EBV AND HHV-8 INTERACTIONS IN PRIMARY EFFUSION LYMPHOMAS

人类疱疹病毒8型(HHV-8)又称卡波西肉瘤相关病毒(KSHV)，于1994年在艾滋病卡波西肉瘤活检组织中首次发现。卡波西氏肉瘤(KS)是一种相对罕见的血管生成肿瘤，随着艾滋病流行的开始，发病率急剧增加。大约20%的患有艾滋病的男同性恋者和双性恋者会患上KS。HHV-8也一直与艾滋病患者的另外两种恶性肿瘤联系在一起：多中心性Castleman病和被称为原发渗出性淋巴瘤(PEL)或体腔淋巴瘤(BCBL)的非霍奇金淋巴瘤的子集。PEL具有一个不同寻常的特征，即大多数人同时感染HHV-8和另一种人类伽玛疱疹病毒Epstein-Barr病毒(EBV)。HHV-8和EBV各自编码多个生长刺激基因，并且存在病毒间相互作用的可能性，这种相互作用调节HHV-8或EBV基因的表达程序，从而允许这种特殊的恶性肿瘤的发展。这项研究项目的一个目标是更好地了解PEL双重感染的后果。LANA是少数在潜伏感染和所有与HHV-8相关的肿瘤细胞中表达的HHV-8基因之一。将探讨LANA在维持HHV-8潜伏期和PEL细胞发育中的作用。这项建议的具体目的是：目的1.将在PEL细胞系中检测EBV潜伏基因的表达、启动子的使用、基因组拷贝数和状态(外体或整合)。HHV-8 LANA可以调节EBV潜伏期启动子活性的可能性将被检测。目的2.建立HHV-8潜伏基因在PEL发生中的作用的遗传分析方法。目的研究HHV-8潜伏期蛋白LANA在HHV-8潜伏期DNA复制中的作用及其通过调节细胞基因表达而在肿瘤发生中的作用。

Human herpesvirus 8 (HHV-8), also called Kaposi's sarcoma- associated virus (KSHV), was first identified in 1994 in AIDS Kaposi's sarcoma biopsies. Kaposi's sarcoma (KS) was a relatively rare angiogenic neoplasm that dramatically increased in incidence with the onset of the AIDS epidemic. Approximately 20 percent of gay and bisexual men with AIDS develop KS. HHV-8 is also consistently assoicated with two other malignancies in AIDS patients: Multicentric Castleman's disease and a subset of non-Hodgkin's lymphomas called primary effusion lymphomas (PELs) or body cavity based lymphomas (BCBLs). PELs have the unusual feature that the majority are co-infected with both HHV-8 and another human gamma herpesvirus Epstein-Barr virus (EBV). HHV-8 and EBV each encode multiple growth stimulatory genes and the potential exists for inter-virus interactions that modulate the program of HHV-8 or EBV gene expression to allow the development of this particular malignancy. A goal of this research project is to better understand the consequences of dual infection in PELs. LANA is one of the few HHV-8 genes that is expressed in latent infection and in all HHV-8 associated tumor cells. LANA's role in the maintenance of HHV-8 latency and in PEL cell development will be explored. The Specific Aims of this proposal are: Aim 1. EBV latency gene expression, promoter usage, genome copy number and status (episomal or integrated) will be examined in PEL cell lines. The possibility that HHV-8 LANA can modulate EBV latency promoter activity will be examined. Aim 2. A genetic assay for the contribution of HHV-8 latency genes to PEL development will be established. Aim 3. The HHV-8 latency protein LANA will be characterized to determine its contribution to HHV-8 latency DNA replication and its potential contribution to tumorigenesis through modulation of cellular gene expression.