Methamphetamine, Innate Immunity and HIV

甲基苯丙胺、先天免疫和艾滋病毒

• 批准号: 9308910
• 负责人: WENZHE HO
• 金额: $ 35.1万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9308910
• 关键词: Address; Astrocytes; Biological Assay; Brain-Derived Neurotrophic Factor; CCL2 gene; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; Cell Count; Cells; Chronic; Clinical; Cytoprotection; Development; Disease; HIV; HIV Infections; HLA-DR Antigens; Health; Immune; Immune response; Immunity; Immunologic Markers; Impairment; In Vitro; Individual; Infection Control; Inflammatory; Interferon-alpha; Interferons; Interleukin-1; Interleukin-10; Interleukin-6; Ligands; Measures; Mediating; Methamphetamine; MicroRNAs; Microglia; Monitor; NTF3 gene; Natural Immunity; Neuroglia; Neuronal Injury; Neurons; Outcome; Peripheral Blood Mononuclear Cell; Persons; Plasma; Predisposition; Production; Research; Signal Pathway; Signal Transduction; Specimen; Study Subject; System; T-Lymphocyte; TLR3 gene; TNF gene; United States; Virus Diseases; base; chemokine; circulating microRNA; clinically relevant; clinically significant; cytokine; drug of abuse; exosome; immune activation; in vivo; macrophage; methamphetamine action; methamphetamine effect; methamphetamine use; methamphetamine user; monocyte; neurotoxicity; neurotropic; novel; public health relevance; response

 DESCRIPTION (provided by applicant): Methamphetamine (METH) is one of the most commonly abused drugs among HIV-infected individuals in the United States. METH use is associated with the worst health outcomes in HIV-infected individuals, as METH adversely impacts immunological responses to viral infections. Although METH has been indicated as a facilitating factor in the development of HIV disease, the mechanism(s) of METH actions on HIV remains to be determined. Our in vitro studies showed that METH could enhance HIV replication and impair intracellular innate immunity. Thus, we proposed further studies using the clinical specimens from the unique and well-characterized study subjects, investigating the in vivo and ex vivo impact of METH on RIG- I/TLR3 signaling-mediated anti-HIV activities. We hypothesize that METH suppresses intracellular innate immunity in primary immune cells (CD4+T cells, monocytes) and CNS cells (astrocytes, microglia), facilitating HIV infection and neuronal injury. We propose three specific aims to address this hypothesis: In aim 1, we will determine the plasma levels of exosome- derived HIV restriction miRNAs and immune activation markers in METH users with or without chronic HIV infection. In aim 2, we will determine the ex vivo and in vitro effects of METH on RIG-I/TLR3 signaling-mediated innate immunity against HIV. We will also examine the mechanisms involved in the actions of METH on RIG-I/TLR3 signaling and HIV infection. In aim 3, we will determine the effect of astroglial RIG-I/TLR3 signaling on HIV replication in microglia (glia-glia interaction) as well as the impact of METH on astroglial RIG-I/TLR3 signaling-mediated anti-HIV effect and neuronal cell protection. These proposed novel studies with combinational in vivo, ex vivo and in vitro approaches are clinically significant and relevant, as they will reveal previously unidentified mechanisms for the METH actions on HIV and the CNS. In addition, the proposed studies will identify the novel immunological markers for monitoring the impact of METH use on the development of HIV disease.

 描述（由申请人提供）：甲基苯丙胺 (METH) 是美国 HIV 感染者中最常滥用的药物之一。冰毒的使用与艾滋病毒感染者最糟糕的健康结果有关，因为冰毒会对病毒感染的免疫反应产生不利影响。尽管冰毒已被证明是艾滋病毒疾病发展的促进因素，但冰毒对艾滋病毒的作用机制仍有待确定。我们的体外研究表明，冰毒可以增强 HIV 复制并损害细胞内先天免疫。因此，我们建议使用来自独特且特征明确的研究对象的临床标本进行进一步的研究，调查 METH 对 RIG-I/TLR3 信号介导的抗 HIV 活性的体内和离体影响。我们假设 METH 抑制初级免疫细胞（CD4+T 细胞、单核细胞）和 CNS 细胞（星形胶质细胞、小胶质细胞）的细胞内先天免疫，促进 HIV 感染和神经元损伤。我们提出了三个具体目标来解决这一假设：在目标 1 中，我们将确定患有或不患有慢性 HIV 感染的 METH 使用者中外泌体衍生的 HIV 限制性 miRNA 和免疫激活标记物的血浆水平。在目标 2 中，我们将确定 METH 对 RIG-I/TLR3 信号介导的针对 HIV 的先天免疫的离体和体外影响。我们还将研究 METH 对 RIG-I/TLR3 信号传导和 HIV 感染的作用机制。在目标 3 中，我们将确定星形胶质细胞 RIG-I/TLR3 信号传导对小胶质细胞中 HIV 复制（胶质细胞-神经胶质细胞相互作用）的影响，以及 METH 对星形胶质细胞 RIG-I/TLR3 信号传导介导的抗 HIV 作用和神经元细胞保护的影响。这些拟议的结合体内、离体和体外方法的新研究具有临床意义和相关性，因为它们将揭示 METH 对 HIV 和 CNS 作用的先前未知的机制。此外，拟议的研究将确定新的免疫学标记物，用于监测冰毒使用对艾滋病毒疾病发展的影响。