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）：在此R21赠款应用中，我们在这里建议研究基因递送以抑制CNS细胞的HIV复制和HIV毒性。 HIV脑病是艾滋病的常见且潜在的毁灭性并发症。 HW脑病的发展在很大程度上反映了脑细胞的HIV感染，尤其是单核细胞衍生的巨噬细胞（MDM）和小胶质细胞。它也可能涉及某些HIV蛋白对神经元的毒性。我们将使用基因递送技术研究对原发性培养的人MDM和小胶质细胞中H1V感染和复制的抑制，并检查神经元免受HIV GP120 Invelope糖蛋白诱导凋亡的能力的保护。源自TALPHAG缺失的SV40（RSV40S）的重组基因递送车永久转导未选择的HW的关键CNS靶标，包括小胶质细胞，神经元和单核细胞衍生的巨噬细胞（MDM），其体外效率> 98％。我们发现HIV在MDM和小胶质细胞中复制，并且带有HIV抑制性转基因的RSV40可保护这些细胞免受HIV复制。我们还发现，GP120在培养的神经元中引起凋亡，并且RSV40载体下调细胞膜CXCR4或提供抗氧化剂（例如过氧化氢酶）保护这些神经元。我们建议利用这些有希望的发现来研究RSV40基因递送，以保护中枢神经系统细胞免受HIV的影响。该建议基于以下假设：为了检验该假设，我们提出以下特定目的：1。）单独识别最佳转基因，并结合使用以抑制CNS细胞中的HIV-1。 2.）使用基因递送保护NT2衍生的神经元免受HIV基因产物诱导的凋亡。尽管CNS HIV感染的频率和可怕后果，但患有HIV脑病的人几乎没有治疗选择。我们建议使用RSV40基因向中枢神经系统递送来应对这一治疗挑战，以保护大脑免受HIV感染的侵害，并减轻HIV诱导的CNS功能障碍。