EVASION OF ANTIGEN PRESENTATION BY RHESUS CYTOMEGALOVIRUS

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。 主要目的是在体外鉴定和表征巨细胞病毒的免疫调节功能，并确定它们在体内免疫逃避中的作用。包括我们在内的几个实验室的工作先前发现，US6家族的四种糖蛋白(US2、US3、US6和US11)抑制HCMV感染细胞中MHC I的组装和运输。我们证明了RhCMV编码这四种免疫调节剂(Rh182、Rh184、Rh185和Rh189)的功能同源物。此外，我们有一个意想不到的发现，即RhCMV编码了一种新的机制，可以拦截MHC I重链(HC)的生物合成，而不是轻链(Beta2m)的生物合成。这项应用的目的是a)研究MHC I干扰机制是否在体内逃避CD8+T细胞控制方面起重要作用，b)检测US6相关和非相关基因在体内免疫逃避中的重要性，以及c)表征VIHCE的分子机制。 具体目的1：鉴定编码VIHCE的基因。这一特定目的的目的是确定RhCMV基因组中哪个开放阅读框架编码与VIHCE表型有关的基因。 具体目标2：VIHCE的功能特征。这一特定目的的目的是进一步表征野生型或VIHCE缺失的RhCMV感染细胞中的VIHCE机制。 具体目标3：MHC I调节剂在建立和维持RhCMV持续感染中的作用。我们将研究VIHCE和US6相关基因在恒河猴再感染模型中对病毒免疫逃避的作用。

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 major goal is to identify and characterize cytomegaloviral immunomodulatory functions in vitro and to define their role for immune evasion in vivo. Work in several laboratories, including ours, previously uncovered that four glycoproteins of the US6-family (US2, US3, US6 and US11) inhibit assembly and transport of MHC I in HCMV-infected cells. We demonstrated that RhCMV encodes functional homologues for each of these four immunomodulators, (Rh182, Rh184, Rh185 and Rh189). Additionally, we made the unexpected discovery that RhCMV encodes a novel mechanism which intercepts biosynthesis of MHC I heavy chains (HC), but not light chains (beta2m). The goals of this application are a) to examine whether MHC I interference mechanisms are important for evading CD8+ T cell control in vivo, b) to examine the importance of US6-related and -unrelated genes in immune evasion in vivo and c) to characterize the molecular mechanism of VIHCE. Specific Aim 1: Identification of the gene encoding VIHCE. The goal of this specific aim is to identify which open reading frame in the RhCMV genome encodes the gene responsible for the VIHCE phenotype. Specific Aim 2: Functional characterization of VIHCE. The goal of this specific aim is to further characterize the VIHCE mechanism in cells infected with wildtype or VIHCE-deleted RhCMV. Specific Aim 3: The role of MHC I modulators for establishment and maintenance of persistent infection by RhCMV. We will examine the role of VIHCE and US6-related genes for viral immune evasion in a re-infection model in rhesus macaques.