COCAINE EFFECTS ON HIV ENCEPHALITIS IN SCID MICE

描述：申请人摘要 艾滋病相关痴呆综合征（HADC）是艾滋病患者的常见疾病， 是50岁以下成年人患痴呆症的最常见原因。 虽然 药物滥用是艾滋病毒感染传播的一个公认因素， 不清楚通常滥用的药物可能对疾病进展有什么影响， 艾滋病毒感染，特别是HADC。 临床研究表明， 可卡因滥用可能会影响HADC的发展和/或过程，但 缺乏直接证据。 除了对大脑功能的影响 和病理学（可能增强HADC中观察到的效应），可卡因具有 深刻的系统性免疫调节后果，这可能会加剧 逆转录病毒感染的免疫效应。 最近的证据表明可卡因 影响小鼠模型中的逆转录病毒感染， 外周血单个核细胞培养物中HIV的产生支持 这种可能性。 这项研究利用了一种艾滋病毒模型， 脑炎的SCID小鼠研究可卡因对 与HIV感染相关的神经病理学和行为异常。 SCID小鼠，脑内接种人外周血 单核细胞和艾滋病毒，发展类似的组织病理学与人类艾滋病毒 脑炎 重要的是，关于拟议的研究，SCID小鼠 HIV脑炎患者也表现出行为异常。 我们假设 长期接触可卡因会增加病理性和 与HIV感染有关的行为异常。 这一假设 将进行测试，具体目的是确定可卡因暴露是否：（1） 改变了艾滋病病毒感染小鼠大脑中的艾滋病病毒数量 （2）导致与脑炎相关的病理学严重程度 以（a）星形胶质细胞增生和（B）神经元数量为指标的HIV脑炎 细胞凋亡;（3）调节HIV脑炎期间的细胞因子活性;（4） 增强与HIV相关的运动减慢和认知功能障碍 根据运动活动测试和a 空间学习任务（Morris迷宫）。 拟议的实验将 有助于了解滥用药物可能在多大程度上改变 HADC的过程，并提供这种变化的可能机制。

DESCRIPTION: Applicant's Abstract HIV-associated dementia complex (HADC), a common illness in AIDS, is one of the most common causes of dementia in adults under the age of 50. Although drug abuse is a recognized factor in the spread of HIV infection, it is unclear what effect commonly abused drugs might have on the progression of HIV infection and, in particular, HADC. Clinical studies suggest that cocaine abuse might influence the development and/or course of HADC, but direct evidence is lacking. In addition to its effects on brain function and pathology (effects which may potentiate those seen in HADC), cocaine has profound systemic immunomodulatory consequences which may compound the immune effects of retroviral infection. Recent evidence that cocaine influences retroviral infection in a murine model and increases the production of HIV in peripheral blood mononuclear cell cultures supports this possibility. The proposed research utilizes a model of HIV encephalitis in SCID mice to investigate the effects of cocaine on the neuropathology and behavioral abnormalities associated with HIV infection. SCID mice, inoculated intracerebrally with human peripheral blood mononuclear cells and HIV, develop similar histopathology to humans with HIV encephalitis. Importantly, with respect to the proposed studies, SCID mice with HIV encephalitis also exhibit behavioral abnormalities. We hypothesize that chronic cocaine exposure will increase the severity of pathological and behavioral abnormalities associated with HIV infection. This hypothesis will be tested with specific aims to determine if cocaine exposure: (1) alters the amount of HIV present in the brains of mice with HIV encephalitis; (2) contributes to the severity of pathology associated with HIV encephalitis as indexed by amounts of (a) astrogliosis and (b) neuronal apoptosis; (3) modulates cytokine activity during HIV encephalitis; (4) enhances the motor slowing and cognitive dysfunction associated with HIV encephalitis as indexed by performance on motor activity tests and on a spatial learning task (Morris Maze). The proposed experiments will contribute toward understanding to what extent abused drugs might alter the course of HADC as well as provide possible mechanisms for such alterations.