HIV-ASSOCIATED CNS DYSFUNCTION IN PEDIATRIC AIDS

在这项提议中要检验的总体假设是暴露于 人类胎儿中枢神经系统(CNS)对HIV-1的反应可能足以 导致儿童艾滋病特有的神经功能障碍。这个 这一假设的基础是有相当数量的儿童患有 艾滋病和其他没有临床症状但患有先天性HIV-1的人 感染表现为认知、行为和神经发育 异常现象。儿童中枢神经系统的显著神经病理改变 感染了HIV-1但没有其他艾滋病迹象的胎儿也 已经被注意到了。此外，HIV-1核酸序列或蛋白质和 在受影响的患者中观察到了生产性病毒感染的迹象 组织和体外研究表明，HIV-1感染胶质细胞 细胞。为了更准确地确定艾滋病毒-1在儿童艾滋病中的作用， 一组神经科学家，每个人都是不同类型的神经细胞的专家， 一起来探讨这个问题，使用形态学， 生物化学和分子生物学技术。因为发生了变化 HIV-1感染儿童的正常认知发展，项目1将 HIV-1对神经元分化影响的研究 在特定的神经递质系统和神经元细胞骨架组件上。 项目2将补充项目1，因为它将主要专注于 HIV-1感染中星形胶质细胞的细胞骨架和代谢功能 儿童艾滋病中所描述的反应性星形细胞增多症与 星形胶质细胞可以诱导细胞因子，从而调节中枢神经系统的功能。项目3 将专注于胎儿中枢神经系统中的小胶质细胞，因为这种细胞类型被认为 在艾滋病神经病理学方面发挥关键作用。该项目将检查HIV-1 体内、外感染小胶质细胞并检测其作用 组织损伤中的细胞因子。因为髓鞘病理在 儿童艾滋病，项目4将检查髓鞘生成和髓鞘功能障碍 HIV-1在体内暴露人胎儿中枢神经系统。该项目还将 利用分离细胞研究髓鞘生物学相关机制 培养和器官型外植体培养。项目5的重点是 内皮细胞参与中枢神经系统疾病的病理生理 因为有证据表明血管内皮细胞可能感染HIV-1 它们为病毒进入中枢神经系统提供了第一道屏障。 此外，内皮细胞产生的细胞因子可能参与 艾滋病的病理生理学。最后，项目6将使用体外培养技术 探索HIV-1基因与宿主细胞相互作用的神经细胞模型 基因表达反过来，宿主细胞控制HIV-1基因的表达。 本计划项目申请中提出的研究应回答许多问题 与儿科神经系统疾病相关的紧迫问题 艾滋病。在这些问题中，包括对直接神经趋向性的确定。 HIV-1；与这种病毒的神经侵袭有关的因素； 以及，艾滋病毒神经毒力的机制。这些研究可能会提出新的 更有效地预防或治疗神经系统疾病的策略 儿科艾滋病。

The overall hypothesis to be tested in this proposal is that exposure of the human fetal central nervous system (CNS) to HIV-1 may be sufficient to cause the neurological dysfunction characteristic of pediatric AIDS. The basis for this assumption is that a significant number of children with AIDS and others without clinical signs of disease but with congenital HIV-1 infection exhibit cognitive, behavioral, and neurodevelopmental abnormalities. Significant neuropathologic changes in the CNS of children and fetuses infected by HIV-1 but without other signs of AIDS have also been noted. Furthermore, HIV-1 nucleic acid sequences or proteins and signs of productive viral infection have been observed in the affected tissues and studies in vitro have demonstrated HIV-1 infection of glial cells. To define the role of HIV-1 in pediatric AIDS more precisely, a group of neuroscientists, each expert in a different neural cell type, has come together to pursue this question using a combination of morphologic, biochemical an molecular biologic techniques. Because of alterations in normal cognitive development in HIV-1 infected children, Project 1 will study the effect of HIV-1 on neuronal differentiation with a focus on specific neurotransmitter systems and on neuronal cytoskeletal components. Project 2 will complement Project 1 in that it will focus primarily on the astrocyte cytoskeleton and metabolic function in HIV-1 infection because of the reactive astrocytosis described in pediatric AIDS and the ability of astrocytes to elicit cytokines which may modulate CNS function. Project 3 will focus on microglia in the fetal CNS because this cell type is believed to be pivotal in AIDS neuropathology. This project will examine HIV-1 infection of microglia in vivo and in vitro and examine the role of cytokines in tissue damage. Because myelin pathology is prominent in pediatric AIDS, Project 4 will examine myelinogenesis and dysmyelination in the human fetal CNS exposed to HIV-1 in vivo. Project will also investigate the mechanisms related to myelin biology using dissociated cell culture and organotypic explant cultures. Project 5 focuses on the involvement of endothelial cells in the pathophysiology of CNS disease because evidence indicates that endothelial cells may be infected by HIV-1 and they provide the first barrier to viral entry into the CNS. Additionally, endothelial cells produce cytokines which may be involved in the pathophysiology of AIDS. Lastly, Project 6 will use an in vitro neuronal cell model to explore the interaction of HIV-1 genes on host cell gene expression and converse, host cell control over HIV-1 gene expression. The studies proposed in this Program Project application should answer many of the pressing questions related to nervous system disease in pediatric AIDS. Among these questions are the determination of a direct neurotropism of HIV-1; factors that are involved in the neuroinvasiveness of this virus; and, mechanisms of HIV neurovirulence. These studies may suggest new strategies to prevent or treat more effectively neurologic disease in pediatric AIDS.