Eight out of ten people carry Epstein-Barr virus or cytomegalovirus for life, and these persistent herpesviruses can distort the immune system in ways that cause disease. This research aims to understand exactly how that happens. The problem is that while most people carry these viruses without obvious symptoms, the chronic infection can lead to glandular fever, certain cancers, and—especially in elderly or immunosuppressed people—a damaging over-expansion of the immune response that contributes to ill health. The researchers will study which viral proteins T cells recognise, how the virus evades immunity, and why some elderly people develop harmful immune expansions. They will also examine how the balance between virus and immune response changes over time, and whether antiviral drugs can restore normal immune function. This is fundamental science: it will not produce a new treatment tomorrow. But understanding the precise mechanisms by which herpesviruses manipulate the immune system could eventually inform vaccines, therapies for chronic infection, and strategies to preserve immune health in ageing populations.
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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.
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