Opioid Modulation of Inflammatory Monocyte Activity Involved in HIV Susceptibilit

阿片类药物对与 HIV 易感性相关的炎症单核细胞活性的调节

• 批准号: 8078920
• 负责人: Thomas J Rogers
• 金额: $ 28.81万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8078920
• 关键词: Acute; Address; Agonist; Alkaloids; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antiviral Agents; Applications Grants; Biochemical; Blood; Blood - brain barrier anatomy; Blood Circulation; Brain; CCL2 gene; CCR5 gene; CXCR4 gene; Cells; Chemokine (C-C Motif) Receptor 5; Clinical Research; Country; Dementia; Depressed mood; Development; Disease; Dynorphins; Elements; Exhibits; Grant; HIV; HIV encephalitis; HIV-1; Health; Individual; Infection; Infectious Agent; Inflammation; Inflammatory; Inflammatory Response; Intravenous; Laboratories; Leucocytic infiltrate; Maps; Mediator of activation protein; Mesylates; Microglia; Modeling; Molecular; Molecular Cloning; Morphine; Nature; Neuraxis; Opioid; Opioid Peptide; Opioid Receptor; Pharmaceutical Preparations; Phase; Phenotype; Physiological Processes; Predisposition; Process; Production; Promoter Regions; Reporting; Research; SIV; Signal Transduction; Surface; T-Lymphocyte; Therapeutic; Transcriptional Regulation; Translational Research; Viral; Viral Encephalitis; Virus; Virus Diseases; alanylglycine; base; chemokine; chemokine receptor; drug abuser; drug of abuse; glycylphenylalanine; inflammatory modulation; macrophage; migration; monocyte; nervous system disorder; neuropathology; peripheral blood; promoter; receptor expression; research and development; trafficking; transmission process

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.

描述（由申请人提供）：最近的研究表明，阿片类药物可以改变对多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，阿片类药物滥用对艾滋病毒感染中枢神经系统（CNS）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，在感染的急性期，病毒向中枢神经系统的最初传播涉及受感染的血源性单核细胞的贩运。单核细胞向中枢神经系统的运输是一个正常的生理过程，但在炎症和/或与脑感染相关的情况下会增加。我们实验室以及其他实验室报告的证据表明，阿片类药物可能促进导致受感染细胞向大脑迁移的贩运过程。我们在这项应用中的假设是，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，具有显著的改变艾滋病毒脑炎发展的能力。我们认为，阿片类药物促进促炎单核细胞的发育，促炎单核细胞产生促炎趋化因子和对促炎趋化因子作出反应的能力提高，并且凭借更大的运输能力，加速病毒感染细胞进入大脑的运输。在这个资助项目中，我们将研究阿片类药物给药对促炎单核细胞表型发展的影响。我们将确定mu和kappa阿片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表达的分子机制。我们的实验室已经证明，急性阿片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，通过克隆CCR2和MCP-1启动子的分子结构来确定这些效应的生化基础。相反，我们的研究结果表明kappa阿片类药物抑制HIV-1共受体的表达，并降低HIV易感性，我们建议研究这种作用的分子基础。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，阿片类药物滥用对艾滋病毒感染中枢神经系统（CNS）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。