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.
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.
(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.