EBV AND HHV-8 INTERACTIONS IN PRIMARY EFFUSION LYMPHOMAS

人类疱疹病毒8（HHV-8），也称为卡波西肉瘤相关病毒（KSHV），于1994年首次在艾滋病卡波西肉瘤活组织检查中被鉴定。 卡波西氏肉瘤（KS）是一种相对罕见的血管生成性肿瘤，其发病率随着艾滋病的流行而急剧增加。 大约20%的同性恋和双性恋男性艾滋病患者会患上KS。 HHV-8也与AIDS患者中的另外两种恶性肿瘤一致相关：多中心Castleman病和称为原发性渗出性淋巴瘤（PEL）或体腔淋巴瘤（BCBL）的非霍奇金淋巴瘤的子集。 PELs具有不寻常的特征，即大多数同时感染HHV-8和另一种人类γ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，并且存在调节HHV-8或EBV基因表达的程序以允许这种特定恶性肿瘤发展的病毒间相互作用的可能性。 该研究项目的目标是更好地了解双重感染在PEL中的后果。 拉娜是在潜伏感染和所有HHV-8相关肿瘤细胞中表达的少数HHV-8基因之一。 将探讨拉娜在维持HHV-8潜伏期和PEL细胞发育中的作用。该提案的具体目标是：目标1。将在PEL细胞系中检查EBV潜伏基因表达、启动子使用、基因组拷贝数和状态（游离型或整合型）。HHV-8拉娜可调节EBV潜伏期启动子活性的可能性将被检查。 目标二。将建立HHV-8潜伏基因对PEL发展的贡献的遗传测定。 目标3：将表征HHV-8潜伏蛋白拉娜以确定其对HHV-8潜伏DNA复制的贡献以及其通过调节细胞基因表达对肿瘤发生的潜在贡献。

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.