De novo fatty acid biosynthesis and HIV replication

从头脂肪酸生物合成和 HIV 复制

基本信息

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
项目类别：
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

项目摘要

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.

抽象的 HIV-1 强行控制宿主新陈代谢，创造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 (FASN) 水平在 HIV-1 感染后增加，并且 FASN 活性是 HIV 复制的后期步骤（病毒蛋白表达之后的步骤）所必需的（例如，蛋白质运输、病毒体组装或病毒体释放）。我们提出的研究的目标是确定如何 FASN 活性和由此产生的脂肪酸 (FA) 从头产生影响 HIV-1 复制的后期。产品 FASN（棕榈酸酯）是一种长链 FA，具有多种细胞作用，也可以修剪成肉豆蔻酸酯或扩展到其他长链 FA。长链 FA 具有许多细胞功能，包括在膜中的作用结构、能量储存和亚细胞蛋白质定位的调节。该提案主要关注两点可能中断 HIV-1 复制周期后期阶段的 FASN 介导机制：生产用于蛋白质翻译后修饰的脂质 (AIM 1)，以及生成 FA 来重新配置细胞脂质组成（目标 2）。如果 HIV-1 需要 FASN 活性来促进病毒蛋白运输或病毒粒子组装，我们将揭示一个基本机制，可以解释为什么许多包膜病毒需要 FASN 要复制的活动。