Opioid Modulation of Inflammatory Monocyte Activity Involved in HIV Susceptibilit

描述（由申请人提供）：最近的研究表明，阿片类药物给药改变了对各种感染因子的易感性，包括人类免疫缺陷病毒（HIV）。据估计，该国三分之一的艾滋病毒感染者是静脉注射阿片类药物滥用者。然而，人们对阿片类药物滥用对中枢神经系统（CNS）HIV感染或相关神经系统疾病（包括痴呆）的影响知之甚少。目前的证据表明，病毒最初传播到中枢神经系统涉及在感染的急性期受感染的血液来源的单核细胞的运输。单核细胞向CNS的运输是正常的生理过程，但在炎症期间和/或与脑感染相关时增加。我们实验室以及其他实验室报告的证据表明，阿片类药物可能会促进导致受感染细胞迁移到大脑的贩运过程。我们在本申请中的假设是，阿片类药物具有通过改变关键趋化因子和趋化因子受体的表达来改变HIV脑炎发展的显著能力。我们认为，阿片类药物给药促进了促炎单核细胞的发育，这些单核细胞具有产生和响应促炎趋化因子的能力，并且由于更大的运输能力，加速了病毒感染细胞进入大脑的转运。在这个资助项目中，我们将研究阿片类药物对促炎单核细胞表型发展的影响。我们将确定μ和κ阿片类药物对关键趋化因子受体CCR2以及非常重要的促炎趋化因子MCP-1表达的影响的分子机制。我们的实验室已经表明，急性μ阿片类药物给药诱导趋化因子受体CCR5和CXCR4的表达。我们将扩展这些研究，以确定这些影响的生化基础，使用克隆的分子结构的CCR 2和MCP-1启动子。相比之下，我们的研究结果表明，κ阿片类药物抑制HIV-1辅助受体的表达，并降低艾滋病毒的易感性，我们建议研究，以检查这种影响的分子基础。我们相信这些研究将大大有助于我们了解阿片类药物对与HIV感染相关的神经病理学影响的分子基础。公共卫生相关性：据估计，该国三分之一的艾滋病毒感染者是静脉注射阿片类药物滥用者。然而，人们对阿片类药物滥用对中枢神经系统（CNS）HIV感染或相关神经系统疾病（包括痴呆）的影响知之甚少。该项目旨在研究阿片类药物对病毒从血液传播到大脑的机制的影响。

DESCRIPTION (provided by applicant): Recent research has suggested that opioid administration alters susceptibility to a variety of infectious agents, including the Human Immunodeficiency Virus (HIV). It is estimated that a third of HIV-infected individuals in this country are intravenous opioid drug abuser. Little is known, however, about the influence of opioid drugs of abuse on HIV infection of the central nervous system (CNS), or associated neurological disorders including dementia. Current evidence indicates that initial transmission of the virus to the CNS involves trafficking of infected blood-derived monocytes during the acute phase of the infection. The traffic of monocytes to the CNS is a normal physiological process, but is augmented during inflammation and/or in association with infection of the brain. Evidence reported from our laboratory, as well as others, suggest that opioid drugs may promote the trafficking process that leads to migration of infected cells to the brain. Our hypothesis in this application is that opioids have a significant ability to alter the development of HIV encephalitis by altering the expression of critical chemokines and chemokine receptors. We believe that the opioid administration promotes the development of pro-inflammatory monocytes which possess an elevated capacity to both produce and respond to pro-inflammatory chemokines, and by virtue of greater trafficking capacity, accelerate the transit of virally infected cells into the brain. In this grant project, we will examine the effect of opioid administration on development of a proinflammatory monocyte phenotype. We will determine the molecular mechanism for mu and kappa opioid effects on the expression of the critical chemokine receptor CCR2, as well as the very important pro-inflammatory chemokine MCP-1. Our laboratory has shown that acute mu opioid administration induces the expression of the chemokine receptors CCR5 and CXCR4. We will extend these studies to determine the biochemical basis for these effects using cloned molecular constructs for the CCR2 and MCP-1 promoters. In contrast, our results suggest that kappa opioids inhibit HIV-1 coreceptor expression, and depress HIV susceptibility, and we propose studies to examine the molecular basis for this effect as well. We believe these studies will contribute significantly to our understanding of the molecular basis for the effects of opioids on the neuropathology associated with HIV infection. PUBLIC HEALTH RELEVANCE: It is estimated that a third of HIV-infected individuals in this country are intravenous opioid drug abuser. Little is known, however, about the influence of opioid drugs of abuse on HIV infection of the central nervous system (CNS), or associated neurological disorders including dementia. This project is intended to investigate the effect of opioid drugs on the mechanism responsible for the spread of the virus from the bloodstream to the brain.