Drugs of Abuse Affecting AIDS Pathogenesis

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，滥用阿片类药物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在很大程度上仍未得到解答的关键问题。在本项目申请中，我们提出了四个项目，将阐明阿片类药物滥用在该疾病发展过程中的作用。项目1将研究吗啡和SIV感染对SIV脑炎发展中起重要作用的关键趋化因子和趋化因子受体表达的联合影响。我们将在细胞和分子水平上研究慢性吗啡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，其直接途径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，间接途径包括免疫调节剂和细胞因子的失调，以及病毒蛋白（如gp120和Tat）在感染和未感染的旁观细胞（包括神经元）中的下游信号通路。在这个研究项目中，我们将把注意力集中在一个直接和间接途径中涉及的细胞因子上，我们将研究吗啡对HIV-1基因表达和复制、神经元细胞功能和凋亡的影响。项目4旨在检查siv感染和未感染的猕猴注射吗啡后免疫参数的变化。将对每个治疗组/感染组的动物免疫能力进行评估。研究将包括对后天免疫系统和先天免疫系统能力的分析。该应用程序还包括行政管理、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。

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