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）：CNS是一种重要的 艾滋病毒的水库，但我们不知道为什么病毒积累在大脑中，也 它是如何离开外围重新播种的。我们发现， 外周血细胞迁移穿过内皮屏障，携带 具有复制能力的病毒，具有更差的预后，其定义为增加 病毒载量，更多的艾滋病相关疾病住院治疗和死亡。的 它的特点不仅仅是存在循环 但事实上，这些患者的白细胞 并携带感染性病毒穿过血管屏障。这些 HIV感染的淋巴细胞建立感染细胞的内皮下病灶。 迁移到这些病灶中的未感染白细胞反向迁移回来 融合的内皮单层携带感染性病毒。我们 假设感染的MNL进出内皮下的运输 白细胞库增加病毒负荷，有助于加速 疾病为了检验这一假设，我们提出以下建议： 我们将确定细胞相互作用和分子信号， 携带有复制能力的病毒的细胞通过 体外脑血管与外周血管屏障。我们推测 大脑中的细胞微环境促进了 并解释了为什么大脑可以成为一个水库， 艾滋病毒- I到其他网站。我们将确定星形胶质细胞和/或小胶质细胞 加速受感染白细胞的跨内皮迁移， 在内皮屏障下蓄积。我们还将研究 这些细胞在引起受感染的T细胞和单核细胞衍生的树突状细胞中发挥作用， 细胞从这些内皮下病灶迁移回血管腔。 在具体的目标#2中，我们将确定炎症刺激对炎症的影响。 复制病毒的细胞逆向迁移。我们推测 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增强内皮下 含有感染细胞的浸润物和反向迁移的产生 携带有复制能力的病毒的细胞。在具体目标#3中，我们将测试 艾滋病病毒感染在患者中加速特别快的假设 其白细胞形成感染细胞的内皮下浸润， 产生大量反向迁移的白细胞， 病毒扩散到远端组织部位。