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Targeting HIV infection of the cns using gene delivery

利用基因传递靶向中枢神经系统的 HIV 感染

基本信息

批准号：
7213345
负责人：
DAVID S STRAYER
金额：
$ 37.22万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7213345
关键词：
Acquired Immunodeficiency Syndrome Address Anti-Retroviral Agents Antioxidants Apoptosis Biological Models Brain Brain Injuries CCR5 gene Cells Clinical Complication Cuprozinc Superoxide Dismutase Effectiveness Enzymes Free Radicals Frequencies Functional disorder Gene Delivery Glutathione HIV HIV Encephalopathy HIV Entry Inhibitors HIV Envelope Protein gp120 HIV Infections HIV-1 Human In Vitro Injection of therapeutic agent Laboratories Measures Mediating Microglia Mutation Neuraxis Neurons Oxidants Peripheral Pharmaceutical Preparations Phase Proteins Rattus Reporting Route Severities Simian virus 40 Site Stress Structure Techniques Testing Therapeutic Time Toxic effect Transgenes catalase cell type compare effectiveness gene delivery system gene therapy in vivo in vivo Model macrophage monocyte neuron apoptosis neuron loss neurotoxicity relating to nervous system retrograde transport tool vector viral gene delivery

项目摘要

DESCRIPTION (provided by applicant): This study is proposed as a proof of principle: that gene delivery to the central nervous system can mitigate the harmful effects of HIV and HIV gene products on the brain. HIV encephalopathy is a potentially devastating complication of AIDS. There is no current therapy for CNS HIV infection: conventional antiretroviral drugs penetrate the brain poorly and anti-HIV CNS gene therapy has not been reported. Transgenes are currently available that are highly potent inhibitors of HIV entry and replication. Further, HIV envelope glycoprotein, gp120, has been implicated in neuron cell death via oxidant-related mechanisms in HIV encephalopathy. We have confirmed that gp120 causes apoptosis in human neurons, and that providing these cells with antioxidant enzymes, such as catalase protects them from apoptosis induced by HIV proteins. We submit that tools are now available to test gene delivery for the first time to address this problem, and propose to use gene delivery techniques to test the following hypothesis - Anti-oxidant and anti-HIV transgenes can protect cns cells from HIV and neural apoptosis caused by HIV gene products. To test this hypothesis, we will use as tools gene delivery vehicles derived from Tag-deleted SV40 (rSV40s). These vectors efficiently transduce key CNS cell targets for HIV and neurotoxicity induced by HIV, i.e., microglia, neurons, and monocyte-derived macrophages (MDM). We propose 4 aims: 1. Identify longitudinally optimal transgenes individually and in combination to inhibit HIV in CNS cells 2. Assess CNS and peripheral routes of administration to deliver rSV40s to the brain most effectively 3. Measure the ability of anti-CCR5 genes delivered in vivo to reduce MDM and microglial CCR5 gene delivery in vitro and in vivo to apoptosis-induced products. Despite the frequency and severity of CNS HIV infection, people with HIV encephalopathy have few treatment options. We propose to address this therapeutic challenge using gene delivery to the CNS, both to protect the brain from HIV infection and to mitigate HIV-induced CNS dysfunction.

描述(申请人提供)：这项研究是作为一项原则的证明：向中枢神经系统输送基因可以减轻艾滋病毒和艾滋病毒基因产品对大脑的有害影响。艾滋病毒脑病是艾滋病的一种潜在的破坏性并发症。目前还没有针对CNS HIV感染的治疗方法：传统的抗逆转录病毒药物对大脑的渗透性很差，抗HIV CNS基因疗法尚未见报道。目前可以获得的转基因是艾滋病毒进入和复制的高度有效的抑制因素。此外，HIV包膜糖蛋白gp120通过与氧化剂相关的机制参与了HIV脑病的神经细胞死亡。我们已经证实gp120导致人类神经元凋亡，为这些细胞提供抗氧化酶，如过氧化氢酶，可以保护它们免受HIV蛋白诱导的凋亡。为了解决这一问题，我们首次提出了测试基因传递的工具，并建议使用基因传递技术来验证以下假设-抗氧化剂和抗HIV转基因可以保护CNS细胞免受HIV和HIV基因产物引起的神经凋亡的影响。为了验证这一假设，我们将使用来自标签删除的SV40(RSV40)的基因递送载体作为工具。这些载体有效地转导针对HIV和HIV诱导的神经毒性的关键CNS细胞靶点，即小胶质细胞、神经元和单核细胞来源的巨噬细胞(MDM)。我们提出了四个目标：1.确定单独和联合使用纵向最优的转基因来抑制CNS细胞中的HIV 2.评估CNS和外周给药途径以最有效地将rSV40传递到脑内3.测量体内传递的抗CCR5基因减少MDM和体内小胶质细胞CCR5基因传递到凋亡诱导产物的能力。尽管中枢神经系统艾滋病毒感染的频率和严重性很高，但艾滋病毒脑病患者的治疗选择很少。我们建议通过向中枢神经系统传递基因来解决这一治疗挑战，既保护大脑免受艾滋病毒感染，又减轻艾滋病毒诱导的中枢神经系统功能障碍。