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: 7195029
• 负责人: Shilpa J. Buch
• 金额: $ 28.55万
• 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/7195029
• 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 Envelope Protein gp120; 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; Smoke; 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

DESCRIPTION (provided by applicant): 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 years old, 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 underlying feature 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, gp120, 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 & gp120 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-CXCL10 on neuronal dysfunction/death in vitro. 3) In vivo abrogation of cocaine and gp120-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 HFV Dementia and b) Develop therapeutic intervention strategies for the treatment of HAD in cocaine-abusers.

描述（由申请人提供）：静脉吸毒和HIV感染是两个联系的全球健康危机，因为针头共享是HTV传播的一种公认的模式。虽然艾滋病毒感染是25-44岁的美国人的主要死亡原因，但注射药物的使用现在约占所有新美国艾滋病案件的三分之一。可卡因经常被HIV感染的患者滥用，有人建议通过未知机制使与HIV相关的痴呆（HAT）恶化。大脑是娱乐性药物和HIV-1的目标器官。曾是病毒感染的重要并发症，是发病率明显和死亡率的原因。围绕两个过程的基本特征：a）大脑中巨噬细胞中病毒的生产效率复制，导致脑炎，b）神经元变性是由受感染巨噬细胞释放的分泌副产物的作用引起的，导致痴呆症。已知可卡因IVDU具有更高的HIV-脑炎，小胶质细胞增殖和临床HIV痴呆症的速率。因此，可卡因的使用加剧了促进大脑中HIV复制的因素。我们的初步研究表明，可卡因增强了单核细胞衍生的巨噬细胞（MDMS）中的病毒和促进病毒细胞因子的产生，IL-10。可卡因还与病毒糖蛋白GP120协同，以诱导神经毒素，CXCL10在人类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了HIV-E的进展：1）可卡因介导的IL-10诱导IL-10诱导增强了大脑中的病毒复制，而2）可可症和GP120 Accelates accelates accelates accelates accelates accelrates neuronal neuronal diest/diest retyruttion/deatt。在此应用中，我们将在3个特定目的中测试假设：1）检查IL-10在可卡因介导的猕猴/人类MDM培养物中SHIV/HIV-1复制的上调，2）确定可卡因和病毒蛋白诱导的CXCL10对神经元死亡/死亡人性造成的毒素的机制。 3）在HTV-诱导的鼠模型中，使用反义CXCL10 DNA治疗可卡因和GP120介导的神经元凋亡的体内消除。相关性：该提案的目的是：a）探索可卡因在加速HFV痴呆症和b）制定治疗性干预策略来治疗可卡因 - 诱捕者中的作用。