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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

基本信息

批准号：
6800556
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
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-15 至 2006-08-31
项目状态：
已结题

项目摘要

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 拨款申请中，我们建议研究基因传递以抑制 HIV 复制和 HIV 对 CNS 细胞的毒性。 HIV 脑病是艾滋病的一种常见且具有潜在破坏性的并发症。 HW脑病的发生很大程度上反映了脑细胞的HIV感染，尤其是单核细胞源性巨噬细胞（MDM）和小胶质细胞。它还可能涉及某些 HIV 蛋白对神经元的毒性。我们将使用基因递送技术来研究对原代培养的人 MDM 和小胶质细胞中 H1V 感染和复制的抑制，并检查对神经元的保护，使其免受 HIV gp120 包膜糖蛋白诱导细胞凋亡的能力的影响。源自 Talphag 删除的 SV40 (rSV40s) 的重组基因递送载体可永久转导 HW 的未选择的关键 CNS 靶标，包括小胶质细胞、神经元和单核细胞源性巨噬细胞 (MDM)，体外效率 > 98%。我们发现 HIV 在 MDM 和小胶质细胞中复制，并且携带 HIV 抑制性转基因的 rSV40 可以保护这些细胞免受 HIV 复制。我们还发现 gp120 会导致培养的神经元凋亡，而下调细胞膜 CXCR4 或提供抗氧化酶（例如过氧化氢酶）的 rSV40 载体可以保护这些神经元。我们建议利用这些有希望的发现来研究 rSV40 基因传递，以保护 CNS 细胞免受 HIV 感染。该提议基于以下假设：为了检验该假设，我们提出以下具体目标： 1.) 单独和组合识别最佳转基因以抑制 CNS 细胞中的 HIV-1。 2.) 使用基因递送来保护 NT2 衍生神经元免受 HIV 基因产物诱导的细胞凋亡。尽管中枢神经系统艾滋病毒感染频繁且后果严重，但患有艾滋病毒脑病的人几乎没有治疗选择。我们建议使用 rSV40 基因递送至中枢神经系统来解决这一治疗挑战，既可以保护大脑免受艾滋病毒感染，又可以减轻艾滋病毒引起的中枢神经系统功能障碍。