COCAINE EFFECTS ON HIV ENCEPHALITIS IN SCID MICE

描述：申请者摘要 HIV相关痴呆症(HADC)是艾滋病的一种常见疾病，是 50岁以下成年人患痴呆症的最常见原因。虽然 吸毒是艾滋病毒感染传播的公认因素，它是 不清楚经常滥用的药物可能会对疾病的进展产生什么影响 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/或进程，但 缺乏直接证据。除了对大脑功能的影响 和病理学(可能加强HADC的影响)，可卡因有 深刻的全身性免疫调节后果可能会使 逆转录病毒感染的免疫效应。最近的证据表明可卡因 在小鼠模型中影响逆转录病毒感染并增加 外周血单核细胞培养产生艾滋病毒支持 这种可能性。这项拟议的研究利用了艾滋病毒的一个模型 可卡因对SCID小鼠脑炎模型的影响 与艾滋病毒感染相关的神经病理和行为异常。 人外周血脑内接种SCID小鼠 单个核细胞和艾滋病毒，会发展成与人类艾滋病毒携带者相似的组织病理学 脑炎。重要的是，关于拟议的研究，SCID小鼠 患有艾滋病毒的脑炎也表现出行为异常。我们假设 长期接触可卡因会增加病理性和 与艾滋病毒感染相关的行为异常。这一假设 将进行有特定目的的测试，以确定是否接触可卡因：(1) 改变携带艾滋病毒的小鼠大脑中的艾滋病毒含量 脑炎；(2)导致与以下疾病相关的病理严重程度 以(A)星形胶质细胞增多症和(B)神经元性脑炎为指标的艾滋病毒脑炎 细胞凋亡；(3)在HIV脑炎过程中调节细胞因子的活性；(4) 增强与艾滋病毒相关的运动减慢和认知功能障碍 脑炎，以运动活动测试的表现和 空间学习任务(Morris迷宫)。拟议中的实验将 有助于了解滥用药物可能在多大程度上改变 并提供可能的机制，以进行这类改变。

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.