Structure and Molecular Composition of KSHV and RRV

KSHV 和 RRV 的结构和分子组成

• 批准号: 7064312
• 负责人: Dean H Kedes
• 金额: $ 37.79万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7064312
• 关键词: Gammaherpesvirinae; Kaposi' s sarcoma; gene expression; human herpesvirus 8; molecular /cellular imaging; protein structure function; virion; virus assembly; virus genetics; virus protein; virus related neoplasm /cancer

DESCRIPTION (provided by applicant): A decade of both epidemiologic and biologic research has firmly established Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) as the infectious cause of the tumor that shares its name. Infection with this gammaherpesvirus can also lead to two other human diseases, multicentric Castlemen's disease, a lymphoproliferative disorder, and primary effusion lymphoma, a B cell tumor most often afflicting persons with acquired immune deficiency syndrome (AIDS). Although initial KSHV exposure is generally asymptomatic and likely results in the latent infection of a limited number of cells in the host, immunosuppression can lead to unchecked viral spread, expansion of latently infected cells and eventual tumor formation. This pathogenic progression as well as person-to-person spread depends on lytic reactivation and replication of virus followed by recruitment, infection and hyperplastic expansion of a critical mass of new target cells. The most remarkable structures to appear following the initiation of lytic replication are the icosahedral capsids that fill the nucleus and, when fully mature, harbor the linear viral genome. Our NIH-sponsored work on KSHV during the initial funding period was the first to explore simultaneously the protein composition, stoichiometry and three-dimensional structure of capsids from a gammaherpesvirus. We propose in this application to extend these studies toward a comprehensive understanding of the composition and structure of the virions, examining both KSHV and its useful primate homolog, Rhesus monkey rhadinovirus (RRV). Since virions must contain the proteins essential for host range determination and initiation of infection, it is critical to comprehensively identify their protein composition. Moreover, knowledge of this composition is a prerequisite for functional investigations. We will integrate molecular and imaging techniques to identify the virion-associated proteins and the genes encoding them while characterizing the finer details of the viral architecture. The results of our proposed studies on viral structure, molecular composition and assembly may help identify new targets for therapeutic intervention in the future.

描述（由申请人提供）：十年的流行病学和生物学研究已经牢固地确立了卡波西肉瘤（KS）相关疱疹病毒（KSHV）作为肿瘤的感染原因，该肿瘤与其同名。这种γ疱疹病毒的感染还可导致两种其他人类疾病，即多中心Castlemen病（一种淋巴组织增生性疾病）和原发性渗出性淋巴瘤（一种最常折磨患有获得性免疫缺陷综合征（AIDS）的人的B细胞肿瘤）。尽管最初的KSHV暴露通常是无症状的，并且可能导致宿主中有限数量的细胞的潜伏感染，但免疫抑制可导致未受抑制的病毒扩散、潜伏感染细胞的扩增和最终的肿瘤形成。这种致病性进展以及人与人之间的传播取决于病毒的裂解再活化和复制，然后是新靶细胞临界量的募集、感染和增生性扩增。裂解复制开始后出现的最显著的结构是二十面体衣壳，其填充细胞核，并且当完全成熟时，具有线性病毒基因组。 在最初的资助期间，我们的NIH赞助的KSHV工作是第一个同时探索γ疱疹病毒衣壳的蛋白质组成，化学计量和三维结构的工作。我们建议在这个应用程序中扩展这些研究对病毒粒子的组成和结构的全面了解，检查KSHV及其有用的灵长类同源物，恒河猴Rhadinovirus（RRV）。由于病毒体必须含有确定宿主范围和启动感染所必需的蛋白质，因此全面鉴定其蛋白质组成至关重要。此外，这种组合物的知识是功能研究的先决条件。我们将整合分子和成像技术，以确定病毒体相关的蛋白质和编码它们的基因，同时表征病毒结构的细节。 我们提出的关于病毒结构、分子组成和组装的研究结果可能有助于确定未来治疗干预的新靶点。