Drugs of Abuse Affecting AIDS Pathogenesis

描述(由申请人提供)：在美国，大约33%感染人类免疫缺陷病毒(HIV)的人是静脉注射吸毒者。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，在很大程度上仍未得到回答。在本计划项目申请中，我们提出了四个项目，将阐明阿片类药物滥用在这一疾病过程中的作用。项目1将讨论吗啡和SIV感染对关键趋化因子和趋化因子受体表达的联合影响，这些关键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。我们将从细胞和分子水平研究长期使用吗啡对这些重要细胞因子及其受体表达的影响。项目2将研究吗啡在恒河猴SIV感染发病机制中的作用。我们将研究病毒载量、免疫细胞免疫表型的影响，以及药物治疗对感染细胞进入中枢神经系统、淋巴结和其他器官的影响。项目3解决了神经发病机制的问题，这是由直接途径引起的，包括感染中枢神经系统中的巨噬细胞、小胶质细胞和星形胶质细胞，以及间接途径，涉及感染和未感染的旁观者细胞(包括神经元)中免疫调节剂和细胞因子的失调及其下游信号通路，如gp120和Tat。在这项研究中，我们将重点关注与直接和间接途径有关的一种细胞因子，并将检测吗啡对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试图检查感染和未感染SIV的猕猴在注射吗啡后免疫参数的变化。将确定对每个治疗/感染组动物的免疫能力的评估。研究将包括后天免疫系统和先天免疫系统的能力分析。这项应用还包括行政、动物、流式细胞术和免疫组织病理学核心，以支持这四个研究项目。 计划项目的特点

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