MOLECULAR BASIS OF RETROVIRUS INDUCED NEUROLOGIC DISEASE

人类逆转录病毒，如艾滋病毒-1，是一种正在增长的重要原因 中枢神经系统疾病。过去十年的密集学习 多年来已成功地确定了临床症状和神经病理学 但未能阐明这些感染的分子基础 这些影响。考虑到获得和获得 处理逆转录病毒感染的人中枢神经系统组织的几种动物模型 已经被开发出来了。我们的实验室已经分离和分子定义了 显示明确中枢神经系统的小鼠白血病病毒(MuLV)分离株 性向和神经病理学。这项建议的重点是进一步 对TR-MuLV亚家族内MuLV的剖析。TR-MuLV是一致的 趋向性脑血管内皮细胞(CVEC)，并可能建立 要么是良性感染，要么是慢性到急性的神经病理 受包膜基因内单核苷酸替代的调节。 这些分子变化与合胞体(SI)的表达有关 与CVEC内非合胞体诱导(NSI)表型的比较。TR-MuLV是一种 分析逆转录病毒进入和感染事件的优秀模型 中枢神经系统内的病理，更具体地说，呈现一种令人兴奋的 体内和体外合胞体形成系统。这样做的目的是 建议阐明调节逆转录病毒的分子事件 依赖型合胞体形成与神经系统疾病。这个目标将是 通过完成以下具体目标实现： 目的1.研究细胞间融合和病毒融合的共同机制 在MULV家族中 目标2：确定包膜SU变化的中介机制 增强的细胞融合 目的3：确定MCAT-1对合体形成的调节作用 促性腺激素受体 目的4.确定逆转录病毒感染对内皮细胞的影响 功能

Human retroviruses, such as HIV-1, are an important and growing cause of central nervous system (CNS) disease. Intensive studies over the past ten years have successfully defined the clinical symptoms and neuropathology of these infections, but have failed to elucidate the molecular basis for these effects. In view of the inherent difficulties of obtaining and working with retrovirus infected human CNS tissue several animal models have been developed. Our laboratory has isolated and molecularly defined isolates of murine leukemia virus (MuLV) that display well defined CNS tropism and neuropathology. This proposal focuses on the further dissection of MuLV within the TR-MuLV subfamily. TR-MuLV are uniformly tropic for cerebral vessel endothelial cells (CVEC), and may establish either benign infection, or chronic to acute neuropathology which is regulated by a single nucleotide substitution within the envelope gene. These molecular changes are linked to the expression of a syncytium (SI) versus non-syncytium inducing (NSI) phenotype within CVEC. TR-MuLV are an excellent model for analysis of the events of retrovirus entry and pathology within the CNS, and more specifically, present an exciting system of in vivo and in vitro syncytium formation. The goal of this proposal is to elucidate the molecular events that regulate retrovirus dependent syncytium formation and neurologic disease. This goal will be achieved through completion of the following specific aims: Aim 1. TO EXAMINE COMMON MECHANISMS OF CELL-TO-CELL AND VIRUS FUSION WITHIN MULV FAMILIES Aim 2: TO DETERMINE THE MECHANISM WHEREBY CHANGES IN ENVELOPE SU MEDIATE ENHANCED CELL FUSION Aim 3: TO DETERMINE THE REGULATION OF SYNCYTIUM FORMATION BY THE mCAT-1 ECOTROPIC RECEPTOR Aim 4. TO DETERMINE THE IMPACT OF RETROVIRUS INFECTION ON ENDOTHELIAL CELL FUNCTION