De novo fatty acid biosynthesis and HIV replication

从头脂肪酸生物合成和 HIV 复制

• 批准号: 10190804
• 负责人: JESSE J KWIEK
• 金额: $ 19.1万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190804
• 关键词: Ablation; Acylation; Affect; Antiviral Agents; Breast; CCR5 gene; CD4 Positive T Lymphocytes; CRISPR screen; Carbon; Cell membrane; Cell physiology; Chemistry; Colorectal; Dependence; Development; Diet; Drug resistance; Environment; Enzymes; Fatty Acids; Fatty Liver; Fatty-acid synthase; Future; Generations; Goals; HIV; HIV Infections; HIV Seronegativity; HIV-1; Hepatitis C virus; Human; Infection; Interruption; Link; Lipids; Malignant Neoplasms; Mediating; Membrane; Metabolic Diseases; Metabolism; Morbidity - disease rate; Myristates; Palmitates; Pathway interactions; Pharmaceutical Preparations; Phosphatidylinositols; Phospholipids; Plasma; Post-Translational Protein Processing; Production; Protein Biosynthesis; Proteins; Reagent; Regulation; Research; Role; Small Interfering RNA; Testing; Therapeutic; Time; Viral; Viral Proteins; Virion; Virus; Virus Replication; West Nile virus; anticancer activity; cancer cell; cell type; experimental study; fatty acid biosynthesis; fatty acylation; inhibitor/antagonist; innovation; insight; lipid disorder; long chain fatty acid; mortality; myristoylation; novel; protein expression; protein transport; small molecule; targeted treatment; virus envelope

ABSTRACT HIV-1 commandeers host metabolism to create a cellular environment favorable to viral replication. We have recently discovered that mammalian fatty acid synthase (FASN) levels increase following HIV-1 infection, and that FASN activity is required for a late step of HIV replication that is subsequent to viral protein expression (e.g. protein trafficking, virion assembly, or virion release). The goal of our proposed research is to determine how FASN activity and resulting de novo fatty acid (FA) production affect a late stage of HIV-1 replication. The product of FASN, palmitate, is a long chain FA that has multiple cellular roles, and can also be trimmed into myristate or extended into other long chain FAs. Long chain FAs have many cellular functions, including roles in membrane structure, energy storage, and regulation of subcellular protein localization. This proposal focuses on two plausible FASN-mediated mechanisms that could interrupt a late stage in the HIV-1 replication cycle: production of lipids for post-translational modification of proteins (AIM 1), and generation of FA to reconfigure cellular lipid composition (AIM 2). If HIV-1 requires FASN activity to facilitate viral protein trafficking or virion assembly, we will have revealed a fundamental mechanism that could explain why many enveloped viruses require FASN activity to replicate.

摘要 HIV-1利用宿主的新陈代谢来创造一个有利于病毒复制的细胞环境。我们有 最近发现，哺乳动物脂肪酸合酶（FATIGATION）水平在HIV-1感染后增加， Festival活性是HIV复制的后期步骤所必需的，该后期步骤在病毒蛋白表达之后（例如， 蛋白质运输、病毒体组装或病毒体释放）。我们研究的目标是确定 脂肪酸活性和由此产生的从头脂肪酸（FA）产生影响HIV-1复制的晚期阶段。产品 脂肪酸棕榈酸酯是一种长链脂肪酸，具有多种细胞作用，也可以修剪成肉豆蔻酸酯或肉豆蔻酸酯。 延伸到其他长链脂肪酸。长链脂肪酸具有多种细胞功能，包括在细胞膜上的作用， 结构、能量储存和亚细胞蛋白定位调节。该提案着重于两个 可能中断HIV-1复制周期后期阶段的合理FASN介导机制： 脂质的翻译后修饰蛋白质（AIM 1），并产生FA重新配置细胞脂质 组合物（AIM 2）。如果HIV-1需要Festival活性来促进病毒蛋白运输或病毒粒子组装，我们 将揭示一种基本的机制，可以解释为什么许多包膜病毒需要FcR 活动复制。