EBV Pathogenesis in a New Mouse Model

B细胞淋巴瘤是ADDS的常见并发症，其中许多淋巴瘤含有EBV 基因组不幸的是，目前还没有广泛使用的小动物模型来检查EBV/HIV 发病机制，并测试潜在的新疗法，在一个完整的免疫系统的背景下。最近， 然而，研究表明，将CD 34+人脐带血细胞注射到辐射过的新生儿Rag 2- /gammaC-双敲除小鼠允许重建整个人类免疫系统，包括 B细胞、T细胞和自然杀伤细胞谱系的发展（63）。此外，当免疫- 重组的Rag 2-/gammaC-双敲除小鼠感染EBV后，它们产生了适当的 控制EBV感染并预防随后淋巴瘤发展的细胞毒性T细胞反应 （63）。在这项资助中，我们建议使用这种新的小鼠模型来研究特定人类的重要性。 免疫细胞亚型和HIV共感染在艾滋病相关EBV诱导的发病机制中的作用 淋巴瘤我们的具体目标是：1）确定rag 2中野生型EBV感染的自然史， /γ C-双敲除小鼠用人造血细胞重建，确定 在原发性与慢性感染期间感染的细胞，以及每个细胞中的病毒基因表达模式 类型;和2）确定是否消耗特定的T细胞亚群，消耗自然杀伤细胞， 免疫抑制剂药物或HIV合并感染促进B细胞淋巴瘤的发展， 用人免疫系统重建的rag 2-/gammaC-双敲除小鼠中的EBV感染

B-cell lymphomas are a common complication of ADDS, and many of these lymphomas contain the EBV genome. Unfortunately, there is currently no widely available small animal model for examining EBV/HIV pathogenesis, and testing potential novel therapies, in the context of an intact immune system. Recently, however, it was shown that injection of CD34+ human cord blood cells into irradiated newborn Rag2- /gammaC- double knock-out mice allows reconstitution of the entire human immune system, including the development of B-cell, T-cell, and natural killer cell lineages (63). Furthermore, when immune- reconstituted Rag2-/gammaC- double knock-out mice are infected with EBV, they develop an appropriate cytotoxic T cell response that controls EBV infection and prevents subsequent lymphoma development (63). In this grant, we propose to use this new mouse model to examine the importance of specific human immune cell subtypes, and HIV co-infection, in the pathogenesis of AIDS-related EBV-induced lymphomas. Our specific aims are to 1) define the natural history of wild-type EBV infection in rag2- /gammaC-double knock-out mice reconstituted with human hematopoietic cells, determining the types of cells infected during primary versus chronic infection, and the viral gene expression pattern in each cell type; and 2) determine if depletion of specific T-cell subsets, depletion of natural killer cells, immunosuppressant drugs or HIV co- infection promote the development of B-cell lymphomas following EBV infection in rag2-/gammaC- double knockout mice reconstituted with the human immune system.