EXTRAVASCULAR TRAFFICKING OF HIV+ CELLS AND PROGNOSIS

HIV 细胞的血管外转运和预后

• 批准号: 6528926
• 负责人: HOLLY H BIRDSALL
• 金额: $ 26.16万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6528926
• 关键词: HIV infections; cell migration; clinical research; human subject; inflammation; leukocytes; nervous system infection; prognosis; vascular endothelium permeability; virus infection mechanism; virus load

DESCRIPTION (Adapted from Applicant's Abstract): The CNS is an important reservoir for HIV, but we do not know why virus accumulates in the brain, nor how it leaves to re-seed the periphery. We have found that patients whose peripheral blood cells migrate across endothelial barriers carrying replication-competent virus, have a worse prognosis as defined by increased viral loads, more hospitalizations for AIDS-related illnesses, and death. The distinguishing feature is not just the presence of circulating provirus-positive cells, but the fact that these patients' leukocytes migrate spontaneously and carry infectious virus across vascular barriers. These HIV-infected lymphocytes establish subendothelial foci of infected cells. Uninfected leukocytes migrating into these foci reverse-migrate back across confluent endothelial monolayers carrying infectious virus with them. We postulate that trafficking of infected MNLs in and out of subendothelial leukocyte depots increases viral burden and helps to accelerate progression of disease. To test this hypothesis we propose the following: In specific Aim #1 we will identify the cellular interactions and molecular signals that regulate the reverse-migration of cells carrying replication-competent virus through cerebrovascular vs. peripheral vascular barriers in vitro. We postulate that the cellular microenvironment within the brain facilitates the development of these foci and explains why the brain can become a reservoir that disseminates HIV- I to other sites. We will determine whether astrocytes and/or microglia accelerate transendothelial migration of infected leukocytes and their accumulation below endothelial barriers. We will also investigate the role these cells play in causing infected T cells and monocyte-derived dendritic cells to migrate back out of these subendothelial foci into the vascular lumen. In specific Aim #2 we will identify the effects of inflammatory stimuli on the reverse-migration of cells carving replication-competent virus. We postulate that encounters with soluble or cell associated immune complexes, cell binding fibronectin fragments, and/or TNF-OL enhance formation of subendothelial infiltrates containing infected cells and the generation of reverse-migratory cells that carry replication-competent virus. In specific Aim #3 we will test the hypothesis that HIV infections accelerate particularly rapidly in patients whose leukocytes form subendothelial infiltrates of infected cells that generate large numbers of reverse-migratory leukocytes that can disseminate virus to distal tissue sites.

描述（改编自申请人的摘要）：中枢神经系统是重要的 艾滋病毒的水库，但我们不知道为什么病毒在大脑中积累，也不知道 它如何离开外围。我们发现患者的患者 外周血细胞跨携带的内皮屏障迁移 具有复制能力的病毒，预后较差。 病毒负荷，与艾滋病相关疾病的更多住院以及死亡。这 区分功能不仅是循环的存在 病毒阳性细胞，但是这些患者的白细胞迁移的事实 自发地携带感染性病毒在血管屏障中。这些 HIV感染的淋巴细胞建立了感染细胞的下皮灶。 未感染的白细胞迁移到这些焦点向后移民返回 融合的内皮单层携带感染性病毒。我们 假设贩运受感染的MNL进入和外皮的贩运 白细胞仓库增加了病毒负担，有助于加速进展 疾病。为了检验这一假设，我们提出以下建议：在特定目的＃1中 我们将确定调节的细胞相互作用和分子信号 通过 体外脑血管与周围血管屏障。我们假设 大脑内的细胞微环境有助于发展 这些焦点并解释了为什么大脑可以成为传播的储层 HIV-我到其他网站。我们将确定星形胶质细胞和/或小胶质细胞是否 加速感染白细胞的跨内皮迁移及其 在内皮壁垒以下积累。我们还将调查角色 这些细胞在引起感染的T细胞和单核细胞衍生的树突状态下起作用 细胞从这些下皮灶中迁移到血管腔中。 在特定的目标＃2中，我们将确定炎症刺激对 雕刻复制能力病毒的细胞的反向迁移。我们假设 遇到可溶性或细胞相关的免疫复合物，细胞结合 纤连蛋白片段和/或TNF-OL增强了下皮的形成 浸润含有感染细胞的浸润和反向迁移的产生 携带具有复制能力的病毒的细胞。在特定的目标＃3中，我们将测试 假说HIV感染在患者中特别迅速加速 其白细胞形成感染细胞的下皮下皮浸润 产生大量可以传播的反迁移白细胞 病毒到远端组织部位。