HIV INFECTION OF CULTURED NEURAL CELLS

培养的神经细胞的 HIV 感染

• 批准号: 6243659
• 负责人: Francisco Gonzalez-Scarano
• 金额: $ 18.16万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-03-01 至 1998-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6243659
• 关键词: AIDS dementia complex; HIV envelope protein gp120; HIV infections; apoptosis; astrocytes; brain cell; flow cytometry; genetic strain; human immunodeficiency virus 1; human tissue; macrophage; microglia; nervous system infection; neurons; neurotropic virus; nucleic acid repetitive sequence; oligodendroglia; tissue /cell culture; virulence; virus cytopathogenic effect; virus genetics; virus infection mechanism; virus replication; western blottings

HIV encephalopathy (HIVE) is recognized as a major complication of HIV infection, yet there are many unknown regarding the role of direct viral infection in its pathogenesis, including which cells harbor virus and whether some virus strains are more likely to invade the nervous system. The central hypothesis of this proposal is that virus tropism for cells of the central nervous system is a critical determinant in the development of HIVE, and that understanding this relationship will lead to the development of a rational approach for its treatment. We will approach this problem with an in vitro system consisting of cultured microglia, oligodendrocyte and astrocytes obtained from adults brain, in conjunction with a cell line. NTera 2, that can be differentiated into post-mitotic neurons. Three specific aims are proposed: in the first aim we will address the hypothesis that HIV microglial-tropism and macrophage-tropism may be separable, and survey both existing and newly isolated viruses to compare replication in microglia and macrophage. We will also adapt HIV strains of growth in microglia and, using linker-substitution mutants, analyze the role of the HIV-1 LTR in microglial replication. The findings from this portion of the proposal may help explain the finding that HIVE develops in only a subset of infected individuals, in spite of the fact that most harbor macrophage-tropic strains. In the second aim we will address the questions of whether oligodendrocyte are injectable by HIV strain served from the central nervous system or peripherally, and explore the possibility that infected microglia could injure oligodendrocyte. This aim will address the mechanisms underlying myelin pallor, the most frequent pathological correlate of HIVE. In the third aim, we will explore the infectability of undifferentiated and differentiated NTera 2 cells by either cell-free or cell-associated mechanisms, and will examine the neurotoxicity of infected microglia using the specialized functions characteristic of these post mitotic neurons. This aim will address the critical role of neurons in the development of dementia using human cells exclusively. The results obtained will help us understand the pathogenesis and pathophysiology of HIVE, and the role of HIV in its development. They will be important in the future design of treatment protocols.

HIV脑病（Hive）被认为是HIV的主要并发症 感染，但是关于直接病毒的作用有很多未知 感染其发病机理，包括哪些细胞含有病毒和 某些病毒菌株是否更有可能侵入神经系统。 该提议的中心假设是细胞的病毒tropism 中枢神经系统的关键决定因素 蜂巢的发展，理解这种关系将领导 开发一种理性的治疗方法。 我们将通过一个包括在内的体外系统来解决这个问题 从成年人获得的培养的小胶质细胞，少突胶质细胞和星形胶质细胞 大脑与细胞系结合。 ntera 2，那可以是 分化为有丝分裂后神经元。 三个具体目标是 提议：在第一个目的中，我们将解决艾滋病毒的假设 小胶质细胞主义和巨噬细胞 - 摩托学可能是可分离的，调查 现有和新隔离病毒以比较 小胶质细胞和巨噬细胞。 我们还将适应HIV的生长菌株 小胶质细胞，并使用接头实体突变体，分析 小胶质细胞复制中的HIV-1 LTR。 这部分的发现 该提案可能有助于解释以下发现，即Hive仅在 尽管大多数港口 巨噬细胞 - 热带菌株。 在第二个目标中，我们将解决 少突胶质细胞是否可通过艾滋病毒菌株注射的问题 从中枢神经系统或周围从中央神经系统中探索 感染小胶质细胞可能会损害少突胶质细胞。 这 AIM将解决髓鞘苍白的基础机制，最多 蜂巢频繁的病理相关。 在第三个目标中，我们将 探索未分化和分化的NTERA的感染性 通过无细胞或相关的机制进行2个细胞，并将 使用专业化检查感染的小胶质细胞的神经毒性 这些后有丝分裂神经元的功能特征。 这个目标 解决神经元在痴呆发展中的关键作用 人类细胞专门。 获得的结果将有助于我们了解发病机理和 Hive的病理生理及其HIV在其发育中的作用。 他们 在将来的治疗方案设计中将很重要。