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Studies on Pathogenesis of Chronic Active Epstein-Barr Virus Infection

慢性活动性EB病毒感染的发病机制研究

基本信息

批准号：
14570750
负责人：
WAKIGUCHI Hiroshi
金额：
$ 2.56万
依托单位：
Kochi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570750/
关键词：
Chronic Active Epstein-Barr Virus Infection T NK-cell proliferation EBV latent gene T, NK細胞増殖

项目摘要

Chronic active Epstein-Barr virus(EBV) infection(CAEBV) is a lethal T-or NK-lymphoproliferative disease often occurring in children. This study aimed to clarify the unknown pathogenesis of CAEBV, from which the establishment of a novel remedial strategy against the disease will also benefit.The approach undertaken in this study is to seek for a latent EBV gene(s) resposible for uncontrolled T-or NK-cell-proliferation, which can functionally replace the role of entire EBV genome in the virus-positive T-or NK-cell lines derived from patients with CAEBV. We prepared improved self-inactivating retroviral vectors(SIN-RVs) that can express individual EBV latent genes, e.g., EBNA1, LMP1, LMP2A, BARF0, A73, RPMS1 and EBERs. Also, we successfully constructed an EBNA1 mutant, and incorporated it into the fiber-replaced adenovirus type 5 vector(Adv5/35f-DNE1). Adv5/35f-DNE1 proved that the EBNA1 mutant efficiently eradicates EBV episomes from infected cells and concomitantly impedes the virus-dependent aggressive growth phenotypes of EBV-positive T-or NK-cell lines, thereby indicating that our EBNA1 mutant can act as a dominant-negative(dn) EBNA1.Based on the above data, we have just entered the final aspect of experiments to identify the EBV latent gene(s) essential to T-or NK-cell-proliferation. In parallel, we are invetigating now into whether our dnEBNA1 will provide an additional therapeutic molecule specifically targeting EBV-associated malignancies, by some ways including animal experiments.

慢性活动性EB病毒感染（Chronic active Epstein-Barr virus infection，CAEBV）是一种常见于儿童的致死性T淋巴细胞或NK淋巴细胞增生性疾病。本研究的目的是寻找一个能够控制T细胞或NK细胞增殖的潜伏性EBV基因，该基因可以在功能上替代整个EBV基因组在CAEBV阳性T细胞或NK细胞中的作用。我们制备了改进的自失活逆转录病毒载体（SIN-RV），其可以表达单个EBV潜伏基因，例如，EBNA 1、LMP 1、LMP 2A、BARF 0、A73、RPMS 1和EBER。此外，我们成功地构建了EBNA 1突变体，并将其整合到纤维替代的腺病毒5型载体（Adv 5/35 f-DNE 1）中。Adv 5/35 f-DNE 1证明EBNA 1突变体有效地从感染的细胞中根除EBV附加体，并伴随地阻碍EBV阳性T细胞系或NK细胞系的病毒依赖性侵袭性生长表型，从而表明我们的EBNA 1突变体可以作为显性阴性（dn）EBNA 1。我们刚刚进入实验的最后一个方面，以鉴定T细胞或NK细胞增殖所必需的EBV潜伏基因。与此同时，我们现在正在研究我们的dnEBNA 1是否会通过包括动物实验在内的某些方式提供一种特异性靶向EBV相关恶性肿瘤的额外治疗分子。