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：
10082548
负责人：
JESSE J KWIEK
金额：
$ 23.02万
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 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10082548
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指挥官托管代谢，创建一个有利于病毒复制的细胞环境。我们有最近发现，HIV-1感染后哺乳动物脂肪酸合酶（FASN）水平升高，并且 FASN活性是在病毒蛋白表达之后的HIV复制的后期步骤所必需的（例如蛋白质运输，病毒体组件或释放病毒体）。我们拟议的研究的目的是确定 FASN活性和从头脂肪酸（FA）的产生影响HIV-1复制的后期。产品 Fasn，棕榈酸酯是一个长链FA，具有多个蜂窝角色，也可以将扩展到其他长链FAS。长链FA具有许多细胞功能，包括在膜中的作用亚细胞蛋白定位的结构，储能和调节。该提议重点是两个合理的FASN介导的机制，可以中断HIV-1复制周期中的后期：生产用于蛋白质后翻译后修饰的脂质（AIM 1）和FA生成以重新配置细胞脂质组成（目标2）。如果HIV-1需要FASN活性以促进病毒蛋白运输或病毒体组装，那么我们将揭示出一种基本机制，该机制可以解释为什么许多包围病毒需要FASN 复制活动。