Rhadinovirus Entry

卡波西肉瘤相关疱疹病毒（KSHV）是第一种人类鼻病毒，与卡波西肉瘤、原发性渗出性淋巴瘤和多中心Castleman病的病因有关。它在旧世界猴子中的近亲是恒河猴Rhadinovirus（RRV）。RRV的两个菌株，其糖蛋白H（gH）和L（gL）的一级序列有很大的不同，但在其他方面几乎是相同的遗传，提供了一个独特的机会，阐明gH/gL复合物在病毒进入和复制过程中的功能。在本项目中，将对这些RRV变异体和KSHV gH/gL进行比较分析。将分析gH和gL彼此之间以及与细胞受体之间的相互作用，这将在资助期间为RRV定义。与最近发现的KSHV gH/gL受体EphA 2的相互作用和激活将得到解决。将鉴定gH/gL的功能关键区域，并通过在细胞培养物和恒河猴感染模型中产生重组突变病毒来分析gH/gL对RRV向性的作用。鉴定这些进化密切相关但不同的病毒中gH/gL复合物的保守和非保守特征将为深入了解鼻病毒进入的机制提供帮助。此外，阐明的功能结构域的鼻病毒糖蛋白将点在潜在的靶位点的干预策略，并促进发展的鼻病毒载体的疫苗或基因治疗。

Kaposi’s sarcoma-associated herpesvirus (KSHV), the first human rhadinovirus, is etiologically linked to Kaposi’s sarcoma, primary effusion lymphoma and the multicentric Castleman’s disease. Its closest relative in old world monkeys is the rhesus rhadinovirus (RRV). Two strains of RRV, which differ considerably in their primary sequence of the glycoproteins H (gH) and L (gL) but are otherwise genetically almost identical, present a unique opportunity to shed light on the functions of the gH/gL complex during virus entry and replication. In this project, comparative analysis of these RRV variants and KSHV gH/gL will be conducted. Interaction of gH and gL with each other and with cellular receptors, which will be defined for RRV in the course of the funding period, will be analyzed. Interaction with and activation of the recently discovered KSHV gH/gL receptor EphA2 will be addressed. Functionally critical regions of gH/gL will be identified and the role of gH/gL for the tropism of RRV will be analyzed through the generation of recombinant mutant viruses both in cell culture and in a rhesus monkey infection model. Identification of conserved and non-conserved features of the gH/gL complex in these evolutionary closely related but divergent viruses will provide insights into the mechanisms of rhadinovirus entry. Moreover, elucidation of the functional domains of the rhadinovirus glycoproteins will point at potential target sites for intervention strategies and facilitate the development of rhadinoviral vectors for vaccines or gene therapy.