TRANSENDOTHELIAL MIGRATION OF ACTIVATED MONOCYTES IN HIV

HIV 中激活的单核细胞的跨内皮迁移

• 批准号: 2270877
• 负责人: HOLLY H BIRDSALL
• 金额: $ 17.34万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-15 至 1997-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2270877
• 关键词: B lymphocyte; HIV infections; T lymphocyte; astrocytes; cell adhesion; cell migration; cytomegalovirus; flow cytometry; human immunodeficiency virus 1; human tissue; immunocytochemistry; interleukin 1; laboratory rat; leukocyte activation /transformation; leukocyte adhesion molecules; monoclonal antibody; monocyte; nervous system infection; tissue /cell culture; vascular endothelium

Perivascular collections of macrophages and endogenous microglial cells appear to be major reservoirs of HIV- l within the central nervous system (CNS) and a source of viral and host cell products which have been implicated in the pathophysiology of dementia and other neurologic manifestations of HIV-l infection. Mechanisms responsible for the accumulation of these mononuclear leukocytes (MNL) in the CNS and, specifically, the contribution of peripheral blood leukocytes to these interstitial infiltrates have not been determined, nor is it clear whether the virus is carried to the CNS within infected PBL. Preliminary studies demonstrate that HIV- l infection stimulates cell surface expression of molecules on MNL which mediate adhesive interactions with endothelium and neural cells. Moreover we have found that peripheral blood monocytes from HIV- l infected subjects are frequently activated. They display increased quantities of these same adhesins and are more likely to adhere to cultured neural cells in vitro. The experiments proposed in this application will evaluate the ability of MNL from HIV-I infected subjects to migrate across endothelial cell monolayers. Using in vitro methods which allow us to harvest, enumerate and compare the phenotypes of leukocytes which have the capacity to adhere to, and migrate across endothelium, we propose to investigate whether HIV- l infected cells are particularly abundant in this population and evaluate whether infection with putatively "neurotropic" strains of HIV- l enhances their ability to migrate across endothelium. Factors which may modulate endothelial transmigration of MNL will also be investigated, including the effects of astrocytes growing in contiguity with endothelial monolayers, infection of endothelial cells with cytomegalovirus and stimulation with cytokines, such as IL- l, that are likely to be released by activated MNL or endothelial cells. Adhesive interactions between MNL, which have demonstrated their ability to migrate through endothelial barriers, and neural cells will be investigated in an attempt to identify the molecular basis for these interactions. Monoclonal antibodies (mAbs) specific for beta integrins, selectins and other molecules known to mediate heterotypic adhesive cellular interactions will be used in an attempt to block the binding of MNL to neural cells. We also plan to raise antibodies to ligands that resist the ability of presently available mAbs to block adhesive interactions in order to fully characterize the array of molecules used by HIV-l infected and/or activated MNL to attach to neural cells. Upon completion, we postulate that the proposed investigations will provide a better understanding of the mechanisms in HIV- l infected individuals which regulate trafficking of MNL across blood vessels and cause them to be retained within the CNS.

巨噬细胞和内源性小胶质细胞的血管周围集合 似乎是中枢神经系统内HIV-1的主要储存库 (CNS)以及病毒和宿主细胞产物的来源， 涉及痴呆和其他神经系统疾病的病理生理学 HIV-1感染的表现。负责执行《公约》 这些单核白细胞（MNL）在CNS中的积累， 特别是，外周血白细胞对这些的贡献 间质浸润尚未确定，也不清楚是否 病毒在感染的PBL内被携带到CNS。初步研究 证明HIV-1感染刺激细胞表面表达 MNL上介导与内皮细胞粘附相互作用的分子， 神经细胞此外，我们还发现， HIV-1感染的受试者经常被激活。他们表现出越来越多的 大量的这些相同的粘附素，更有可能粘附在 体外培养的神经细胞。在此提出的实验 应用程序将评估MNL从HIV-1感染受试者的能力 迁移穿过内皮细胞单层。使用体外方法 这使我们能够收获，枚举和比较表型， 白细胞具有粘附和迁移的能力， 内皮细胞，我们建议调查是否HIV-1感染的细胞是 在这个人群中特别多，并评估是否感染 HIV-1的"嗜神经性"菌株增强了他们的能力， 迁移穿过内皮。可能调节内皮细胞的因素 还将研究MNL的迁移，包括 星形胶质细胞与内皮细胞单层接触生长， 用巨细胞病毒和细胞因子刺激内皮细胞， 如IL-1，其可能由活化的MNL释放，或 内皮细胞MNL之间的粘附相互作用， 证明了它们通过内皮屏障迁移的能力， 神经细胞将被研究，试图确定分子 这些互动的基础。特异性单克隆抗体（mAb） β整联蛋白、选择蛋白和其它已知介导异型性的分子 粘附细胞相互作用将被用来试图阻止 MNL与神经细胞的结合。我们还计划提高抗体， 这些配体抵抗目前可用的mAb阻断 粘合剂相互作用，以便充分表征 HIV-1感染和/或激活的MNL所使用的分子，以附着到神经细胞上， 细胞完成后，我们假设拟议的调查将 更好地了解HIV-1感染的机制 管制MNL通过血管贩运的个人， 使它们滞留在中枢神经系统内。