PROTECTING CNS CELLS FROM HIV AND HIV-INDUCED INJURY

保护中枢神经系统细胞免受艾滋病毒和艾滋病毒引起的损伤

• 批准号: 6696436
• 负责人: DAVID S STRAYER
• 金额: $ 15.7万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6696436
• 关键词: AIDS dementia complex; HIV envelope protein gp120; apoptosis; brain cell; clinical research; cytoprotection; detoxification; free radical oxygen; gene therapy; human immunodeficiency virus; human subject; macrophage; microglia; neurons; patient oriented research; technology /technique development; tissue /cell culture; transfection; transfection /expression vector; virus cytopathogenic effect; virus genetics; virus replication

DESCRIPTION (provided by applicant): In this R21 grant application, we propose here to study gene delivery to inhibit HIV replication and HIV toxicity for CNS cells. HIV encephalopathy is a common and potentially devastating complication of AIDS. Development of HW encephalopathy largely reflects HIV infection of brain cells, especially monocyte-derived macrophages (MDM) and microglia. It also may involve toxicity of certain HIV proteins for neurons. We will use gene delivery techniques to study inhibition of H1V infection and replication in primary cultured human MDM and microglia, and to examine protection of neurons from the ability of HIV gp120 envelope glycoprotein to induce apoptosis. Recombinant gene delivery vehicles derived from Talphag-deleted SV40 (rSV40s) permanently transduce unselected key CNS targets for HW, including microglia, neurons, and monocyte-derived macrophages (MDM) with >98% efficiency in vitro. We have found that HIV replicates in MDM and microglia, and that rSV40s carrying HIV inhibitory transgenes protect these cells from HIV replication. We have found as well that gp120 causes apoptosis in cultured neurons, and that rSV40 vectors that downregulate cell membrane CXCR4 or that provide antioxidant enzymes, such as catalase, protect these neurons. We propose to exploit these promising findings to study rSV40 gene delivery to protect the CNS cells from HIV. This proposal is based on the following hypothesis: To test this hypothesis, we propose the following specific aims: 1.) Identify optimal transgenes individually and in combination to inhibit HIV-1 in CNS cells. 2.) use gene delivery to protect NT2-derived neurons from apoptosis induced by HIV gene products. Despite the frequency and dire consequences of CNS HIV infection, people afflicted with HIV encephalopathy have few treatment options. We propose to address this therapeutic challenge using rSV40 gene delivery to the CNS, both to protect the brain from HIV infection and to mitigate HIV-induced CNS dysfunction.

描述（由申请人提供）：在这项R21资助申请中，我们在这里提出研究基因递送以抑制HIV复制和HIV对CNS细胞的毒性。艾滋病脑病是艾滋病的一种常见和潜在的破坏性并发症。HW脑病的发展在很大程度上反映了脑细胞，特别是单核细胞衍生的巨噬细胞（MDM）和小胶质细胞的HIV感染。它还可能涉及某些HIV蛋白对神经元的毒性。我们将使用基因传递技术来研究抑制H1 V感染和复制的原代培养的人MDM和小胶质细胞，并检查保护神经元的能力，HIV gp 120包膜糖蛋白诱导细胞凋亡。来源于TSV 40缺失的重组基因递送载体（rSV 40）在体外以>98%的效率永久地抑制HW的关键CNS靶点，包括小胶质细胞、神经元和单核细胞衍生的巨噬细胞（MDM）。我们已经发现HIV在MDM和小胶质细胞中复制，并且携带HIV抑制转基因的rSV 40保护这些细胞免受HIV复制。我们还发现gp 120在培养的神经元中引起细胞凋亡，并且下调细胞膜CXCR 4或提供抗氧化酶（如过氧化氢酶）的rSV 40载体保护这些神经元。我们建议利用这些有希望的发现来研究rSV 40基因递送以保护CNS细胞免受HIV感染。这个建议是基于以下假设：为了验证这个假设，我们提出了以下具体目标：1。确定最佳的转基因单独和组合，以抑制中枢神经系统细胞中的HIV-1。2.）的情况。使用基因传递来保护NT 2衍生的神经元免受HIV基因产物诱导的细胞凋亡。尽管CNS HIV感染的频率和可怕的后果，患有HIV脑病的人几乎没有治疗选择。我们建议使用rSV 40基因递送到CNS来解决这一治疗挑战，既保护大脑免受HIV感染，又减轻HIV诱导的CNS功能障碍。