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: 8900552
• 负责人: JEROME E GROOPMAN
• 金额: $ 36.77万
• 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/8900552
• 关键词: 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; high risk; innovation; macrophage; 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（由适用提供）：甲基苯丙胺（甲基苯丙胺）是艾滋病毒流行病学的主要危险因素，促进行为，既可以增加病毒的接触并降低对治疗的依从性。但是，除了对行为的影响之外，甲基苯丙胺似乎增加了艾滋病毒的复制并加速艾滋病的进展。我们假设这种滥用药物可以通过禁用宿主细胞内防御的特定组成部分来成为HIV感染和传播的潜在促进者。该假设是基于我们最近的发现，即甲明显降低了反对HIV的细胞蛋白的表达，特别是RNA诱导的沉默复合物（RISC）成分，Argonaute-1（AGO1），介导miRNA处理和功能，P-boty构成P-body构成APOBEC3G。此外，甲基苯丙胺在调节宿主分子PCAF和PUR-A的CD4+ T细胞中降低了miRNA物种，并已知会限制HIV复制。据我们所知，以前没有关于甲基苯丙胺对限制HIV复制和传播的细胞内介质的影响的报道。我们将在下面概述的一系列目的中追求这种新的Meth Meth范式，以解除特定的细胞内防御和增强HIV。创新的特定点包括：（1）探索甲基对RISC组件AGO1的独特效果，反对艾滋病毒； （2）了解甲基苯丙胺如何调节miRNA和细胞HIV依赖性因素，重点是PCAF和PUR-A； （3）表征甲基对树突状细胞和巨噬细胞中肌动蛋白细胞骨架的作用，因此HIV将HIV贩运到外泌体中，而不是病毒降解，而不是在免疫突触时更容易传播到CD4+ T细胞。在我们新的初步数据的基础上，我们将在实验中追求以下特定目的：（1）表征分子机制，其中甲基甲基苯丙胺可以降低AGO-1的表达和功能，并与HIV-1保持在改变P体的结构完整性时与HIV-1坐标。 （2）进一步表征了通过甲基甲基苯丙胺调节不同调节的细胞miRNA物种的变化，以及这些变化如何增强HIV-1的复制。 （3）表征了甲基对树突状细胞中肌动蛋白细胞骨架和薄片的影响的影响，重点是将RISC和相关miRNA的运输以及HIV转移到外部途径上，而不是溶酶体降解。通过进一步产生这一新知识，我们希望为限制甲基苯丙胺用户的艾滋病毒感染的创新策略提供基础，这是艾滋病的重要危险因素。