HIV-1 cap epigenetic modification

HIV-1帽表观遗传修饰

• 批准号: 10866730
• 负责人: Kathleen A. Boris-Lawrie
• 金额: $ 57.24万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10866730
• 关键词: 5' Untranslated Regions; Address; Affect; Antiviral Therapy; Attenuated; Binding; Cell Nucleus; Cell physiology; Cells; Cellular biology; Chemicals; Chronic; Clinic; Clinical; Closure by clamp; Comparative Study; Complex; Data; Development; Dimerization; Drug Design; Drug resistance; Elements; Epigenetic Process; Failure; Future; Generations; Genetic Transcription; Guanosine; HIV; HIV-1; Hypermethylation; Immune; Infection; Instruction; Introns; Investigation; Knowledge; Licensing; Macrophage; Messenger RNA; Methylation; Methyltransferase; Modeling; Modification; Molecular; Molecular Probes; Mutagenesis; Nuclear; Nuclear Export; Pathway interactions; Patients; Pharmaceutical Preparations; Process; Proliferating; Protein Biosynthesis; Proteins; Publishing; RNA; RNA Caps; RNA Splicing; RNA helicase A; RNA metabolism; RNA-Binding Proteins; RNA-Protein Interaction; Regulation; Reporting; Role; Structure; T-Lymphocyte; Transcript; Translations; Viral; Viral Load result; Virion; Virus; Virus Replication; Work; antiretroviral therapy; antiviral drug development; attenuation; immune activation; knock-down; messenger ribonucleoprotein; monocyte; novel; pathogenic virus; rev-Responsive Elements; small molecule; small molecule inhibitor; success; targeted treatment; viral RNA

Project summary HIV-1 is made of proteins and RNA. The instructions to make all HIV proteins in proper amounts are presented on mRNAs that are 5'-capped. The 5'-cap of HIV-1 mRNAs gains chemical modifications that bolster HIV proliferation significantly. Preliminary revealed that ABX464, a new generation of HIV drug that compromises replication of HIV clinical isolates without positive selection for drug resistance, abrogated the modified cap in HIV mRNAs. The proposed interdisciplinary investigation will characterize the molecular details regulating HIV-1 cap hypermethylation using ABX464 as a novel molecular probe. ABX464 does not directly interact with Rev nor interfere with Rev/RRE interaction, and has been proposed to inhibit Rev:CBC interaction. The hypothesis is that Rev and RNA helicase A recognize structural elements in the proviral RNA and together bind TGS1 for cap hypermethylation that licenses the mRNA to enter translation pathways to make HIV-1 proteins in the right amounts. To address the hypothesis, three aims are proposed that evaluate the role of cap hypermethylation in HIV proliferation and systemic chronic immune activation, and characterize the molecular interactions for cap epigenetic modification. Aim 1. What are the viral and host protein-interaction framework for 5'- cap epigenetic modification and the subsequent balanced HIV proviral RNA expression? Aim 2. Are the molecular interactions for cap epigenetic modification conserved in primary T cells, monocyte-derived macrophages, and does the cap epigenetic modification affect host chronic immune activation? Aim 3. What RNA structural elements and RNA:protein interaction are necessary for the HIV cap epigenetic modification? The comparative studies with ABX464 are expected to pave the way for the future development of novel antiviral therapies targeting previously underestimated pathways.

项目摘要 HIV-1由蛋白质和RNA组成。使所有艾滋病毒蛋白质适量的说明 被呈递在5 '-加帽的mRNA上。HIV-1 mRNA的5 '端获得化学修饰 这些修饰显著促进了艾滋病毒的增殖。初步显示，ABX 464，一个新的 产生HIV药物，其损害HIV临床分离株的复制， 药物抗性的选择，废除了HIV mRNA中的修饰帽。拟议 跨学科的研究将描述调节HIV-1帽的分子细节 使用ABX 464作为新的分子探针，ABX 464不直接相互作用 不干扰Rev/RRE相互作用，并已提议抑制Rev：CBC 互动假设Rev和RNA解旋酶A识别蛋白质中的结构元件。 前病毒RNA和一起结合TGS 1，使其帽超甲基化，从而允许mRNA进入 翻译途径来制造适量的HIV-1蛋白。为了解决这个假设， 提出了三个目标，评估帽超甲基化在HIV增殖中的作用， 系统性慢性免疫激活，并表征CAP的分子相互作用 表观遗传修饰目标1.病毒和宿主蛋白质相互作用的框架是什么？ 盖表观遗传修饰和随后平衡的HIV前病毒RNA表达？目标2. cap表观遗传修饰的分子相互作用是否在原代T细胞中保守， 单核细胞衍生的巨噬细胞，以及帽表观遗传修饰是否影响宿主慢性 免疫激活？目标3.什么是RNA结构元件和RNA：蛋白质相互作用 艾滋病病毒帽的表观遗传修饰所必需的？与ABX 464的比较研究如下： 预计将为未来开发新的抗病毒治疗方法铺平道路， 以前被低估的道路。