EBV Pathogenesis in a New Mouse Model

描述(申请人提供)：B细胞淋巴瘤是艾滋病的常见并发症，其中许多含有EBV基因组。不幸的是，目前还没有广泛可用的小动物模型来研究EBV/HIV的发病机制，并在完整的免疫系统的背景下测试潜在的新疗法。然而，最近有研究表明，将CD34+人脐血细胞注射到受辐射的新生Rag2-/GammaC-双基因敲除小鼠中，可以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系的发育(63)。此外，当免疫重建的Rag2-/GammaC-双基因敲除小鼠感染EBV时，它们会产生适当的细胞毒性T细胞反应，控制EBV感染并防止随后的淋巴瘤发展(63)。在这项资助中，我们建议使用这个新的小鼠模型来检查特定的人类免疫细胞亚型和HIV共同感染在艾滋病相关EBV诱导的淋巴瘤发病机制中的重要性。我们的具体目标是：1)确定由人造血细胞重组的RAG2/GammaC双基因敲除小鼠中野生型EBV感染的自然历史，确定在初次感染和慢性感染期间感染的细胞类型，以及每种细胞类型中病毒基因的表达模式；以及2)确定特定T细胞亚群的耗尽、自然杀伤细胞的耗尽、免疫抑制药物或HIV合并感染是否促进了以人类免疫系统重组的RAG2/GammaC双基因敲除小鼠中EBV感染后B细胞淋巴瘤的发展。

DESCRIPTION (provided by applicant): B-cell lymphomas are a common complication of AIDS, 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.