Structure and Molecular Composition of KSHV and RRV

描述(申请人提供)：十年的流行病学和生物学研究已经确定卡波西肉瘤(KS)相关疱疹病毒(KSHV)是与其同名的肿瘤的感染原因。感染这种伽马疱疹病毒还可能导致另外两种人类疾病，多中心性Castlman病，一种淋巴增生性疾病，以及原发渗出性淋巴瘤，一种B细胞肿瘤，最常困扰获得性免疫缺陷综合征(AIDS)的人。虽然最初的KSHV暴露通常是无症状的，并可能导致宿主中有限数量的细胞潜伏感染，但免疫抑制可导致病毒不受控制的传播，潜伏感染细胞的扩张，最终形成肿瘤。这种致病进展以及人与人之间的传播依赖于病毒的裂解重新激活和复制，随后是大量新的靶细胞的招募、感染和增生性扩张。在裂解复制开始后出现的最显著的结构是充满细胞核的二十面体衣壳，当完全成熟时，它包含线性病毒基因组。 在最初的资助期，我们由美国国立卫生研究院赞助的KSHV研究工作是第一次同时探索伽马疱疹病毒衣壳的蛋白质组成、化学计量和三维结构。在这项应用中，我们建议将这些研究扩展到全面了解病毒粒子的组成和结构，检测KSHV及其有用的灵长类同源物恒河猴轮状病毒(RRV)。由于病毒粒子必须包含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，对这种成分的了解是进行功能研究的先决条件。我们将结合分子和成像技术来识别病毒粒子相关蛋白和编码它们的基因，同时表征病毒结构的更精细细节。 我们对病毒结构、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。

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.