Functional analysis of Epstein-Barr Virus genome variation in relation to cell growth and disease

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Most people are infected by Epstein-Barr virus (EBV) as young children, and carry the virus for their whole life with no ill effects, but the virus can cause several human diseases. Glandular fever occurs when people who were not infected as children first become infected with EBV as teenagers or adults. Also, several specific types of cancer are caused by EBV; together these cancers account for 1.5% of all human cancers worldwide. EBV may also play a role in multiple sclerosis. These diseases occur at quite different rates in different parts of the world and we suspect that the different EBV strains present in those parts of the world may be part of the reason for that. We therefore need to understand what variation is actually present in EBV strains and find out whether it makes a difference to function of the virus, in ways that might be relevant to the human diseases associated with EBV. We have recently published the first large scale DNA sequencing of EBV from different parts of the world, and from various EBV-cancers. This application will make use of this new information to understand how the variation in EBV sequence has an impact on EBV biology. In fact, we now know that most EBV research so far has used EBV lab strains that are poor representatives of the viruses that circulate in the human population. We shall therefore isolate - in a pure form suitable for research - a set of diverse EBV strains and assess their characteristics. The viruses will be tested by infection of human cells relevant to the diseases, both in the lab and in an animal model.We shall also test two specific examples of the impact of virus diversity on biology and disease that have been highlighted by our preliminary work. First we shall investigate how two of the EBV genes (called EBNA2 and EBNA3) work together to determine the much greater ability of certain EBV strains to cause growth of white blood cells, likely relevant to some of the blood cancers associated with EBV. Second, we shall test whether specific differences we have identified in Chinese EBV may help to explain the very high incidence of EBV associated nasopharyngeal cancer that occurs in Hong Kong and nearby parts of China.