Cellular immunity to herpesvirus infections: studies with Epstein-Barr virus (EBV) and human cytomegalovirus (CMV)

Lead Research Organisation: University of Birmingham
Department Name: Cancer Sciences

Abstract

Human herpes viruses are a group of eight related viruses which cause a range of diseases such as glandular fever, chicken pox and some cancers. One remarkable feature is that they are never eradicated from our bodies after infection but persist for many decades. However, these ?chronic infections? may be associated with clinical complications arising from virus-induced distortion of the immune system.
Over many years we have studied the immune response to two of these viruses, Epstein Barr Virus (EBV) and Cytomegalovirus (CMV, which infect the vast majority of the human population. We have studied the immune response that develops against the viruses both in healthy donors and those who are immune-suppressed.
We now propose to continue our work in three main areas.
Firstly, we will study how a major component of the immune response, T cells, control the viruses. We will focus on which viral proteins are ?seen? by the T cells and how this is related to proteins the virus makes to evade immunity. We will determine which responses survive over time and the mechanisms behind this. We will also study how immunity is maintained in elderly individuals and which factors underlie the potentially damaging expansion of the immune response in some elderly people.
Secondly we will make a detailed study of the proteins that the virus makes in order to suppress the immune response such that it can survive. This is important to understand both the profile of immune response that is observed and also how we may improve this in the future.
Thirdly, we will study the balance between the virus and the immune response, as seen in healthy people and in patients, to understand the effect of these viruses on the general immune function of the population. We will determine what level of virus different people are carrying, whether the level is stable over rtime and how this determines the nature of the immune response. We will study how single infection with either EBV or CMV, or dual infection with both viruses, influences the immune system, and how anti-viral drugs might improve immune function.
Overall this work should provide the most detailed analysis of the interaction between our immune systems and herpesviruses. EBV and CMV are increasingly recognised as major global pathogens and our programme is an important opportunity to determine the factors and mechanisms that contribute to viral disease.

Technical Summary

Our work focuses on two human herpesviruses, Epstein-Barr virus (EBV) and cytomegalovirus (CMV), which elicit strong T cell-mediated responses in the immunocompetent host but are life-threatening in immunocompromised settings. We propose three areas of work on:-.

(i) Immunodominance and the evolution of viral immune responses : we shall study the different hierarchy of CD8 immunodominance among immediate early (IE), early (E) and late (L) antigens of the EBV lytic cycle (IE E L) with that found for CMV, where strong responses to IE, E and L antigens exist. Experiments, involving both infectious mononucleosis (IM) and X-linked lymphoproliferative disease (XLP) patients, will test the hypothesis that EBV-induced CD8 responses are directly primed by virus-infected B cells. We shall also compare the CD8 response to known immunodominant CMV epitopes with that to a range of new, subdominant epitopes, looking for inter-epitope differences in phenotype and age-dependent response inflation. Parallel work will study the size and kinetics of CD4 responses to newly-defined EBV and CMV epitopes in primary and persistent infection and ask whether, superimposed on the cross-primed response, there is enhanced reactivity to antigens which naturally access the MHC II pathway in lytically-infected cells.

(ii) Immune evasion : here we extend the study of CD8 immune evasion by EBV, using gene-deleted viruses to ask what influence the three EBV lytic cycle proteins with known evasion function (BNLF2a, BGLF5 and BILF1) have upon antigen presentation in the natural context of the lytically-infected cell, in particular how their separate functions complement one another at different stages of lytic cycle. In parallel, we shall use the methods that have identified natural killer (NK) evasion functions in CMV to screen the whole EBV lytic gene set for evidence of similar NK evasion effects, and use newly-developed experimental approaches to examine the functional importance of four lytic cycle proteins (BZLF1, BGLF5, BCRF1 and gp42) which are candidate effectors of CD4 immune evasion.

(iii) Virus-host balance in the immunocompetent and immunosuppressed : here we analyse virus-host interactions at the tissue level, looking at the homing and intra-tissue localisation of virus-specific T cells, and at the whole organism level through cross-sectional and prospective studies on newly-established cohorts of young immunocompetent, elderly and patient groups. There we focus on issues of response magnitude in relation to latent and lytic virus load, the antigen-dependence of response persistence, and the effect of virus carriage on overall composition of the T cell pool.

Publications

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Cowley NJ (2017) Cytomegalovirus in Patients in the Intensive Care Unit-Reply. in JAMA internal medicine

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Firth C (2016) Cytomegalovirus infection is associated with an increase in systolic blood pressure in older individuals. in QJM : monthly journal of the Association of Physicians

 
Description Funding from US Biotech
Amount £80,000 (GBP)
Organisation Palleon Pharmaceuticals Inc 
Start 10/2017 
End 09/2018
 
Description MRC Confidence in Concept Award
Amount £70,000 (GBP)
Organisation University of Birmingham 
Sector Academic/University
Country United Kingdom
Start 10/2017 
End 10/2018
 
Description MRC Programme Grant
Amount £1,360,000 (GBP)
Funding ID MR/R011230/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 06/2018 
End 05/2023
 
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 MRC Centre For Immune Regulation 
Organisation University of Birmingham
Department MRC Centre for Immune Regulation
Country United Kingdom 
Sector Public 
PI Contribution Theme Lead Cellular immunity to viral infections
Collaborator Contribution Studentships and facilities
Impact Studentships and papers
Start Year 2006
 
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 Regional
Primary Audience Participants in your research and patient groups
Results and Impact Over 100 members of the public visited the research laboratories, were given a presentation of the work performed, and taken for a guided tour of the laboratories to observe practical demonstrations.

This activity increased the public profile of the MRC Centre and the University of Birmingham as a research-based institution.
Year(s) Of Engagement Activity 2010,2011,2012,2013,2014
 
Description Media enquiries 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact Several press articles were published.

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