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（由申请人提供）：甲基苯丙胺（Meth）是艾滋病毒流行病学中的一个主要危险因素，它会促进增加接触病毒和坚持治疗的行为，但除了对行为的影响之外，甲基苯丙胺似乎还会增强艾滋病毒的复制和我们。我们认为，这种滥用药物可以通过禁用宿主细胞内防御的特定成分来充当艾滋病毒感染和传播的有效促进剂。这一假设是基于我们最近的发现，即甲基苯丙胺显着加速了艾滋病毒的减少。对抗 HIV 的细胞蛋白的表达，特别是介导 miRNA 加工和功能的 RNA 诱导沉默复合物 (RISC) 成分 Argonaute-1 (AGO1) 以及 P 体成分 APOBEC3G 此外，冰毒还减少了 miRNA 种类。在 CD4+ T 细胞中，调节宿主分子 PCAF 和 Pur-a，并已知其限制 HIV 复制，之前没有关于 Meth 对限制 HIV 复制和细胞内介质的影响的报道。我们将追求这种新的冰毒模式，以解除特定的细胞内防御并增强艾滋病毒的一系列目标，具体创新点包括：（1）探索冰毒对抵抗艾滋病毒的 RISC 成分 AGO1 的独特作用； Meth 如何调节 miRNA 和细胞 HIV 依赖性因子，重点关注 PCAF 和 Pur-a (3) 表征 Meth 对树突状细胞和巨噬细胞中肌动蛋白细胞骨架的影响，从而根据溶酶体中病毒降解的过程，HIV 被运输到外泌体，并且更容易在免疫突触处传播到 CD4+ T 细胞。基于我们新的初步数据，我们将通过实验实现以下具体目标：（1）表征 Meth 的分子机制。可以降低 AGO-1 的表达和功能，并与 HIV-1 合作改变 P 体的结构完整性 (2) 进一步表征受 Meth 差异调节的细胞 miRNA 种类的变化，以及这些变化的方式。 (3) 表征 Meth 对树突状细胞中肌动蛋白细胞骨架和片状足形成的影响，重点关注 RISC 和相关 miRNA 向 P 体的运输，以及通过进一步生成这种物质将 HIV 分流至外泌体途径而不是溶酶体降解。我们希望为限制冰毒使用者感染艾滋病毒的创新策略奠定基础，冰毒是艾滋病的一个突出危险因素。