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

使用正常感染和癌细胞中发现的自然变异对 Epstein-Barr 病毒感染和潜在基因功能进行功能研究

• 批准号: MR/S022597/1
• 负责人: Paul Farrell
• 金额: $ 116.68万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS022597%2F1
• 关键词: Functional; investigation; Epstein; Barr; virus

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.

EB病毒（Epstein-Barr virus，EBV）可导致多种类型的癌症，包括霍奇金淋巴瘤、伯基特淋巴瘤、弥漫性大B细胞淋巴瘤、移植后淋巴组织增生性疾病、鼻咽癌和胃癌。它也会引起大多数传染性单核细胞增多症（腺热）。近年来，在开发一些EBV相关癌症的早期诊断方面取得了重大进展，并且正在进行临床试验以改善免疫疗法。美国国家癌症研究所也在支持EB病毒疫苗的开发。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发生频率或严重程度，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，这将为更广泛有效地预防疾病的改进治疗和策略奠定基础：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生物学差异的机制，以及它们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EBNA 2和EBNA 3蛋白如何共同作用来操纵感染的细胞，并检查病毒表面的蛋白（即疫苗候选物）是否改变EBV可以感染的细胞。其次，我们将研究EBNA 1基因多样性的意义。EBNA 1是所有EBV相关癌症中产生的唯一EBV蛋白，并且是EBV在这些癌症中持续存在所必需的，因此它是有吸引力的治疗靶点。EBNA 1蛋白序列之间的差异可能会影响其对癌症的贡献和对潜在EBV药物的反应。我们已经确定了EBNA 1的主要变异体，现在将能够测试这些广泛存在的自然变异的影响，以确保病毒多样性被纳入提供新疗法和免疫的努力中，并了解EBV相关疾病的生物学。

项目成果

A Polymorphism in the Epstein-Barr Virus EBER2 Noncoding RNA Drives In Vivo Expansion of Latently Infected B Cells.

• DOI: 10.1128/mbio.00836-22
• 发表时间: 2022-06-28
• 期刊: mBio
• 影响因子: 6.4

EBV and MS: The evidence is growing stronger.

EBV 和 MS：证据越来越充分。

• DOI: 10.1016/j.cell.2023.11.023
• 发表时间: 2023
• 期刊: Cell
• 影响因子: 64.5
• 作者: Farrell PJ

Oncogenic herpesvirus KSHV triggers hallmarks of alternative lengthening of telomeres.

• DOI: 10.1038/s41467-020-20819-4
• 发表时间: 2021-01-21
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Lippert TP;Marzec P;Idilli AI;Sarek G;Vancevska A;Bower M;Farrell PJ;Ojala PM;Feldhahn N;Boulton SJ
• 通讯作者: Boulton SJ

Do Epstein-Barr Virus Mutations and Natural Genome Sequence Variations Contribute to Disease?

• DOI: 10.3390/biom12010017
• 发表时间: 2021-12-23
• 期刊: Biomolecules
• 影响因子: 5.5
• 作者: Farrell PJ;White RE
• 通讯作者: White RE

Iron metabolism as a novel therapeutic target.

铁代谢作为新的治疗靶点。

• DOI: 10.1182/blood.2021013086
• 发表时间: 2021
• 期刊: Blood
• 影响因子: 20.3
• 作者: Farrell PJ