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.

项目总结 HIV-1病毒由蛋白质和RNA组成。使所有HIV蛋白质达到适量的说明 呈现在5‘-帽的mRNAs上。HIV-1mRNAs的5‘-帽获得化学作用 显著促进艾滋病毒扩散的修改。初步显示，ABX464是一种新的 HIV药物的产生危及HIV临床分离株的复制而不呈阳性 对耐药性的选择，取消了HIV mRNAs中修改后的帽。建议数 跨学科研究将确定调控HIV-1帽的分子细节 以ABX464为新型分子探针的超甲基化ABX464不直接交互 与REV也不干扰REV/RRE相互作用，并已被提出抑制REV：CBC 互动。假设REV和RNA解旋酶A识别细胞中的结构元素 前病毒RNA和共同结合TGS1以进行帽超甲基化，从而允许mRNA进入 翻译途径，以制造适量的HIV-1蛋白质。为了解决这一假设， 提出了三个目标，以评估CAP超甲基化在HIV增殖和 全身慢性免疫激活，并表征CAP的分子相互作用 表观遗传修饰。目的1.病毒和宿主蛋白相互作用的框架是什么？ CAP表观遗传修饰和随后的HIV前病毒RNA平衡表达？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， 单核细胞来源的巨噬细胞，以及帽的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结构元素和RNA：蛋白质相互作用 有必要对HIV帽进行表观遗传修饰吗？与ABX464的比较研究如下 有望为未来靶向抗病毒新疗法的发展铺平道路 之前低估了路径。