Drugs of Abuse Affecting AIDS Pathogenesis

影响艾滋病发病机制的滥用药物

• 批准号: 8069845
• 负责人: Thomas J Rogers
• 金额: $ 137.43万
• 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: 2008-07-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8069845
• 关键词: Drugs; Abuse; Affecting; AIDS; Pathogenesis

DESCRIPTION (provided by the applicant): In the United States, approximately 33% of individuals who are infected by the Human Immunodeficiency Virus (HIV) are intravenous drug abusers. Current evidence suggests that opioid abuse may promote the disease that occurs following this infection. We believe that the issue of the precise nature of the influence of opioid drugs of abuse in the development of HIV encephalitis is a critical question which remains largely unanswered. In this Program Project application, we propose four projects which will clarify the role of opioid abuse in the development of this disease process. Project 1 will address the combined influence of morphine and SIV infection on the expression of critical chemokines and chemokine receptors that play an important role in the development of SIV encephalitis. We will investigate the impact of both chronic morphine administration on expression of these crucial cytokines and their receptors at both the cellular and molecular level. Project 2 will investigate the effect of morphine on the pathogenesis of SIV infection in rhesus macaques. We will investigate the effect of viral load, immunophenotype of immune cells, and investigate the effect of drug treatment on the trafficking of infected cells into the CNS, lymph nodes, and other organs. Project 3 addresses the issue of the neuropathogenesis that is caused by a direct pathway that includes infection of macrophages, microglia, and astrocytes in the CNS, and an indirect pathway that involves dysregulation of immunomodulators and cytokines, and their downstream signaling pathways by viral proteins, such as gp120 and Tat, in both infected and uninfected bystander cells including neurons. In this research project we will focus our attention on a cytokine which has been implicated in direct and indirect pathways, and we will examine the effect of morphine on HIV-1 gene expression and replication, neuronal cell function, and apoptosis. Project 4 seeks to examine alterations in immune parameters following administration of morphine in both SIV-infected and non-infected macaques. An assessment of the immunological competence of animals in each treatment/infection group will be determined. Studies will include an analysis of the competence of both the acquired and innate immune systems. This application also includes administrative, animal, flow cytometry, and immunohistopathology cores to support the four research projects. PROGRAM PROJECT CHARACTERISTICS

描述（由申请人提供）：在美国，大约 33% 的人类免疫缺陷病毒 (HIV) 感染者是静脉注射药物滥用者。 目前的证据表明，阿片类药物滥用可能会促进这种感染后发生的疾病。 我们认为，滥用阿片类药物对艾滋病毒脑炎发展的影响的确切性质是一个关键问题，但在很大程度上仍未得到解答。 在此计划项目申请中，我们提出了四个项目，这些项目将阐明阿片类药物滥用在这种疾病过程发展中的作用。 项目 1 将解决吗啡和 SIV 感染对关键趋化因子和趋化因子受体表达的综合影响，这些趋化因子和趋化因子受体在 SIV 脑炎的发展中发挥重要作用。 我们将在细胞和分子水平上研究长期吗啡给药对这些关键细胞因子及其受体表达的影响。 项目2将研究吗啡对恒河猴SIV感染发病机制的影响。 我们将研究病毒载量、免疫细胞免疫表型的影响，并研究药物治疗对感染细胞转运至中枢神经系统、淋巴结和其他器官的影响。 项目 3 解决神经发病机制的问题，该问题是由直接途径引起的，包括中枢神经系统中巨噬细胞、小胶质细胞和星形胶质细胞的感染，以及涉及免疫调节剂和细胞因子及其下游信号传导途径病毒蛋白失调的间接途径，例如 gp120 和 Tat，存在于受感染和未受感染的旁观细胞（包括神经元）中。 在这个研究项目中，我们将重点关注与直接和间接途径有关的细胞因子，我们将检查吗啡对 HIV-1 基因表达和复制、神经细胞功能和细胞凋亡的影响。 项目 4 旨在检查 SIV 感染和未感染的猕猴服用吗啡后免疫参数的变化。 将确定每个治疗/感染组中动物的免疫能力的评估。 研究将包括对获得性免疫系统和先天免疫系统能力的分析。 该应用程序还包括管理、动物、流式细胞术和免疫组织病理学核心，以支持四个研究项目。 计划项目特点