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

描述（由申请人提供）：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，因为共用针头是艾滋病毒传播的一种公认模式。虽然艾滋病毒感染是25- 44岁美国人死亡的主要原因，但注射毒品现在占美国每年报告的所有新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机制使HIV相关性痴呆（HAD）恶化。大脑是娱乐性毒品和HIV-1的靶器官。HAD是病毒感染的一种重要并发症，也是显著发病率和死亡率的原因。HAD的潜在特征围绕两个过程：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。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痴呆症的发病率。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，可卡因增强生产的病毒和病毒促进细胞因子，白细胞介素-10单核细胞衍生的巨噬细胞（MDM）。辅酶Ⅱ还与病毒糖蛋白gp 120协同作用，诱导神经毒素CXCL 10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HIV-E的进展：1）可卡因介导的IL-10诱导增强大脑中的病毒复制，以及2）可卡因和gp 120协同诱导CXCL 10加速神经元功能障碍/死亡。在本申请中，我们将在3个具体目标中检验假设：1）检查IL-10在猕猴/人MDM培养物中可卡因介导的SHIV/HIV-1复制上调中的作用，2）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)在HTV痴呆小鼠模型中使用反义CXCL 10 DNA治疗体内消除可卡因和gp 120介导的神经元凋亡。相关性：该提案旨在：a）探索可卡因在加速HFV痴呆症发展中的作用，和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.