Immunopathogenesis of HIV-1 Infection: Role of Methamphetamine

HIV-1 感染的免疫发病机制：甲基苯丙胺的作用

基本信息

批准号：
7209758
负责人：
MADHAVAN P. NAIR
金额：
$ 33.35万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7209758
关键词：
1-Phosphatidylinositol 3-Kinase AIDS Dementia Complex Abbreviations Adam11 gene Affect Antigen Presentation Antigen-Presenting Cells Antigens Biological Models CCL22 gene CCL3 gene CCL4 gene CCR5 gene CD209 gene CD4 Antigens CD4 Lymphocyte Count CD4 Positive T Lymphocytes CD40 Antigens CD80 gene CXCL12 gene CXCR4 gene Catabolism Cell Maturation Cell Proliferation Cell physiology Cell surface Cells Cocaine Data Dendritic Cells Dioxygenases Disease Disease Progression Dopamine Dopamine D1 Receptor Dopamine Receptor Drug abuse Enzymes Epidemic Essential Amino Acids Figs - dietary Functional disorder Gene Expression Growth Factor HIV Receptors HIV-1 High Prevalence Immune System Diseases Immune response Immune system Immunity Immunologic Deficiency Syndromes Immunosuppressive Agents Immunotherapeutic agent In Vitro Infection Injecting drug user Inositol Kynurenine Lead Lymphocyte antigen CD50 Lymphoid Tissue MAPK1 gene MAPK14 gene MAPK3 gene MHC Class I Genes Macrophage Inflammatory Proteins Mediating Methamphetamine Microbe Mitogen-Activated Protein Kinases Mitogens Molecular Neuraxis Neurotoxins Numbers Pathogenesis Pathway interactions Patients Peptides Peripheral Blood Mononuclear Cell Persons Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide Phosphotransferases Play Population Predisposition Process Production Protein Kinase Proteins Quinolinic Acid Quinolinic Acids RANTES Rate Recreational Drugs Reporting Research Rest Risk Role Signal Transduction Signal Transduction Pathway Small Inducible Cytokine A3 Small Interfering RNA Stromal Cell-Derived Factor 1 T-Cell Activation T-Cell Proliferation T-Lymphocyte TNFRSF5 gene Testing Therapeutic Translational Research Tryptophan Up-Regulation Viral Load result Virus Virus Diseases Work antigen processing base cell mediated immune response cell motility chemokine chemokine receptor chlorambucil/dactinomycin/methotrexate protocol club drug drug of abuse enzyme pathway experience genetic variant immune function in vivo indolamine inhibitor/antagonist methyl tryptophan monocyte novel prevent receptor research study response stress activated protein kinase stress-activated protein kinase 1 tissue processing

