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

说明（由申请人提供）：静脉注射吸毒和艾滋病毒感染是两个相互关联的全球卫生危机，因为共用针头是公认的艾滋病毒传播方式。虽然艾滋病毒感染是25- 44岁美国人死亡的主要原因，但注射吸毒现在占美国每年报告的新艾滋病病例的三分之一左右。经常被艾滋病毒感染患者滥用的可卡因已被认为通过未知的机制使艾滋病毒相关痴呆（HAD）恶化。大脑是消遣性毒品和HIV-1的目标器官。HAD是病毒感染的一种重要并发症，也是引起显著发病率和死亡率的原因。HAD的潜在特征围绕两个过程展开：a)大脑巨噬细胞中病毒的多产复制，导致脑炎；b)受感染巨噬细胞释放的分泌副产物的作用导致神经元变性，导致痴呆。已知可卡因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痴呆率。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，可卡因增强了单核细胞源性巨噬细胞（MDMs）中病毒和促病毒细胞因子IL-10的产生。可卡因还与病毒糖蛋白gp120协同作用，诱导神经毒素CXCL10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诱导增强了病毒在大脑中的复制，2)可卡因和gp120协同诱导CXCL10加速了神经元功能障碍/死亡。在本研究中，我们将从三个方面验证这些假设：1)检验IL-10在可卡因介导的猴/人MDM培养物中上调SHIV/HIV-1复制中的作用；2)确定可卡因和病毒蛋白诱导的cxcl10在体外神经元功能障碍/死亡中的作用机制。3)在小鼠htv -痴呆模型中，使用反义CXCL10 DNA治疗，在体内消除可卡因和gp120介导的神经元凋亡。相关性：本提案旨在：a)探索可卡因在加速HFV痴呆发展中的作用；b)制定治疗可卡因滥用者HAD的治疗干预策略。

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.