Project 3

感染人类免疫缺陷病毒（HIV-1）的个体经常表现出严重的进行性行为、认知和运动缺陷（称为神经艾滋病），并伴有脑内病理改变（包括神经胶质瘤、脑炎和空泡性脊髓病）。目前的证据强烈表明，这种疾病（也称为神经艾滋病）的发病机制涉及由以下途径介导的神经毒性途径：(1)HIV-1相关产物，如包膜蛋白gp120；(2)宿主反应产物，如活化的巨噬细胞/小胶质细胞和星形胶质细胞释放的细胞因子，如IL-6、IFN-和TNF。甲基苯丙胺（冰毒）的滥用往往造成严重的急性和长期的神经损伤，这在HIV-1感染者中很普遍。我们在此假设，这些病毒、宿主和甲基苯丙胺的结合会产生附加甚至协同作用，从而导致神经病理后遗症的恶化和神经艾滋病功能性神经精神缺陷的加速进展。确定中枢兴奋剂药物甲基苯丙胺与宿主源性和HIV-1相关产物相互作用影响中枢神经系统（CNS）结构和功能性损伤的程度和进展的性质和机制。在艾滋病患者中观察到由HIV-1感染以及其他感染因子感染引起的外周免疫功能失调。因此，我们将定义甲基安非他明和外周免疫刺激（通过腹腔注射强效免疫刺激物脂多糖实现）之间的相互作用，以影响中枢神经系统宿主反应和神经病理学的严重程度和进展。在大脑中表达il - 6、TNF-、TNF-或gp120的转基因小鼠概括了神经艾滋病的许多结构和功能特征，并将在拟议的研究中用于阐明甲基苯丙胺与宿主或HIV-1相关产物的中枢生产之间的相互作用，从而促进中枢神经系统宿主反应和神经病理学的发展和进展。最后，铜/锌超氧化物歧化酶（SOD）过表达或组织型纤溶酶原激活物（tPA）表达不足的转基因小鼠可能是甲基苯丙胺与宿主反应产物或HIV-1之间致病性相互作用的基础。该研究计划整合了药物对中枢神经系统的影响分析，因为它与HIV疾病进展的组成部分有关，这是临床前和临床研究的一个重要问题，因为药物滥用者暴露于病毒的风险很高。拟议的研究应该在确定关键的病毒和宿主源性因素方面走得更远，这些因素与滥用药物（如甲基安非他明）的病理作用的易感性增加以及随之而来的神经毒性有关。

Individual's infected with the human immunodeficiency virus (HIV-1) frequently exhibit serious, progressive behavioral, cognitive and motor deficits (termed NeuroAIDS) in association with pathological changes (including gliosis, encephalitis and vacuolar myelopathy) in the brain. Current evidence strongly indicate the pathogenesis of this disorder (also known as NeuroAIDS) involves neurotoxic pathways mediated by: (1) HIV-1 related products e.g. the envelope protein gp120 and (2) products of the host response exemplified by cytokines such as IL-6, IFN- and TNF, release from activated macrophage/microglia and astroglia. Methamphetamine (METH) abuse which is frequently accomplished by significant acute and long-term neuronal damage is prevalent amongst HIV-1 infected individuals. We hypothesize here that the combination of these viral, host and METH insults produce additive or even synergistic actions that result in the worsening of the neuropathological sequelae and an accelerated progression to the functional neuropsychiatric deficits of NeuroAIDS. To determine the nature and mechanisms by which the central stimulant drug METH interacts with host-derived and HIV-1 related products to influence the degree and progression of structural and functional central nervous system (CNS) injury. Dysregulated peripheral immune function resulting from HIV-1 infection as well as infection from additional infectious agents is observed in individuals with AIDS. Therefore, we will define the interactions between METH and peripheral immune stimulation (achieved by intraperitoneal injection of the potent immune stimulant lipopolysaccharide) to influence the severity and progression of both CNS host responses and neuropathology. Transgenic mice with cerebral expression of IL6, TNF-, TNF- or gp120 recapitulate many of the structural and functional features of NeuroAIDS and will be used in the proposed studies to elucidate the interactions between METH and the central production of host- or HIV-1- related products to the development and progression of CNS host responses and neuropathology. Finally, transgenic mice with over-expression of Cu/Zn superoxide dismutase (SOD) or deficient expression of tissue-type plasminogen activator (tPA) that may underlie the pathogenic interactions between METH and products of the host response or HIV-1. This research plan integrates analysis of drug effects on the CNS as it relates to components of HIV disease progression is an important question for pre clinical and clinical research, as substance abusers have a high risk for exposure to the virus. The proposed studies should go far in identifying critical viral- and host-derived factors associated with increased susceptibility to the pathological effects of drugs of abuse such as METH and consequent neurotoxicity.