Methamphetamine, Innate Immunity and HIV

甲基苯丙胺、先天免疫和艾滋病毒

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：甲基苯丙胺（甲基苯丙胺）是美国艾滋病毒感染者中最常见的药物之一。甲基苯丙胺的使用与艾滋病毒感染者中最恶劣的健康结果有关，因为甲基甲基苯丙胺对病毒感染的免疫反应不利。尽管已经将甲基甲表示为艾滋病毒疾病发展的支持因素，但仍有待确定甲基甲基动物作用的机制。我们的体外研究表明，甲基苯酚可以增强HIV复制并损害细胞内先天免疫史。这是我们提出的进一步研究，使用来自独特且特征良好的研究对象的临床标本，研究了METH对RIG-I/TLR3信号介导的抗HIV活性的体内和体内影响。我们假设METS抑制原发性免疫分布细胞（CD4+T细胞，单核细胞）和CNS细胞（星形胶质细胞，小胶质细胞）中的细胞内先天性免疫史，支持HIV感染和神经元损伤。我们提出了三个特定的目的来解决这一假设：在AIM 1中，我们将确定具有或没有慢性HIV感染的甲基甲基甲烷类使用者中外泌体衍生的HIV限制miRNA和免疫激活标记的血浆水平。在AIM 2中，我们将确定METH对RIG-I/TLR3信号介导的对HIV的先天免疫的离体和体外作用。我们还将检查甲基对RIG-I/TLR3信号传导和HIV感染的作用所涉及的机制。在AIM 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（Glia-Glia相互作用）中HIV复制的影响，以及METH对星形胶质细胞RIG-I/TLR3信号介导的抗HIV介导的抗HIV和神经元细胞的影响。这些提出的新型研究在体内，体内和体外方法具有临床意义和相关性，因为它们将揭示以前未识别的甲基甲基动物作用的HIV和CNS的机制。此外，拟议的研究将确定新的免疫学标记物，以监测使用甲基甲基苯丙胺对艾滋病毒疾病发育的影响。