Structure and Molecular Composition of KSHV and RRV

描述（由申请人提供）：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）是肿瘤的感染原因。感染这种伽玛疱疹病毒还可导致另外两种人类疾病：多中心卡斯尔门病（一种淋巴细胞增生性疾病）和原发性积液性淋巴瘤（一种B细胞肿瘤，最常见于获得性免疫缺陷综合征（艾滋病）患者）。虽然最初的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激活和复制，随后是新靶细胞的募集、感染和增殖性扩增。裂解复制开始后出现的最显著的结构是二十面体衣壳，它填充细胞核，当完全成熟时，容纳线性病毒基因组。

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.