HIV-Encephalitis and Cocaine Abuse: Mechanism of Synergy and Therapy

HIV脑炎和可卡因滥用：协同作用和治疗机制

• 批准号: 7470999
• 负责人: Shilpa J. Buch
• 金额: $ 2.3万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470999
• 关键词: AIDS Dementia Complex; Accounting; Acquired Immunodeficiency Syndrome; Acute; American; Animals; Antisense DNA; Apoptosis; Binding; Brain; CXCL10 gene; CXCR4 gene; Case Study; Cause of Death; Cells; Cessation of life; Clinical; Cocaine; Cocaine Abuse; Complication; Corpus striatum structure; DNA; DNA delivery; Dementia; Development; Disease Progression; Drug usage; Encephalitis; External Capsule; Glycoproteins; Gray unit of radiation dose; HIV; HIV Infections; HIV encephalitis; HIV-1; Health; Human; In Vitro; Individual; Infection; Infiltration; Injection of therapeutic agent; Interleukin-10; Intervention; Lead; Ligands; Link; Lung diseases; Macaca; Macaca mulatta; Mediating; Microglia; Modeling; Morbidity - disease rate; Mus; Needle Sharing; Nerve Degeneration; Neuronal Dysfunction; Neurons; Neurotoxins; Nodule; Opportunistic Infections; Organ; Pathogenesis; Patients; Phase; Process; Production; Rate; Recreational Drugs; Reporter Genes; Research Personnel; Role; Schistosoma mansoni; Smoking; System; Technology; Testing; Therapeutic Intervention; Transcriptional Activation; Up-Regulation; Vesicular stomatitis Indiana virus; Viral; Viral Proteins; Virus; Virus Diseases; Virus Replication; base; chemokine; concept; cytokine; egg; fetal; gene therapy; in vivo; innovation; intravenous drug use; intravenous injection; latent infection; macrophage; methyl(arginyl)-lysyl-prolyl-tryptophyl-tert-leucyl-leucine; monocyte; mortality; neuron apoptosis; novel; programs; release of sequestered calcium ion into cytoplasm; response; sigma receptors; transmission process

Intravenous drug use and HIV infections are two linked global health crises since needle sharing is a well recognized mode of HTV transmission. While HIV infection is the leading cause of death among Americans 25- 44 yearsold, injection drug use now accounts for about one-third of all new US AIDS cases reported each year. Cocaine, often abused by HIV-infected patients, has been suggested to worsen the HIV-associated dementia (HAD) via unknown mechanisms. The brain is a target organ for both, the recreational drugs and HIV-1. HAD is an important complication of viral infection and a cause of significant morbidity, and mortality. The underlyingfeature of HAD revolves around two processes: a) productive replication of the virus in macrophages in the brain, leading to encephalitis, and b) neuronal degeneration resulting from the action of secreted byproducts released from infected macrophages, leading to dementia. Cocaine IVDUs are known to have higher rates of HIV-encephalitis, microglial proliferation and clinical HIV dementia. The use of cocaine therefore exacerbates factors that promote HIV replication in the brain. Our preliminary studies demonstrated that cocaine enhanced production of both, the virus and of the virus-promoting cytokine, IL-10 in monocyte-derived macrophages (MDMs). Cocaine also synergized with viral glycoprotein, gp!20, to induce the expression of the neurotoxin, CXCL10 in human neuronal cultures. Based on these findings, we hypothesize that cocaine accelerates the progression of HIV-E by two mechanisms: 1) Cocaine-mediated induction of IL-10 enhances virus-replication in the brain, and 2) synergistic induction of CXCL10 by cocaine & gp!20 accelerates neuronal dysfunction/death. In this application we will test the hypotheses in 3 specific aims: 1) Examine the role of IL-10 in cocaine-mediated up-regulation of SHIV/HIV-1 replication in macaque/human MDM cultures, 2) To determine the mechanism(s) of cocaine & virus protein induced-CXCLlO on neuronal dysfunction/death in vitro. 3) In vivo abrogation of cocaine and gp!20-mediated neuronal apoptosis using antisense CXCL10 DNA therapy in murine models of HTV-dementia. Relevance: This proposal aims to: a) Explore the role of cocaine in accelerating the development of HFVDementia and b) Develop therapeutic intervention strategies for the treament of HAD in cocaine-absuers

静脉吸毒和艾滋病毒感染是两个相互关联的全球健康危机，因为共用针头是公认的 HTV传播模式。虽然艾滋病毒感染是25- 44岁美国人死亡的主要原因， 注射毒品现在占美国每年报告的艾滋病新病例的三分之一。科摩，往往 被艾滋病毒感染者滥用，已被建议通过未知的途径恶化艾滋病毒相关性痴呆（HAD） 机制等大脑是娱乐性毒品和HIV-1的靶器官。HAD是一种重要的并发症 病毒感染和显著发病率和死亡率的原因。民政事务总署的基本特色是 两个过程：a）病毒在脑中的巨噬细胞中的生产性复制，导致脑炎，和B） 由感染的巨噬细胞释放的分泌副产物的作用引起的神经元变性，导致 痴呆众所周知，Coplanar IVDU有更高的艾滋病毒脑炎，小胶质细胞增殖和临床艾滋病毒感染率。 痴呆因此，可卡因的使用加剧了促进艾滋病毒在大脑中复制的因素。我们的初步 研究表明，可卡因可以增强病毒和病毒促进细胞因子IL-10的产生， 单核细胞衍生的巨噬细胞（MDM）。辅酶Ⅱ还协同病毒糖蛋白，gp！第20章，我的天！ 神经毒素CXCL 10在人神经元培养物中的表达。基于这些发现，我们假设， 可卡因通过两种机制加速HIV-E的进展：1）可卡因介导的IL-10诱导增强 病毒复制在大脑中，和2）协同诱导CXCL 10的可卡因和糖蛋白！20个神经元加速 功能障碍/死亡。在本申请中，我们将在3个具体目标中测试假设：1）检查IL-10在 可卡因介导的猕猴/人MDM培养物中SHIV/HIV-1复制的上调，2）为了确定 可卡因和病毒蛋白诱导的CXCL 10对体外神经元功能障碍/死亡的机制。3)体内 废除可卡因和gp！20-使用反义CXCL 10 DNA治疗在小鼠模型中介导的神经元凋亡 艾滋病痴呆症 相关性：本提案旨在：a）探讨可卡因在加速HFV痴呆症发展方面的作用， B）制定治疗可卡因滥用者HAD的治疗干预策略