NEURAL CELL TROPISM OF HIV-1 ISOLATES

本提案要检验的假设是，不同的人类 免疫缺陷病毒 1 (HIV-1) 分离株的神经系统 (CNS) 各不相同 器官型组织培养模型。 此外，由于这些变化 体内的神经病理变化范围可能反映出来 与获得性免疫缺陷综合症（艾滋病）有关，实验将 旨在探索体外和体内之间的相关性 病理变化。 神经功能障碍是一种常见的症状，有时是首发症状 以及艾滋病的诊断、发现。 在成人艾滋病中，两者之间的关系 HIV-1 和神经病理学仍不清楚，但在儿科艾滋病中 这种提出的病毒与病理学之间的直接关系较少 有争议的。 支持因果关系的证据 HIV-1 与儿童艾滋病神经病理学之间的关系 来自先天性 HIV-1 感染儿童的临床观察 以及调查儿童和人类胎儿大脑的病理学研究 结合使用免疫细胞化学和核酸技术 光学和电子显微镜。 因为这些神经环境更 艾滋病患者的大脑比成人的原始状态有更直接的关系 HIV-1 与神经系统病理学之间的关联出现了。 在 观察到儿童大脑和脊髓的一系列变化 范围从亚急性脑炎到中枢神经系统血管病变到轴突和 髓鞘病。 研究中、我们的研究中也出现了类似的多样化景象。 实验室，研究胎儿大脑中 HIV-1 相关的神经病理学。 因为 最近，有观点认为 HIV-1 可能表现出不同的细胞 向性，最常见的是淋巴细胞营养性 (L) 和 单核细胞营养 (M) 分离株；这项研究的目的是探索 这个问题使用了最近开发的人类组织培养模型 胎儿中枢神经系统组织维持在器官型培养物中。 该培养物中的细胞 系统发育并分化成神经元，形成突触、星形胶质细胞、 表达细胞类型的少突胶质细胞、小胶质细胞和血管内皮细胞 具体标记。 初步研究表明 IIIb 和 RF2 实验室分离的 HIV-1 可以诱导良好的形态学变化 分化的培养物与体内观察到的变化相似。 因此， 该提案将进一步探索和定义 HIV-1 的能力 直接或间接引起中枢神经系统病变。 这些见解可能 允许设计改进的预防或治疗方案 对抗艾滋病毒感染。

The hypothesis to be tested in this proposal is that different human immunodeficiency virus-1 (HIV-1) isolates vary in their neural system (CNS) organotypic tissue culture model. Additionally, because these variations may be reflected in vivo by the spectrum of neuropathologic changes associated with acquired immunodeficiency syndrome (AIDS), experiments will be conducted to explore the correlation between in vitro and in vivo pathologic changes. Neurologic dysfunction is a common, sometimes initial and diagnostic, finding in AIDS. In adult AIDS, the relationship between HIV-1 nd neuropathology remains unclear but, however, in pediatric AIDS this proposed direct relationship between virus and pathology is less controversial. The evidence to support a causal relationship between HIV-1 and the neuropathology of pediatric AIDS stems from clinical observations of children born with congenital HIV-1 infection and pathologic studies which surveyed pediatric and human fetal brains using immunocytochemical and nucleic acid techniques in combination with light and electron microscopy. Because these neural environments are more pristine than adult brains of AIDS patients, a more directly related association between HIV-1 and nervous system pathology emerged. In pediatric brain and spinal cord an array of changes were observed which ranges from subacute encephalitic to CNS vasculopathy to axon and myelinopathy. A similarly diverse picture is emerging in studies, in our laboratories, on HIV-1 related neuropathology in fetal brain. Because recently, opinion has developed that HIV-1 may exhibit different cellular tropisms, the most common of which are the lymphocytotrophicc (L) and monocytotrophic (M) isolates; this study was conceived so as to explore this question using a recently developed tissue culture model of human fetal CNS tissue maintained in organotypic culture. Cells in this culture system develop and differentiate into neurons forming synapses, astrocytes, oligodendtocytes, microglia and vascular endothelia which express cell-type specific markers. Preliminary studies have shown that the IIIb and RF2 laboratory isolates of HIV-1 can induce morphologic changes in well- differentiated cultures similar to changes observed in vivo. Therefore, this proposal will further explore and define the ability of HIV-1 to either directly or indirectly cause CNS pathology. Such insights may permit the design of improved preventative or therapeutic protocols for combatting HIV infection.