Novel Mechanisms of Disarming Anti-HIV Host Defenses by Methamphetamine

甲基苯丙胺解除抗艾滋病毒宿主防御的新机制

• 批准号: 9113553
• 负责人: JEROME E GROOPMAN
• 金额: $ 34.6万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9113553
• 关键词: APOCEC3G gene; Acquired Immunodeficiency Syndrome; Actins; Adherence; Behavior; CD4 Positive T Lymphocytes; Cells; Cytoskeleton; Data; Dendritic Cells; Dependency; Down-Regulation; Drug user; Endosomes; Epidemiology; Exposure to; Foundations; Goals; HIV; HIV Infections; HIV-1; Host Defense; Immune; Immunosuppressive Agents; Infection; Knowledge; Lysosomes; Mediating; Mediator of activation protein; Messenger RNA; Methamphetamine; MicroRNAs; Molecular; PCAF gene; Pathway interactions; Population; Process; Proteins; RNA-Induced Silencing Complex; Reporting; Research; Risk Factors; Series; Synapses; Viral Genes; Virus; base; drug of abuse; exosome; high risk; innovation; macrophage; methamphetamine effect; methamphetamine user; monocyte; novel; prevent; public health relevance; trafficking; transmission process

 DESCRIPTION (provided by applicant): Methamphetamine (Meth) is a major risk factor in the epidemiology of HIV, promoting behavior that both increases exposure to virus and reduces adherence to treatment. But beyond such effects on behavior, Meth appears to augment HIV replication and accelerate progression to AIDS. We hypothesize that this drug of abuse can act as a potent facilitator of HIV infection and transmission by disabling specific components of host intracellular defense. This hypothesis is based on our recent findings that Meth markedly decreased expression of cellular proteins that oppose HIV, specifically the RNA-induced silencing complex (RISC) component, Argonaute-1 (AGO1), which mediates miRNA processing and function, and the P-body constituent, APOBEC3G. In addition, Meth reduced miRNA species in CD4+ T-cells that regulate host molecules PCAF and Pur-a, and are known to restrict HIV replication. To our knowledge, there are no previous reports of these effects of Meth on intracellular mediators that limit HIV replication and transmission. We will pursue this new paradigm of Meth disarming specific intracellular defenses and enhancing HIV in a series of aims outlined below. Specific points of innovation include: (1) exploring unique effects of Meth on the RISC component AGO1 which opposes HIV; (2) understanding how Meth can regulate miRNAs, and cellular HIV dependency factors, focusing on PCAF and Pur-a; (3) characterizing effects of Meth on the actin cytoskeleton in dendritic cells and macrophages, so that instead of virus degradation in lysosomes, HIV is trafficked to exosomes and more readily transmitted at the immune synapse to CD4+ T-cells. Building on our novel preliminary data, we will pursue experimentally the following specific aims: (1) Characterize the molecular mechanisms whereby Meth can reduce AGO-1 expression and function, and cooperate with HIV-1 in altering the structural integrity of P-bodies. (2) Further characterize changes in cellular miRNA species that are differentially modulated by Meth, and how these changes augment HIV-1 replication. (3) Characterize effects of Meth on the actin cytoskeleton and lamellipoda formation in dendritic cells, focusing on trafficking of the RISC and associated miRNA to P-bodies, and shunting of HIV to an exosome pathway rather than to lysosomal degradation. By further generating this new knowledge, we hope to provide the foundation for innovative strategies to limit HIV infection in users of Meth, a prominent risk factor for AIDS.

 描述（由申请人提供）：甲基苯丙胺（Methe）是HIV流行病学中的一个主要风险因素，促进既增加病毒暴露又降低治疗依从性的行为。但除了对行为的这种影响外，冰毒似乎还增加了艾滋病毒的复制，加速了艾滋病的发展。 我们推测，这种药物的滥用可以作为一个强有力的艾滋病毒感染和传播的促进剂，通过禁用特定的组件主机细胞内的防御。这一假设是基于我们最近的发现，即甲基显着降低细胞蛋白的表达，对抗艾滋病毒，特别是RNA诱导的沉默复合物（RISC）的组成部分，Argonaute-1（AGO 1），介导的miRNA加工和功能，和P-体成分，APOBEC 3G。此外，Meth减少了调节宿主分子PCAF和Pur-a的CD 4 + T细胞中的miRNA种类，并且已知其限制HIV复制。据我们所知，没有以前的报告，这些影响的甲基对细胞内介质，限制艾滋病毒的复制和传播。我们将在下面概述的一系列目标中追求这种新的甲基解除特定细胞内防御和增强HIV的范例。 具体的创新点包括：（1）探索Meth对对抗HIV的RISC组分AGO 1的独特作用;（2）了解Meth如何调节miRNA和细胞HIV依赖因子，重点是PCAF和Pur-a;（3）表征甲硫氨酸对树突细胞和巨噬细胞中肌动蛋白细胞骨架的作用，从而代替溶酶体中的病毒降解，HIV被运输到外泌体，并且更容易在免疫突触处传播到CD 4 + T细胞。 基于我们新的初步数据，我们将在实验上追求以下具体目标：（1）表征Meth可以降低AGO-1表达和功能的分子机制，并与HIV-1合作改变P体的结构完整性。(2)进一步表征细胞miRNA种类的变化，差异调节甲基，以及这些变化如何增加HIV-1复制。(3)表征甲氧苯甲醚对树突状细胞中肌动蛋白细胞骨架和板状伪足形成的影响，重点关注RISC和相关miRNA向P体的运输，以及HIV向外泌体途径而不是溶酶体降解的分流。 通过进一步产生这种新的知识，我们希望为创新战略提供基础，以限制艾滋病的一个突出的危险因素-甲基苯丙胺使用者的艾滋病毒感染。