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

大多数人在幼儿时期就感染了爱泼斯坦-巴尔病毒(EBV)，并在一生中携带该病毒，没有任何不良影响，但该病毒可导致多种人类疾病。当儿童时期没有感染的人在青少年或成年后首次感染EBV时，就会发生腺热。此外，几种特定类型的癌症是由EBV引起的；这些癌症加起来占全球所有人类癌症的1.5%。EBV也可能在多发性硬化症中发挥作用。这些疾病在世界不同地区的发病率非常不同，我们怀疑世界这些地区存在的不同EBV毒株可能是造成这种情况的部分原因。因此，我们需要了解EBV毒株中实际存在的变异，并找出它是否会以可能与EBV相关的人类疾病相关的方式对病毒的功能产生影响。我们最近发表了来自世界不同地区和各种EBV癌症的第一个大规模EBV DNA测序。这项应用将利用这一新信息来了解EBV序列的变异如何对EBV生物学产生影响。事实上，我们现在知道，到目前为止，大多数EBV研究都使用了EBV实验室毒株，这些毒株不能很好地代表在人类群体中传播的病毒。因此，我们将以一种适合研究的纯形式分离一组不同的EBV毒株，并评估它们的特征。这些病毒将在实验室和动物模型中通过感染与疾病相关的人类细胞进行测试。我们还将测试病毒多样性对生物学和疾病的影响的两个具体例子，这两个例子已经在我们的初步工作中得到了强调。首先，我们将研究两个EBV基因(称为EBNA2和EBNA3)如何协同工作，以确定某些EBV毒株导致白细胞生长的能力更强，这可能与一些与EBV相关的血癌有关。第二，我们将测试我们在中国人EB病毒中发现的特定差异是否有助于解释为什么EB病毒相关性鼻咽癌在香港和中国附近地区发生的非常高的发病率。

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.