IMMUNE EVASION BY GAMMA 2 HERPESVIRUSES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本项目的目标是了解免疫逃避机制如何促进卡波西肉瘤相关疱疹病毒（KSHV）的发病机制和卡波西肉瘤（KS）的发展。我们关注两个密切相关的开放式阅读框架K3和K5的功能。这些蛋白质，也称为MIR 1和MIR 2，是细胞膜相关RING-CH（MARCH）蛋白家族的病毒同源物，其包含跨膜泛素连接酶，所述跨膜泛素连接酶募集细胞泛素缀合酶用于降解跨膜蛋白。在之前的资助期间，我们确定了KSHV-K5在KSHV介导的KS蛋白质组重编程中的新功能，这表明这些泛素连接酶不仅参与免疫逃避，而且参与KSHV介导的肿瘤发生。 在这两年中，我们将解决两个主要问题：1）K5表达对KSHV感染的内皮细胞（EC）功能及其与先天免疫细胞的相互作用有什么影响？使用基于EC的KS体外模型，我们将研究EC/EC和EC/白细胞粘附的KSHV的调制。2)KSHV为什么以及如何消除BST 2/Tetherin？初步数据显示，K5泛素化并降解将包膜病毒颗粒束缚到宿主细胞膜的BST 2/Tetherin。我们将检验K5抵消BST 2对KSHV排出的抑制的假设。 完成这些研究后，我们将有一个更好的了解病毒调节宿主过程，预计将是中央建立和维持长期感染的健康个体和KS发展的免疫功能低下。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this project is to understand how immune evasion mechanisms contribute to pathogenesis of Kaposi's sarcoma associated herpesvirus (KSHV) and the development of Kaposi's sarcoma (KS). We focus on the function of two closely related open reading frames, K3 and K5. These proteins, aka MIR1 and MIR2, are viral homologs of the cellular membrane-associated RING-CH (MARCH) protein family comprising transmembrane ubiquitin ligases that recruit cellular ubiquitin-conjugating enzymes for degradation of transmembrane proteins. In the previous funding period we identified novel functions for KSHV-K5 in KSHV-mediated reprogramming of the KS proteome which suggested that these ubiquitin ligases are not only involved in immune evasion, but also in KSHV-mediated tumorigenesis. In these two years, we will address two major questions: 1) What are the consequences of K5 expression for the function of KSHV-infected endothelial cells (ECs) and their interaction with innate immune cells? Using EC-based in vitro models of KS we will examine the modulation of EC/EC and EC/leukocyte adhesion by KSHV. 2) Why and how does KSHV eliminate BST2/Tetherin? Preliminary data show that K5 ubiquitinates and degrades BST2/Tetherin which tethers enveloped viral particles to host cell membranes. We will examine the hypothesis that K5 counteracts the inhibition of KSHV egress by BST2. Upon completion of these studies we will have a better understanding of viral modulation of host processes that are expected to be central to the establishment and maintenance of longterm infection in healthy individuals and KS development in the immunocompromised.