Targeting HIV infection of the cns using gene delivery

描述（由申请人提供）：本研究提出的原理证明：基因传递到中枢神经系统可以减轻HIV和HIV基因产物对大脑的有害影响。艾滋病毒脑病是艾滋病的潜在毁灭性并发症。目前还没有针对中枢神经系统HIV感染的治疗方法：传统的抗逆转录病毒药物很难穿透大脑，抗HIV中枢神经系统基因治疗尚未报道。目前已有的转基因是HIV进入和复制的高效抑制剂。此外，HIV包膜糖蛋白gp120在HIV脑病中通过氧化相关机制参与神经元细胞死亡。我们已经证实gp120可以引起人类神经元的凋亡，并且为这些细胞提供过氧化氢酶等抗氧化酶可以保护它们免受HIV蛋白诱导的凋亡。我们提出，现在首次有工具可以测试基因传递来解决这一问题，并建议使用基因传递技术来验证以下假设-抗氧化和抗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细胞凋亡。为了验证这一假设，我们将使用来自标记缺失SV40 （rSV40s）的基因传递载体作为工具。这些载体有效地转导HIV和HIV诱导的神经毒性的关键中枢神经系统细胞靶点，即小胶质细胞、神经元和单核细胞源性巨噬细胞（MDM）。我们提出了四个目标：在CNS细胞中单独和联合鉴定纵向最佳的抑制HIV的转基因2。评估中枢神经系统和外周给药途径，以最有效地将rSV40s输送到大脑3。测量体内递送抗CCR5基因减少MDM的能力，以及体外和体内递送小胶质细胞CCR5基因到凋亡诱导产物的能力。尽管中枢神经系统HIV感染的频率和严重程度，但患有HIV脑病的人几乎没有治疗选择。我们建议利用基因传递到中枢神经系统来解决这一治疗挑战，既可以保护大脑免受HIV感染，又可以减轻HIV诱导的中枢神经系统功能障碍。

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.