HIV drug abusers, polymorphisms and brain plasticity

描述(由申请人提供)：人类免疫缺陷病毒-1(HIV)相关性痴呆(HAD)的特征是整个大脑中神经元和纤维的严重丧失。据估计，美国三分之一的艾滋病毒感染者是静脉注射阿片类药物的吸毒者。据认为，海洛因、吗啡和其他静脉注射鸦片类药物可能会加剧艾滋病毒的神经毒性作用。然而，尽管关于决定这些患者缓慢但进行性神经元死亡的复杂因素的知识有了巨大的扩展，但对这种效应的分子和细胞机制知之甚少。阿片剂，特别是吗啡，已被证明会导致包括小胶质细胞在内的免疫细胞功能异常，并使这些细胞更容易受到艾滋病毒感染。然而，实验数据表明，即使在没有小胶质细胞的情况下，吗啡也能与艾滋病毒病毒蛋白协同作用，导致细胞凋亡。因此，仅靠免疫/神经胶质细胞的改变不能解释HAD神经元的丢失。慢性阿片类药物会改变 趋化因子受体CCR5和CXCR4，已知介导艾滋病毒的神经毒性效应。因此， 阿片类药物可能利用这种细胞机制来放大艾滋病毒的神经毒性。HIV蛋白 Gp120可降低大鼠脑组织中脑源性神经营养因子BDNF的水平。BDNF是 趋化因子受体表达的天然调节剂。因此，我们提出这样的假设 HAD源于阿片剂和HIV之间的多步骤相互作用，导致深刻的 神经保护和可塑性的内源性细胞机制的改变。为了测试这一点 假设我们将首先使用啮齿动物(体外和体内研究)来测试吗啡和两种 HIV包膜蛋白gp120株对趋化因子及其受体和神经元的影响 生死存亡。此外，我们还提出了一系列针对人类对象的全面研究，旨在 探讨脑源性神经营养因子和脑源性神经营养因子基因多态性在HAD发病中的作用。这类研究 包括对有海洛因滥用史受试者死后大脑进行脑源性神经营养因子分析，如 以及对艾滋病毒感染者队列的检查(来自妇女机构间艾滋病毒研究 队列)进行BDNF基因多态性分析。我们认为缺乏脑源性神经营养因子是HAD的一个危险因素。《长河》 本申请的术语目标是建立一种新的艾滋病毒阿片类药物相互作用机制，以解释 为什么吸毒者的神经元比非吸毒者更容易发生细胞凋亡。这一机制 包括营养支持的减少和促凋亡趋化因子受体的增强 神经元。证明这种机制将有助于开发有效的药物疗法来逆转或延迟 有。公共卫生相关性：感染人类免疫缺陷病毒-1的人中至少有三分之一是吸毒者。感染、吗啡、海洛因添加(或其他药物)的组合被认为对大脑有毒。这项应用将研究机制以及基因异常，这些可能是这些受试者发生脑损伤的风险因素。

DESCRIPTION (provided by applicant): Human Immunodeficiency virus -1 (HIV)-associated dementia (HAD) is characterized by a severe loss of neurons and fibers throughout the brain. It is estimated that a third of HIV-infected individuals in the USA are intravenous opiate drug abusers. It is believed that heroin, morphine and other intravenous opiate drugs may exacerbate the neurotoxic effect of HIV. However, little is known about the molecular and cellular mechanisms of this effect despite the enormous expansion of knowledge regarding the complex factors that determine slow but progressive neuronal death in these patients. Opiates, and in particular morphine, have been shown to cause abnormalities in the functioning of immune cells including microglia and to render these cells more "susceptible" to HIV infection. However, experimental data have shown that morphine synergizes with HIV viral proteins in causing apoptosis even in the absence of microglia. Thus, alteration of immune/glial cells alone cannot explain loss of neurons in HAD. Chronic opiates alter the expression of chemokine receptors CCR5 and CXCR4, known to mediate the neurotoxic effect of HIV. Thus, opiates may use this cellular mechanism to amplify HIV neurotoxic property. The HIV protein gp120 reduces the levels of brain-derived neurotrophic factor BDNF (BDNF) in rat brain. BDNF is a natural modulator of chemokine receptor expression. Therefore, we propose the hypothesis that HAD derives from a multiple step interaction between opiates and HIV that causes a profound alteration of endogenous cellular mechanisms of neuroprotection and plasticity. To test this hypothesis we will first use rodents (in vitro and in vivo studies) to test the role of morphine and two strains of HIV envelop proteins gp120 on chemokine and chemokine receptors and neuronal survival. Moreover, we propose a series of comprehensive studies in human subjects aimed at establishing the role of BDNF and BDNF polymorphism on the development of HAD. Such studies include BDNF analysis of post-mortem brains of HAD subjects with a history of heroin abuse, as well as examination of a cohort of HIV infected subjects (from the Women's Interagency HIV Study cohort) for BDNF polymorphisms. We believe that lack of BDNF is a risk factor for HAD. The long term aim of this application is to establish a new mechanism of HIV opiates interaction that explains why neurons of drug abusers are more vulnerable to apoptosis than non abusers. This mechanism includes reduction of trophic support and enhancement of pro-apoptotic chemokine receptors in neurons. Proving such mechanism will help develop effective drug therapy to reverse or delay HAD. PUBLIC HEALTH RELEVANCE: At least a third of subjects infected with Human Immunodeficiency Virus-1 are drug abusers. The combination of infection, morphine, heroin addition (or other drugs) is believed to be toxic to the brain. This application will study the mechanisms as well as the genetic abnormalities that may be risk factors for developing brain damage in these subjects.