IMMUNE EVASION BY GAMMA 2 HERPESVIRUSES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本项目的目的是了解免疫逃避机制如何在卡波西肉瘤相关疱疹病毒(KSHV)的发病机制和卡波西肉瘤(KS)的发生发展中起作用。我们关注两个密切相关的开放阅读框架K3和K5的功能。这些蛋白，又名MIR1和MIR2，是细胞膜相关RING-CH(MARCH)蛋白家族的病毒同源物，包括跨膜泛素连接酶，招募细胞泛素结合酶降解跨膜蛋白。在之前的资助期间，我们发现了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的表达对KSHV感染的内皮细胞(ECs)的功能及其与天然免疫细胞的相互作用有何影响？利用基于EC的KS体外模型，研究KSHV对EC/EC和EC/白细胞黏附的调节作用。2)KSHV为什么以及如何消除BST2/Tetherin？初步数据显示，K5泛素化并降解BST2/Tetherin，BST2/Tetherin将包裹的病毒颗粒拴在宿主细胞膜上。我们将检验K5抵消BST2对KSHV出口抑制的假设。这些研究完成后，我们将更好地了解病毒对宿主过程的调节，这些过程有望在健康个体中建立和维持长期感染以及在免疫受损的人中发展KS。

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.