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

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传输方式。虽然艾滋病毒感染是25-44岁美国人的主要死亡原因， 现在，注射吸毒约占美国每年新增艾滋病病例的三分之一。可卡因，经常 被HIV感染者滥用，已被认为通过未知的方式加重HIV相关痴呆(HAD) 机械装置。大脑是娱乐毒品和HIV-1病毒的靶器官。HAD是一个重要的并发症 这是病毒感染的主要原因，也是导致严重发病率和死亡率的原因。HAD的基本特征围绕着 两个过程：a)病毒在脑内巨噬细胞中的高效复制，导致脑炎；b) 由受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 痴呆症。可卡因静脉注射吸毒者有较高的艾滋病毒脑炎、小胶质细胞增殖和临床艾滋病毒的发生率。 痴呆症。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。我们的预赛 研究表明，可卡因促进了病毒和促进病毒的细胞因子IL-10的产生 单核细胞来源的巨噬细胞(MDM)。可卡因还与病毒糖蛋白GP！20协同作用，诱导 神经毒素CXCL10在人神经细胞培养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 病毒在大脑中的复制，以及2)可卡因和GP！20协同诱导CXCL10加速神经元 功能障碍/死亡。在本申请中，我们将在3个特定目标中检验假设：1)检查IL-10在 可卡因介导的SIV/HIV-1在猕猴/人MDM培养中的复制上调，2)确定 可卡因和病毒蛋白诱导的CXCL10对神经元功能障碍/死亡的作用机制(S)3)活体内 反义CXCL10 DNA治疗消除可卡因和GP！20诱导的小鼠神经细胞凋亡 HTV-痴呆症的症状。 相关性：本提案旨在：a)探讨可卡因在加速肾综合征出血热痴呆和 B)制定治疗可卡因戒除者HAD的治疗干预策略

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