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

EB病毒(Epstein-Barr Virus，EBV)与多种癌症有关，包括霍奇金淋巴瘤、伯基特淋巴瘤、弥漫性大B细胞淋巴瘤、移植后淋巴增生性疾病、鼻咽癌和胃癌。它还导致大多数传染性单核细胞增多症(腺热)病例。近年来，在一些EBV相关癌症的早期诊断方面取得了重大进展，改进免疫疗法的临床试验正在进行中。美国国家癌症研究所也在支持EBV疫苗的开发。越来越多的证据表明，EBV基因组DNA序列的自然变异可以影响疾病的频率或严重程度，并影响正常的EBV生物学和感染。我们将研究EBV基因组变异的两个主要方面，这将支持改进的治疗和预防疾病的策略更广泛有效：首先，EBV最大的自然变异将病毒株分为两种类型，称为1型和2型，这导致病毒生物学上的显著差异。它们有不同的地理分布，1型(更多样化)发生在世界各地，但2型在撒哈拉以南非洲和其他传染病非常严重的世界其他地区发病率最高。我们的目标是了解这些病毒类型在生物学上的差异背后的机制，以及它们可能如何以不同的方式导致疾病。特别是，我们将研究不同类型的EBNA2和EBNA3蛋白如何共同作用来操纵受感染的细胞，并检查病毒表面的蛋白质(即候选疫苗)是否改变了EBV可以感染的细胞。第二，我们将调查EBNA1基因多样性的意义。EBNA1是所有EBV相关癌症中唯一的EBV蛋白，对EBV在这些癌症中的持续存在是必不可少的，因此它是一个有吸引力的治疗靶点。EBNA1蛋白序列的差异可能会影响其对癌症的贡献以及对潜在EBV药物的反应。我们已经确定了EBNA1的主要变异，现在将能够测试这些广泛的、自然发生的变异的影响，以确保在提供新的治疗和免疫接种的努力中考虑病毒多样性，并了解EBV相关疾病的生物学。

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.