Development of Neuronal gene therapy for HIV-dementia

描述(由申请人提供)：HIV-1相关性痴呆症是病毒感染的重要并发症，也是导致严重发病率和死亡率的原因。HIV-1引起的神经系统疾病的基本特征围绕两个过程：a)病毒在大脑中的巨噬细胞中高效复制，导致脑炎；b)受感染的巨噬细胞分泌的副产物产生的作用导致神经元退化，导致痴呆。我们早期对微阵列分析的研究表明，希氏脑炎猕猴大脑中的趋化因子CXCL10显著上调。此外，我们还发现，病毒糖蛋白(Gp120)与神经元的结合导致CXCL10的诱导以及随后这些细胞(87)的凋亡。我们推测，HIV/SIY感染者中枢神经系统中CXCL10水平的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而导致艾滋病痴呆患者的神经元功能障碍。这项建议旨在探索一种创新和新型的基因治疗方法，包括将反义CXCL10 DNA靶向大脑中的神经元，以期消除神经元的凋亡。我们将使用基于猫免疫缺陷病毒(FFV)的慢病毒载体(2)的独特方法来转导小鼠大脑中邻近白质束的神经元。这项应用的长期目标(不是这项提议的一部分)是为感染SHTV的猕猴的HAD开发治疗干预策略。在这一应用中，我们将在两个特定的目标上检验这一假说：1)检测CXCL10过表达对小鼠脑内神经元功能障碍的影响；2)通过引入反义CXCL10 DNA来消除小鼠脑内神经元的凋亡。

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.