DYNORPHIN AND GLIAL CELL IMMUNOMODULATION

内源性阿片肽被认为可以调节人类免疫缺陷病毒(HIV)-1的神经发病机制，HIV -1是获得性免疫缺陷综合征（AIDS）痴呆的病因。在这项拨款更新申请中提出的主要假设是，kappa阿片样物质通过抑制HIV-1表达和减少病毒诱导的神经元损伤，在HIV-1诱导的脑部疾病中具有神经保护作用。在过去的几年里，我们发现kappa阿片受体（KOR）配体在急性感染的人小胶质细胞培养物中抑制HIV-1的表达。在初步研究中，KOR配体似乎也抑制病毒在人单核细胞（小胶质细胞的前体细胞）培养中的表达。虽然这种抗病毒作用的机制尚未阐明，但kappa阿片类物质被认为通过以下一种或多种机制触发一系列细胞事件，导致病毒表达减少：1)抑制病毒进入靶细胞，2)降低活化HIV-1复制所需的细胞转录因子核因子- kappab的激活，3)抑制HIV-1启动子活性，或4)阿片类药物处理细胞增强抗病毒β趋化因子的产生。此外，u50488的抗病毒作用将使用原代HIV-1分离株进行测试（Specific Aim 1）。除了抗病毒活性外，还将利用hiv -1 SF162菌株和原代分离株评估KOR配体对hiv -1诱导毒性的神经保护活性。据推测，KOR配体的保护机制包括：1)通过抑制小胶质细胞和单核细胞诱导的神经毒素（即喹啉酸盐、Tat或细胞因子[白细胞介素-1 β和肿瘤坏死因子- α]）产生的间接机制；2)保护神经元免受这些毒素诱导的毒性的直接机制（Specific Aim 2）。这些研究的发现将潜在地为kappa阿片类药物的抗病毒和神经保护作用的相关机制提供见解，并有望导致艾滋病痴呆的新治疗方法的发展。

Endogenous opioid peptides have been postulated to modulate the neuropathogenesis of human immunodeficiency virus (HIV)-1, the etiologic agent of acquired immunodeficiency syndrome (AIDS) dementia. The principal hypothesis of the work proposed in this grant renewal application is that kappa opioids have a neuroprotective role in HIV-l-induced brain disease by suppressing HIV-1 expression and by reducing viral-induced neuronal injury. In the past several years, we have found that kappa opioid receptor (KOR) ligands inhibit HIV-1 expression in acutely infected human microglial cell cultures. In preliminary studies, KOR ligands also appear to suppress viral expression in cultures of human monocytes, the precursor cells of microglia. Although the mechanism of this antiviral effect has not yet been elucidated, kappa opioids are proposed to trigger a cascade of cellular events resulting in reduced viral expression by one or more of the following mechanisms: 1) inhibition of viral entry into target cells, 2) reduced activation of nuclear factor-kappaB, a cellular transcription factor required for the activation of the HIV-1 replication, 3) suppression of HIV-1 promoter activity, or 4) potentiation of the production of antiviral beta-chemokines by opioid-treated cells. Also, the anti-viral effects of U5O,488 will be tested using primary HIV-1 isolates (Specific Aim l). In addition to their antiviral activity, KOR ligands will be evaluated for their neuroprotective activity against HIV-1-induced toxicity using the HIV-l SF162 strain and primary isolates. The protective mechanism of KOR ligands is postulated to involve either l) an indirect mechanism by inhibiting microglial cell- and monocyte- induced production of neurotoxins (i.e., quinolinate, Tat, or cytokines [interleukin-1beta and tumor necrosis factor-alpha] or 2) a direct mechanism protecting neurons against toxicity induced by these toxins (Specific Aim 2). The findings from these studies will potentially provide insights into mechanisms associated with antiviral and neuroprotective effects of kappa opioids and hopefully will lead to development of new therapeutic approaches for AIDS dementia.