Project 3

人类免疫缺陷病毒(HIV-1)感染者经常表现出严重的进行性行为、认知和运动障碍(称为神经艾滋病)，并伴随着大脑的病理变化(包括胶质增生、脑炎和空泡性脊髓病)。目前的证据有力地表明，这种疾病(又称神经艾滋病)的发病机制涉及以下神经毒性途径：(1)HIV-1相关产物，如包膜蛋白gp120；(2)宿主反应的产物，如IL-6、干扰素和肿瘤坏死因子，从激活的巨噬细胞/小胶质细胞和星形胶质细胞释放。甲基苯丙胺(甲基苯丙胺)滥用常常是由严重的急性和长期的神经元损伤造成的，在艾滋病毒-1感染者中很普遍。我们在这里假设，这些病毒、宿主和冰毒侮辱的组合产生相加甚至协同作用，导致神经病理后遗症的恶化，并加速进展为神经艾滋病的功能性神经精神缺陷。确定中枢兴奋剂药物冰毒与宿主来源的产物和HIV-1相关产物相互作用的性质和机制，以影响结构和功能中枢神经系统(CNS)损伤的程度和进展。HIV-1感染以及其他感染源感染导致的外周免疫功能失调在艾滋病患者中被观察到。因此，我们将确定冰毒和外周免疫刺激之间的相互作用(通过腹腔注射有效的免疫刺激剂脂多糖来实现)，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。脑内表达IL6、肿瘤坏死因子、肿瘤坏死因子或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冰毒与宿主或HIV-1相关产物的中心产生之间的相互作用，以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氨酸与宿主反应产物或HIV-1之间致病相互作用的基础。这项研究计划整合了对中枢神经系统药物影响的分析，因为它与艾滋病毒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，因为药物滥用者接触病毒的风险很高。拟议的研究应该在确定关键的病毒和宿主衍生因素方面走得更远，这些因素与滥用药物(如冰毒)的病理影响和随之而来的神经毒性增加有关。

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.