of the CMV-induced CD8 response by in vitro reactivation with a CMV strain deleted for the US2-11 immunoevasion genes and study how the presentation of these new targets by CMV-infected fibroblasts is affected by US2-11 action.
(iii) CD4+ T cell responses : we shall continue work characterizing the large CD4 memory response to CMV in terms of phenotype, function and antigenic specificity, and examine its age-dependent expansion against that seen for CMV-specific CD8 memory. We shall initiate parallel studies looking at hierarchies of CD4 immunodominance among EBV lytic cycle proteins, at the capacity of such responses to recognise lytically-infected cells and at the potential influence of viral evasion strategies on those parameters.
(iv) Immunological intervention against viral disease: we shall continue our contributions to translational work, extending the range of viral epitopes available for tetramer-based selection and adoptive CD8+ T cell therapy against CMV disease and developing protocols for the selection of CMV-specific CD4+ T cells. Looking further towards vaccine development, we shall extend our series of heterologous viral vectors carrying single or multiple CMV antigen inserts and examine their recognition by epitope-specific CD4+ and CD8+ T cells.

Publications

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Fox CP (2010) EBV meets its match. in Blood

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Hislop AD (2005) Tonsillar homing of Epstein-Barr virus-specific CD8+ T cells and the virus-host balance. in The Journal of clinical investigation

 
Description Participation in scientific advisory committees of research establishments.
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
Impact This activity has informed the strategic disciplinary themes of establishments with influence on the topics and contents of medical research projects.
 
Description Participation in scientific advisory committees with concern for training strategy.
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact This activity has informed the doctoral training guidelines of establishments with influence on the topics and contents of medical research projects.
 
Description Graham Taylor - Mechanisms of Endogenous Antigen Processing by the MHC Class II Pathway: Studies with Viral and Cellular Proteins
Amount £439,864 (GBP)
Funding ID G0801936 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2009 
End 09/2012
 
Description Graham Taylor - Towards a Prophylactic Epstein-Barr Virus (EBV) Vaccine to Prevent EBV-Associated Malignancies
Amount £281,306 (GBP)
Funding ID 13174 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2012 
End 01/2014
 
Description Heather Long - CD4+T Cells Recognising Human B Cell Lymphomas: Target Antigen Identification and Therapeutic Potential
Amount £173,792 (GBP)
Organisation Leukaemia and Lymphoma Research 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2012 
End 09/2015
 
Title Prospective blood and serum samples 
Description Prospective blood samples from infectious mononucleosis patients and large numbers of medical school entrants, for virologic/immunologic studies. 
Type Of Material Database/Collection of Data/Biological Samples 
Provided To Others? No  
Impact This data will be made freely available to other researchers within/beyond the University of Birmingham after journal publication. 
 
Description Evasion of T cell recognition by EBV BNLF2a protein 
Organisation Utrecht University
Country Netherlands 
Sector Academic/University 
PI Contribution Our research group has contibuted expertise in understanding the physiological relevance of the effects of the immune evasion protein in affecting the immune recognition of virally-infected cells.
Collaborator Contribution Collaborators have brought a greater understanding of the processes and effects of this immune evasion protein
Impact Our research group has contibuted expertise in understanding the physiological relevance of the effects of the immune evasion protein in affecting the immune recognition of virally-infected cells.
Start Year 2007
 
Description Immunity to EBV in XLP patients and XLP carriers 
Organisation The Garvan Institute for Medical Research
Country Australia 
Sector Hospitals 
PI Contribution Our research group has contrubuted expertise in studying the EBV infection of lymphocyte subsets and immune assays of anti-viral T cell control.
Collaborator Contribution Collaborators have brought access to patient samples, in particular analysis of lymphocyte sub-populations.
Impact NA
Start Year 2008
 
Description MRC Centre for Immune Regulation 
Organisation University of Birmingham
Department MRC Centre for Immune Regulation
Country United Kingdom 
Sector Academic/University 
PI Contribution Theme Lead Cellular immunity to viral infections
Collaborator Contribution Core facilities and studentships
Impact Most of the outputs in this return
 
Description Charity fund-raisers, Birmingham 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact Hosting laboratory visits

Contuned support from community
Year(s) Of Engagement Activity 2006,2007,2008,2009
 
Description Media enquiries 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact various articles in press

This activity increased public awareness of immune approaches to cancer therapy.
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2013,2014