ROLE OF INFLAMMATORY CELLS IN AIDS DEMENTIA

炎症细胞在艾滋病痴呆中的作用

• 批准号: 3388167
• 负责人: Dana Giulian
• 金额: $ 22.35万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-01 至 1995-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3388167
• 关键词: AIDS dementia complex; HIV envelope protein gp120; HIV infections; antiAIDS agent; biomarker; brain cell; chick embryo; drug screening /evaluation; embryo /fetus tissue /cell culture; ganglions; gas chromatography mass spectrometry; genetic strain; high performance liquid chromatography; human immunodeficiency virus 1; human tissue; in situ hybridization; ion exchange chromatography; laboratory rat; lymphocyte; macrophage; microglia; monocyte; neurons; neurotoxins; nuclear magnetic resonance spectroscopy; pathologic process; phagocytes; polymerase chain reaction; stereotaxic techniques; zidovudine

Nearly 60% of all adult patients and more than 75% of all pediatric patients with AIDS will suffer cognitive dysfunction ranging from memory loss and delirium to global dementia. The paradox is that despite profound cognitive impairment autopsy findings often show little change in neurons. For the most part, HIV-1 infects a specific class of brain cells, the CD4(+) mononuclear phagocytes which consist of reactive microglia and invading macrophages. Because neurons are rarely infected, the mechanisms to account for AIDS encephalopathy are unknown. Using an in vitro assay system, we have found that HIV-1-infected human mononuclear phagocytes, but not lymphocytes, release neurotoxins. Moreover, biochemical analyses suggest that these neurotoxins are a class of compounds unlike any known cytokine or cytotoxin secreted by microglia or macrophages. We will extend these important observations by identifying classes of HIV-1-infected cells that secrete neurotoxins and by determining the composition of secreted toxins. Neuron survival assays using chick embryo and fetal rat cells as target neurons will be used to monitor neuron killing activity produced by HIV-1-infected human test cells including various monocytoid or lymphoid cell lines as well as primary human monocytes and lymphocytes from AIDS and normal blood donors. Neurotoxins secreted by HIV-1 infected cell lines or peripheral blood mononuclear cells will be concentrated by ion exchange chromatography and isolated using conventional HPLC chromatographic techniques. Purified toxins will be infused into the brain of rat to assess in vivo effects. And finally, a series of experiments will examine mechanisms to activate cellular production of neurotoxins as well as to test the effectiveness of anti-viral drugs to inhibit production of neurotoxins. Uncovering specific cellular and molecular mechanisms of HIV-1-associated neurotoxicity may lead to new strategies for treatment of AIDS dementia.

所有成年患者中的近60％，所有儿科的75％以上 艾滋病患者将遭受记忆的认知功能障碍 全球痴呆症的损失和ir妄。 悖论是尽管 深刻的认知障碍尸检结果通常显示出很少的变化 在神经元中。 在大多数情况下，HIV-1感染一类特定的大脑 细胞，CD4（+）单核吞噬细胞，由反应性组成 小胶质细胞和入侵巨噬细胞。 因为神经元很少感染，所以 解释艾滋病脑病的机制尚不清楚。 使用一个 体外测定系统，我们发现HIV-1感染的人 单核吞噬细胞，而不是淋巴细胞，释放神经毒素。 此外，生化分析表明这些神经毒素是一类 与小胶质细胞分泌的任何已知细胞因子或细胞毒素不同的化合物 或巨噬细胞。 我们将通过 识别分泌神经毒素和的HIV-1感染细胞 通过确定分泌毒素的组成。 神经元的生存 使用雏鸡胚胎和胎儿大鼠细胞作为靶神经元的测定将是 用于监测由HIV-1感染的人产生的神经元杀死活动 测试细胞，包括各种单核苷或淋巴样细胞系以及 来自艾滋病和正常血液的原发性人单核细胞和淋巴细胞 捐助者。 由HIV-1感染的细胞系或周围分泌的神经毒素 血液单核细胞将通过离子交换浓缩 色谱法和使用常规HPLC色谱分离 技术。 纯化的毒素将被注入大鼠的大脑中 评估体内效应。 最后，一系列实验将 还检查激活神经毒素细胞产生的机制 为了测试抗病毒药物抑制产生的有效性 神经毒素。 发现特定的细胞和分子机制 HIV-1相关的神经毒性可能会导致新的治疗策略 艾滋病痴呆症。