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，阿片类药物的使用改变了对各种传染病的敏感性，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，关于滥用阿片类药物对中枢神经系统(CNS)艾滋病毒感染或包括痴呆症在内的相关神经疾病的影响，人们知之甚少。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运输受感染的血液来源的单核细胞。单核细胞向中枢神经系统的转运是一个正常的生理过程，但在炎症和/或与脑感染相关的过程中会增加。我们实验室和其他实验室报告的证据表明，阿片类药物可能会促进贩运过程，导致感染细胞迁移到大脑。我们在这一应用中的假设是，阿片类药物通过改变关键趋化因子和趋化因子受体的表达，具有显著改变HIV脑炎发展的能力。我们认为，阿片类药物的使用促进了促炎单核细胞的发育，单核细胞具有更高的产生和反应促炎趋化因子的能力，并凭借更大的转运能力，加速了病毒感染细胞进入大脑的转运。在这个赠款项目中，我们将研究阿片类药物给药对致炎单核细胞表型发育的影响。我们将确定Mu和kappa阿片类药物影响关键趋化因子受体CCR2以及非常重要的促炎趋化因子MCP-1表达的分子机制。本实验室研究表明，阿片类药物急性给药可诱导趋化因子受体CCR5和CXCR4表达。我们将通过克隆CCR2和MCP-1启动子的分子结构来扩展这些研究，以确定这些效应的生化基础。相反，我们的结果表明，kappa阿片类药物抑制了HIV-1辅助受体的表达，并降低了HIV的易感性，我们建议进行研究，以检验这一效应的分子基础。我们相信，这些研究将有助于我们理解阿片类药物对与艾滋病毒感染相关的神经病理影响的分子基础。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，关于滥用阿片类药物对中枢神经系统(CNS)艾滋病毒感染或包括痴呆症在内的相关神经疾病的影响，人们知之甚少。该项目旨在调查阿片类药物对导致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.