Cocaine/Immuno and Neuropathogenesis of HIV-1 Infection

HIV-1 感染的可卡因/免疫和神经发病机制

基本信息

批准号：
7261939
负责人：
MADHAVAN P. NAIR
金额：
$ 33.99万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-08-15 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7261939
关键词：
Abbreviations Adam11 gene Affect Anti-HIV Therapy Antigen Presentation Antigen-Presenting Cells Antigens Biological Models CCL2 gene CCL22 gene CD209 gene CD4 Lymphocyte Count CD4 Positive T Lymphocytes CD40 Antigens CD80 gene Catabolism Cell Differentiation process Cell Maturation Cell physiology Cell surface Cells Clonal Expansion Cocaine Cocaine Abuse Data Dendritic Cells Dioxygenases Disease Disease Progression Drug abuse Drug usage Enzymes Epidemic Essential Amino Acids Extracellular Signal Regulated Kinases Figs - dietary Functional disorder Funding Gene Expression HIV HIV Infections HIV-1 Homologous Gene Immune response Immune system Immunity Immunologic Deficiency Syndromes Immunosuppressive Agents Immunotherapeutic agent In Vitro Infection Inflammatory Injecting drug user Intercellular adhesion molecule 1 Kynurenine Lead Lymphocyte Subset Lymphocyte antigen CD50 Lymphoid Tissue MHC Class I Genes Macrophage Inflammatory Proteins Mediating Microbe Mitogen-Activated Protein Kinases Molecular Monocyte Chemoattractant Protein-1 Neuropathogenesis Neurotoxins Numbers Pathogenesis Pathway interactions Patients Peptides Peripheral Blood Mononuclear Cell Persons Phosphotransferases Play Population Predisposition Process Production Proteins Quinolinic Acid Quinolinic Acids Rate Receptor Inhibition Research Rest Role Signal Transduction Small Interfering RNA T-Cell Activation T-Cell Proliferation T-Lymphocyte TDO2 gene TNFRSF5 gene Testing Tryptophan Up-Regulation Viral Load result Virus Virus Diseases Work antigen processing base cell mediated immune response cell motility chemokine chlorambucil/dactinomycin/methotrexate protocol cofactor cohort cytokine drug of abuse enzyme pathway immune function in vitro Model in vivo indolamine inhibitor/antagonist macrophage methyl tryptophan monocyte novel prevent receptor research study tissue processing

项目摘要

DESCRIPTION (provided by applicant): This is a revised competing, continuation application for studies on the role of cocaine in the immunopathogenesis of HIV-1 infection that was first funded in 1999. In the present application, we propose to build on this earlier work and move forward. The current application focuses on novel, dendritic cell (DC) based immunotherapeutic strategies against susceptibility to and progression of HIV infections in drug using, HIV-1 infected populations. Blood monocyte derived DC are the first line of defense against HIV-1 infection and are the initial target of HIV-1 in injection drug users. They play a critical role in harboring HIV and possibly infecting T cells and/or modulating T cell immune responses. Cocaine is one of the most widely abused drugs in the U.S. and the last decade has witnessed a great, entangled epidemic of cocaine abuse and HIV-1 infections. Although previous studies, including our own, have shown that cocaine exerts significant immunomodulatory activities on lymphocyte subpopulations, the effects of drug abuse on dendritic cell activities that lead to disease progression in the drug-using population with or without HIV infection has not been examined. Consequently, the following hypothesis will be tested by the proposed experiments: cocaine is a cofactor in the pathogenesis of HIV infections by acting in synergy with certain HIV proteins on dendritic cell functions subsequently leading to dysregulation of the immune system of the infected host. Further, we propose that cocaine mediates these effects on DC through several mechanisms including: 1) down regulating the expression of various costimulatory molecules and proinflammatory cytokines/chemokines (that are necessary for DC maturation, effective antigen presentation, cell migration, and T cell proliferation), 2) upregulating indolamine 2,3 dioxygenase (IDO) that is known to suppress T cell immune functions, and 3) upregulating the DC-specific, CD4 independent virus attachment receptor, DC-SIGN and its homolog DC-SIGNR that is active on DC. Further, we shall determine the mechanism(s) of cocaine- mediated dysregulation of DC functions by examining signal transduction and use of siRNA and cocaine specific receptor inhibition studies. Our preliminary studies show that cocaine significantly downregulates costimulatory molecules with a reciprocal upregulation of DC-SIGN and IDO and these effects appears to be mediated via dysregulation of MAPKs. Data will be stratified on the basis of HIV disease status, CD4 counts, HIV viral load and cocaine use. These studies may lead to novel anti-HIV therapies such as targeting the CD4 independent, virus attachment receptor, DC-SIGN, or devising inhibitors of TDO and DC-SIGN or stimulating costimulatory molecules.

描述（由申请人提供）：这是一项修订后的竞争性延续申请，旨在研究可卡因在 HIV-1 感染的免疫发病机制中的作用，该申请于 1999 年首次资助。在本申请中，我们建议以这项早期工作为基础并继续前进。目前的申请重点是基于树突状细胞 (DC) 的新型免疫治疗策略，以对抗吸毒、HIV-1 感染人群中 HIV 感染的易感性和进展。血液单核细胞衍生的 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。它们在携带 HIV 并可能感染 T 细胞和/或调节 T 细胞免疫反应方面发挥着关键作用。可卡因是美国滥用最广泛的药物之一，过去十年见证了可卡因滥用和 HIV-1 感染的严重且相互交织的流行。尽管之前的研究（包括我们自己的研究）已表明可卡因对淋巴细胞亚群具有显着的免疫调节活性，但药物滥用对树突状细胞活性的影响尚未得到研究，而树突状细胞活性会导致感染或未感染艾滋病毒的吸毒人群疾病进展。因此，以下假设将通过拟议的实验进行检验：可卡因是 HIV 感染发病机制中的辅助因子，通过与树突状细胞功能上的某些 HIV 蛋白协同作用，随后导致受感染宿主的免疫系统失调。此外，我们提出可卡因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和促炎细胞因子/趋化因子的表达（对于 DC 成熟、有效抗原呈递、细胞迁移和 T 细胞增殖是必需的） )，2) 上调吲哚胺 2,3 双加氧酶 (IDO)，已知该酶可抑制 T 细胞免疫功能，以及 3) 上调 DC 特异性、CD4 独立的病毒附着受体 DC-SIGN及其在 DC 上活跃的同系物 DC-SIGNR。此外，我们将通过检查信号转导和使用 siRNA 以及可卡因特异性受体抑制研究来确定可卡因介导的 DC 功能失调的机制。我们的初步研究表明，可卡因显着下调共刺激分子，同时上调 DC-SIGN 和 IDO，这些效应似乎是通过 MAPK 失调介导的。数据将根据 HIV 疾病状况、CD4 计数、HIV 病毒载量和可卡因使用情况进行分层。这些研究可能会带来新的抗 HIV 疗法，例如靶向 CD4 独立的病毒附着受体 DC-SIGN，或设计 TDO 和 DC-SIGN 抑制剂或刺激共刺激分子。