Role of Cocaine in Neuro-AIDS by HIV 1B and C Clades

可卡因在 HIV 1B 和 C 分支引起的神经艾滋病中的作用

• 批准号: 7685336
• 负责人: MADHAVAN P. NAIR
• 金额: $ 33.78万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7685336
• 关键词: AIDS Dementia Complex; Abbreviations; Acquired Immunodeficiency Syndrome; Affect; Africa South of the Sahara; Age; American; Anti-Inflammatory Agents; Anti-inflammatory; Antiviral Agents; Asia; Astrocytes; Attenuated; Biological Models; Brain; CCL2 gene; Cells; Classification; Clinical; Cocaine; Cocaine Abuse; Cocaine Users; Cognitive; Complement; Contracts; Country; Crack Cocaine; Crime; Dementia; Dendritic Cells; Development; Dioxygenases; Disease Progression; Drug abuse; Drug usage; Enzymes; Epidemic; Europe; Experimental Models; Family; Figs - dietary; Future; Gene Expression; Genetic Variation; HIV; HIV Infections; HIV-1; Household; Human; Immune; Immune response; In Vitro; India; Infection; Inflammatory; Inositol; Institutes; Integration Host Factors; Interleukin-6; Investigation; MAPK14 gene; Macrophage Inflammatory Proteins; Mediating; Microglia; Military Personnel; Minor; Mitogen-Activated Protein Kinases; Mitogens; Neuraxis; Neurologic; Neurons; Neuropathogenesis; Neurotoxins; Nomads; Organ; Pathogenesis; Patients; Persons; Pharmaceutical Preparations; Phosphotransferases; Population; Preventive; Production; Property; Protein Kinase; Proteins; Quinolinic Acid; RANTES; Recombinants; Reporting; Risk; Risk Factors; Role; Signal Transduction; Signal Transduction Pathway; Small Interfering RNA; Surveys; T-Cell Activation; Therapeutic; Time; United States; Vaccines; Viral; Virus; Virus Diseases; Western World; chemokine; cocaine use; cytokine; design; drug of abuse; epidemiologic data; frontal lobe; gp-120 Antigen; indolamine; inhibitor/antagonist; macrophage; member; methyl tryptophan; mitogen-activated protein kinase p38; monocyte; motor disorder; neurotoxic; novel; novel strategies; pandemic disease; prevent; public health relevance; stress activated protein kinase; stress-activated protein kinase 1; therapeutic target

DESCRIPTION (provided by applicant): The predominant HIV-1 subtype found in US and Western World is clade B, which differs significantly from clade C that exists in sub-Saharan Africa and Asia. Estimates suggest that out of about 46 million people infected with HIV-1, more than 56 % of the infection is with clade C alone and HIV-1C infection is rapidly spreading to other parts of the world. AIDS is often accompanied by neuropathological abnormalities. Cocaine is one of the most widely abused drugs in the U.S. Current understandings of HIV-1 neuropathogenesis or the role of cocaine emanate from B clade from U.S. and Western countries and no information is available on the interactive role of cocaine on neuropathogenesis of C clade. We hypothesize that clade B and C exert differential effects on CNS cells leading to differential neuropathogenesis and cocaine exacerbates these effects and the mechanisms may be mediated by dysregulation of mitogen activated protein (MAP) kinases signal transduction pathways. Accordingly we will study (Aim #1a) for the first time the effects of in vitro infection with clade B and C virus in presence or absence of cocaine on production and gene expression of pro-inflammatory cytokines, (TNF1 &IL-6), chemokines (MCP-1& RANTES), and neurotoxin (IDO) by primary monocytes and CNS cells (astrocytes, neurons, microglial cells), and whether :(Aim #1b) the mechanism of differential dysregulation is mediated by modulation of mitogen activated protein (MAP) kinases signal transduction pathways. Further these in vitro infection studies will be compared, correlated and complemented with ex vivo studies (Aim #2) using monocytes from naive HIV-1B infected subjects who are using and non using cocaine being studied in Miami and cocaine using and non using HIV-1C infected subjects being studied at the collaborating institute in India. The results emanating from these studies may a) help to develop therapeutically useful drugs or agents which could attenuate or prevent the neuropathogenesis associated with clade specific HIV-1 infection and cocaine use and b) design novel strategies to develop preventive and therapeutic global vaccines that can induce cross-clade antiviral immune response against multiclade or recombinant pandemic HIV-1 infection that is currently facing the world including United States where non B subtypes have been recently reported in migrant populations and among our military personals. PUBLIC HEALTH RELEVANCE This application has significant relevance to the purpose of the PA-07-307.This project will study for the first time the interactive role of cocaine on production and gene expression of neuropathogenic molecules in HIV-1B and HIV-C infection by both in vitro and ex vivo model system. Identification of the mechanism of clade specific neuropathogenesis will help to design novel strategies to develop preventive and therapeutic global vaccines in drug using and non-using HIV infected subjects that can induce cross-clade antiviral immune response against multiclade or recombinant pandemic HIV-1 infection that is currently facing the world including United States.

描述（由申请人提供）：在美国和西方世界中发现的主要HIV-1亚型是Bade B，它与撒哈拉以南非洲和亚洲的进化枝C有很大不同。估计表明，在感染HIV-1的大约4600万人中，只有56％的感染是单独使用进化枝C，而HIV-1C感染迅速传播到世界其他地区。艾滋病通常伴有神经病理学异常。可卡因是美国当前对HIV-1神经病发生的理解或可卡因从美国和西方国家发出的可卡因作用的最广泛滥用的药物之一，没有关于可卡因在C型神经病发生的互动作用的信息。我们假设进化枝B和C对中枢神经系统细胞产生差异作用，从而导致差异神经病发生，可卡因加剧了这些作用，并且该机制可能是通过有丝分裂原活化蛋白（MAP）激酶信号转导途径的失调来介导的。 Accordingly we will study (Aim #1a) for the first time the effects of in vitro infection with clade B and C virus in presence or absence of cocaine on production and gene expression of pro-inflammatory cytokines, (TNF1 &IL-6), chemokines (MCP-1& RANTES), and neurotoxin (IDO) by primary monocytes and CNS cells (astrocytes, neurons,小胶质细胞）以及是否：（目标＃1B）差异失调的机理是通过调节有丝分裂原活化蛋白（MAP）激酶信号转导途径的调节介导的。此外，这些体外感染研究将被比较，相关并与过体研究（AIM＃2）进行比较，并使用来自幼稚的HIV-1B感染受试者的单核细胞使用，这些受试者使用和非可卡因在迈阿密和可卡因中使用的可卡因研究，并使用与印度协作研究所一起研究的HIV-1C感染受试者。 The results emanating from these studies may a) help to develop therapeutically useful drugs or agents which could attenuate or prevent the neuropathogenesis associated with clade specific HIV-1 infection and cocaine use and b) design novel strategies to develop preventive and therapeutic global vaccines that can induce cross-clade antiviral immune response against multiclade or recombinant pandemic HIV-1 infection that is currently facing the world including United States where最近在移民人口和我们的军人中有非B亚型。公共卫生相关性与PA-07-307的目的有关。该项目将首次研究可卡因对HIV-1B和HIV-C-C感染中神经病分子的生产和基因表达的交互作用，并通过体外和EX VIVO模型系统。鉴定进化枝特异性神经发生机制将有助于设计新型策略，以使用和非利用HIV感染的受试者在药物中开发预防和治疗性全球疫苗，这些受试者可以诱导针对多层或重组的Pandemic HIV-1感染的交叉抗病性免疫反应，目前正面临着包括世界在内的世界在内的抗病毒。