Development of Neuronal gene therapy for HIV-dementia

描述（由申请人提供）：HIV-1相关痴呆是病毒感染的一种重要并发症，也是显著发病率和死亡率的原因。HIV-1诱导的神经系统疾病的潜在特征围绕两个过程：a）病毒在脑中巨噬细胞中的生产性复制，导致脑炎，和B）由受感染的巨噬细胞释放的分泌副产物的作用引起的神经元变性，导致痴呆。我们早期对微阵列分析的研究表明，在患有SHIV脑炎的猕猴的大脑中，趋化因子CXCL 10在神经元中显著上调。此外，我们还发现病毒糖蛋白（gp 120）与神经元的结合导致CXCL 10的诱导和随后这些细胞的凋亡（87）。我们推测，在HIV/SIY感染的受试者中枢神经系统中CXCL 10水平升高，可能通过与神经元上表达的趋化因子受体直接相互作用，导致在艾滋病痴呆中观察到的神经元功能障碍。该建议旨在探索一种创新的和新型的基因治疗，涉及递送靶向脑中神经元的反义CXCL 10 DNA，以期消除神经元凋亡。我们将使用基于猫免疫缺陷病毒（FFV）的慢病毒载体（2）的独特方法来刺激小鼠大脑中邻近白色物质束的神经元。本申请的长期目标（不是本提案的一部分）是开发SHTV感染猕猴HAD的治疗干预策略。在本申请中，我们将在两个特定目的中检验该假设：1）检测CXCL 10过表达对小鼠脑中神经元功能障碍的影响，和2）通过在小鼠脑中引入反义CXCL 10 DNA来消除神经元凋亡。

DESCRIPTION (provided by applicant): HIV-1 associated dementia is an important complication of viral infection and a cause of significant morbidity and mortality. The underlying feature of HIV-1 induced neurological disease revolves around two processes: a) productive replication of the virus in macrophages in the brain, leading to encephalitis, and b) neuronal degeneration resulting from the action of secreted byproducts released from infected macrophages, leading to dementia. Our earlier studies on microarray analysis demonstrated a significant up-regulation of the chemokine, CXCL10 in the neurons in the brains of macaques with SHIV-encephalitis. Furthermore, we also showed that binding of viral glycoprotein (gp120) to the neurons led to the induction of CXCL10 and subsequent apoptosis of these cells (87). We hypothesize that elevated levels of CXCL10 in the CNS of HIV/SIY-infected subjects could contribute to the neuronal dysfunction observed in AIDS dementia through direct interactions with chemokine receptors expressed on neurons. This proposal is aimed at exploring an innovative and novel type of gene therapy involving delivery of antisense CXCL10 DNA targeted to neurons in the brain with a view to abrogating neuronal apoptosis. We will use the unique approach of feline immunodeficiency virus (FFV) based lentivirus vectors (2) to transduce the neurons adjacent to the white matter tract in the mouse brain. The long-term goal of this application (not a part of this proposal) is to develop therapeutic intervention strategy for HAD in SHTV-infected macaques. In this application we will test the hypothesis in two specific aims: 1) To examine the effect of CXCL10 over-expression on neuronal dysfunction in the brains of mice and, 2) To abrogate neuronal apoptosis by introduction of antisense CXCL10 DNA in mouse brain.