MOLECULAR BASIS OF RETROVIRUS INDUCED NEUROLOGIC DISEASE

人类逆转录病毒（例如HIV-1）是导致艾滋病毒/艾滋病的一个重要且日益增长的原因。 中枢神经系统（CNS）疾病。在过去的十年里， 多年来已成功地确定了临床症状和神经病理学 这些感染，但未能阐明的分子基础， 这些影响。鉴于获得和 使用逆转录病毒感染的人CNS组织， 已经被开发出来了。我们的实验室已经分离并从分子上定义了 显示明确CNS的鼠白血病病毒（MuLV）分离株 向性和神经病理学。该提案的重点是进一步 TR-MuLV亚家族中MuLV的解剖。TR-MuLV一致 嗜脑血管内皮细胞（CVEC），并可能建立 无论是良性感染，还是慢性到急性神经病理学， 由包膜基因内的单核苷酸取代调节。 这些分子变化与合胞体（SI）的表达有关 与CVEC内的非合胞体诱导（NSI）表型相比。TR-MuLV是一种 用于分析逆转录病毒进入事件的极好模型， 中枢神经系统内的病理学，更具体地说，呈现出令人兴奋的 体内和体外合胞体形成系统。这个目标 一项提案是阐明调节逆转录病毒的分子事件 依赖性合胞体形成和神经系统疾病。这一目标将 通过完成以下具体目标实现： 目标1.探讨细胞与细胞及病毒融合的共同机制 关于我们 目的2：确定膜脂SU介导的变化所导致的机制 增强的细胞融合 目的3：确定mCAT-1对合胞体形成的调节 向异性受体 目标4。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