项目摘要

DESCRIPTION (provided by applicant): The US is currently experiencing a serious epidemic of methamphetamine (Meth) use as a recreational drug and as of July 2005, Meth use has surpassed cocaine use as a street or club drug. Recent studies also show a high prevalence of HIV-1 infection among Meth users. Blood monocyte derived dendritic cells (DC) are the first line of defense against HIV-1 infection and are the initial target of HIV-1 in injection drug users. Although evidence of immune dysfunctions has been reported in Meth users, the molecular basis of the immunopathogenesis of HIV-1 infection in Meth users has not been delineated. Further, the effects of Meth abuse on the activities of DC that lead to HIV-1 disease progression in the Meth using population has not been examined. The current application focuses on novel, DC based immunotherapeutic and/or translational research strategies against susceptibility to and progression of HIV-1 infections in Meth using populations. Consequently, the following hypothesis will be tested by the proposed experiments: Meth is a co-factor in the pathogenesis of HIV-1 infections by acting in synergy with certain HIV-1 proteins on DC functions subsequently leading to dysregulation of the immune system of the infected host. Further, we propose that Meth mediates these effects on DC through several mechanisms including: 1) down regulating the expression of various costimulatory molecules, chemokines (that are necessary for DC maturation, effective antigen presentation, cell migration, and T cell proliferation), and a reciprocal upregulation of HIV-1 entry coreceptors (CCR5 and CXCR4) that are known to facilitate HIV-1 infection; 2) upregulating indolamine 2,3 dioxygenase (IDO) that suppresses T cell immune functions; and 3) upregulating the DC-specific, CD4 independent virus attachment receptor, DC-SIGN, present on DC. Further, we shall determine the mechanism(s) of Meth mediated dysregulation of DC functions by examining signal transduction pathways and using Meth specific siRNA and receptor inhibitors. Our preliminary studies show that Meth significantly downregulates the expression of costimulatory molecules and HIV-1 suppressing (3-chemokines with a reciprocal upregulation of HIV-1 coreceptors, DC-SIGN and IDO, and these effects appear to be mediated via dysregulation of mitogen-activated protein (MAP) kinases. Resultant data will be stratified on the basis of HIV-1 disease status, CD4 counts, HIV-1 viral load and Meth use. These studies may lead to novel anti-HIV-1 therapeutic or translational research strategies such as targeting the CD4 independent virus attachment receptor, DCSIGN, or devising inhibitors of IDO, DC-SIGN, CCR5/CXCR4 and specific dopamine receptors or stimulating the expression of costimulatory-and (3-chemokine molecules in high risk Meth using and non using HIV-1 infected subjects.

描述（由申请人提供）：美国目前正经历严重流行的甲基苯丙胺 (Meth) 作为娱乐性毒品的使用，截至 2005 年 7 月，甲基苯丙胺 (Meth) 作为街头或俱乐部毒品的使用已超过可卡因。最近的研究还表明，冰毒使用者中 HIV-1 感染率很高。血液单核细胞衍生的树突状细胞 (DC) 是抵抗 HIV-1 感染的第一道防线，也是注射吸毒者中 HIV-1 的最初目标。尽管有证据表明冰毒使用者存在免疫功能障碍，但冰毒使用者 HIV-1 感染免疫发病机制的分子基础尚未阐明。此外，冰毒滥用对导致冰毒使用人群中 HIV-1 疾病进展的 DC 活性的影响尚未得到研究。目前的申请重点是基于 DC 的新型免疫治疗和/或转化研究策略，以对抗冰毒使用人群中 HIV-1 感染的易感性和进展。因此，以下假设将通过所提出的实验进行检验：冰毒是 HIV-1 感染发病机制中的辅助因子，通过与 DC 功能上的某些 HIV-1 蛋白协同作用，随后导致免疫系统的失调。被感染的主机。此外，我们提出 Meth 通过多种机制介导对 DC 的这些影响，包括：1）下调各种共刺激分子、趋化因子（DC 成熟、有效抗原呈递、细胞迁移和 T 细胞增殖所必需的）的表达，以及HIV-1 进入辅助受体（CCR5 和 CXCR4）的相互上调已知会促进 HIV-1 感染； 2) 上调吲哚胺2,3双加氧酶(IDO)，抑制T细胞免疫功能； 3) 上调 DC 上存在的 DC 特异性、不依赖于 CD4 的病毒附着受体 DC-SIGN。此外，我们将通过检查信号转导途径并使用 Meth 特异性 siRNA 和受体抑制剂来确定 Meth 介导的 DC 功能失调的机制。我们的初步研究表明，Meth 显着下调共刺激分子和 HIV-1 抑制（3-趋化因子）的表达，同时上调 HIV-1 辅助受体、DC-SIGN 和 IDO，这些效应似乎是通过有丝分裂原的失调介导的。结果数据将根据 HIV-1 疾病状态、CD4 计数、HIV-1 病毒载量和冰毒使用情况进行分层。研究可能会带来新的抗 HIV-1 治疗或转化研究策略，例如针对 CD4 独立病毒附着受体 DCSIGN，或设计 IDO、DC-SIGN、CCR5/CXCR4 和特定多巴胺受体的抑制剂，或刺激共刺激的表达-和（3-趋化因子分子在高风险冰毒使用和不使用HIV-1感染受试者中。