Functional investigation of Epstein-Barr virus infection and latent gene function using natural variants found in normal infections and cancer cells

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Epstein-Barr virus (EBV) contributes to several types of cancer including Hodgkin's lymphoma, Burkitt's lymphoma, diffuse large B cell lymphoma, post-transplant lymphoproliferative disease, nasopharyngeal carcinoma and gastric carcinoma. It also causes most cases of infectious mononucleosis (glandular fever). In recent years there has been major progress in developing early diagnosis of some EBV associated cancers and clinical trials are in progress for improved immunotherapy. The US National Cancer Institute is also supporting development of an EBV vaccine. There is increasing evidence that natural variation in the EBV genome DNA sequence can affect the frequency or severity of disease, and affects normal EBV biology and infections.We shall investigate two major aspects of EBV genome variation that will underpin making improved therapies and strategies for prevention of disease more widely effective:First, the largest natural variation of EBV divides virus strains into two types, called type 1 and type 2, which leads to striking differences in virus biology. They have different geographic distributions, with type 1 (which is more diverse) occuring worldwide but type 2 having its highest incidence in sub-Saharan Africa and other parts of the world where other infectious diseases are very intense. We aim to understand the mechanisms that underlie the differences in biology of these virus types, and how they might differently contribute to disease. In particular we will investigate how different types of EBNA2 and EBNA3 proteins work together to manipulate the infected cell and examine whether proteins on the virus surface (that are the vaccine candidates) alter what cells EBV can infect.Secondly, we shall investigate the significance of diversity of the EBNA1 gene. EBNA1 is the only EBV protein made in all EBV associated cancers, and is essential to EBV persisting in those cancers, so it is an attractive target for therapy. The differences between EBNA1 protein sequences may affect its contribution to cancer and response to potential EBV drugs. We have identified the main variants of EBNA1 and will now be able to will test the effects of these widespread, naturally occurring variations to ensure virus diversity is factored into efforts to provide new therapies and immunisations, and to understand the biology of EBV associated diseases.