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

• 批准号: 7495036
• 负责人: MADHAVAN P. NAIR
• 金额: $ 40.3万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 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/7495036
• 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

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）：美国目前正经历一场严重的流行病，甲基苯丙胺（冰毒）作为一种娱乐性药物，截至2005年7月，冰毒的使用已超过可卡因作为街头或俱乐部药物。最近的研究还表明，甲氧苯使用者中艾滋病毒-1感染的流行率很高。血液单核细胞来源的树突状细胞（DC）是HIV-1感染的第一道防线，也是HIV-1在注射吸毒者中的最初靶点。虽然有证据表明甲基苯丙胺使用者存在免疫功能障碍，但甲基苯丙胺使用者中HIV-1感染的免疫发病机制的分子基础尚未阐明。此外，还没有研究过甲基苯丙胺滥用对导致甲基苯丙胺使用人群中HIV-1疾病进展的DC活性的影响。本申请集中于针对使用甲硫氨酸的人群中HIV-1感染的易感性和进展的新型基于DC的免疫学和/或转化研究策略。因此，将通过所提出的实验来检验以下假设：甲氧苯甲醚是HIV-1感染发病机制中的辅因子，其通过与某些HIV-1蛋白协同作用于DC功能，随后导致受感染宿主的免疫系统失调。进一步，我们提出，Meths通过以下几种机制介导对DC的这些作用：1）下调各种共刺激分子、趋化因子的表达（这是DC成熟、有效抗原呈递、细胞迁移和T细胞增殖所必需的），以及HIV-1进入辅助受体的相互上调。在一些实施方案中，本发明的方法包括：1）上调已知促进HIV-1感染的CCR 5和CXCR 4; 2）上调抑制T细胞免疫功能的吲哚胺2，3双加氧酶（IDO）;和3）上调DC上存在的DC特异性、CD 4非依赖性病毒附着受体DC-SIGN。此外，我们将通过检查信号转导途径和使用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，甲基苯丙胺显著下调共刺激分子和HIV-1抑制性β-趋化因子的表达，同时相互上调HIV-1共受体DC-SIGN和IDO，这些作用似乎是通过丝裂原活化蛋白（MAP）激酶的失调介导的。将根据HIV-1疾病状态、CD 4计数、HIV-1病毒载量和甲基苯丙胺使用情况对所得数据进行分层。这些研究可能会导致新的抗HIV-1治疗或转化研究策略，如靶向CD 4非依赖性病毒附着受体DCSIGN，或设计IDO，DC-SIGN，CCR 5/CXCR 4和特异性多巴胺受体的抑制剂，或刺激高危使用和未使用甲基苯丙胺的HIV-1感染受试者中共刺激因子和β-趋化因子分子的表达。