Regulation of HIV-1 and related lentiviruses by the DNA damage response

DNA 损伤反应对 HIV-1 和相关慢病毒的调节

基本信息

批准号：
9204186
负责人：
Oliver I Fregoso
金额：
$ 16万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-02 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9204186
关键词：
AIDS/HIV problem Address Affect Antiviral Agents Biochemistry Biology CRISPR/Cas technology Cell Cycle Arrest Cells Characteristics Complex Conflict (Psychology)DNA DNA Damage DNA Repair Data Deoxyribonuclease I Developing Countries Environment Evolution Family Foundations Funding Gene Expression Genes Goals HIV HIV-1 Health Homeostasis Human Human Biology Immune response Infection Integration Host Factors Knowledge Light Molecular Molecular Biology Molecular Virology Nature Pathogenesis Pathway interactions Primate Lentiviruses Primates Proteins RNA Recording of previous events Recruitment Activity Regulation Research Research Project Grants Role Signaling Protein Structure Subfamily lentivirinae Testing Underserved Population Variant Viral Viral Proteins Virus Work cofactor fight against follow-up in vivo interdisciplinary approach novel pandemic disease pathogen research study response success ubiquitin ligase viral transmission virus host interaction vpr Gene Products vpr Genes

项目摘要

PROJECT SUMMARY/ABSTRACT HIV presents a major obstacle to human health, particularly in developing nations. The success of HIV is largely due to its ability to adapt to the human host environment and circumvent our innate immune responses. This is principally achieved through viral accessory proteins, which engage cellular proteins to both antagonize host antiviral factors and usurp host cellular machinery. The understanding of these interactions is critical to our fight against HIV. My proposal will determine how cellular proteins involved in the DNA damage response interact with HIV and related lentiviruses to modulate their lifecycle. I hypothesize that the DNA damage response is both anti-viral and pro-viral, as this protein-signaling cascade can sense aberrant DNA and RNA structures and can directly affect cellular homeostasis. HIV belongs to a family of viruses called lentiviruses that infect at least 40 primate species, including humans. Using the natural variation present in lentiviruses, I will determine how Vpr, a viral accessory protein that is common to all extant lentiviruses, has evolved to engage the host DNA damage response through both activation of DNA damage response pathways and direct interactions with DNA damage response proteins. I will specifically test the hypothesis that Vpr directly causes DNA damage in order to activate this cellular response. Furthermore, I will determine if engagement with the DNA damage response is a conserved, and therefore important, function for all lentiviruses, or if it is specific to HIV-1, and thus critical for adaptations and pathogenesis in humans. In addition, I will expand our knowledge of the role of the DNA damage response in lentiviral biology by identifying novel regulators of HIV-1 that are also involved in this cellular response. I will perform an evolution- guided screen to identify candidate DNA damage response proteins and pathways, and I will follow up these hits with specific experiments to elucidate their roles. These studies will identify the DNA damage response as important regulators of HIV-1 and related lentiviruses. They will shed light on lentiviral evolution, on the cellular response to infection, and on the multifaceted roles of the DNA damage response, while helping to identify potential antiviral targets in our fight against HIV.

项目概要/摘要艾滋病毒是人类健康的主要障碍，特别是在发展中国家。艾滋病毒的成功在于主要是由于它能够适应人类宿主环境并规避我们的先天免疫反应。这主要是通过病毒辅助蛋白来实现的，病毒辅助蛋白与细胞蛋白结合以拮抗宿主抗病毒因子并篡夺宿主细胞机器。了解这些相互作用对于我们与艾滋病毒的斗争。我的建议将确定细胞蛋白如何参与 DNA 损伤反应与 HIV 和相关慢病毒相互作用以调节其生命周期。我推测DNA损伤反应既是抗病毒的又是促病毒的，因为这种蛋白质信号级联可以感知异常的 DNA 和 RNA 结构并能直接影响细胞稳态。 HIV 属于慢病毒家族，可感染至少 40 种灵长类动物，包括人类。利用慢病毒中存在的自然变异，我将确定 Vpr（一种病毒辅助蛋白）如何这是所有现存慢病毒所共有的，已经进化到通过以下两种方式参与宿主 DNA 损伤反应： DNA 损伤反应途径的激活以及与 DNA 损伤反应蛋白的直接相互作用。我将专门测试 Vpr 直接导致 DNA 损伤的假设，以激活该细胞回复。此外，我将确定与 DNA 损伤反应的参与是否是保守的，并且因此对于所有慢病毒都很重要，或者如果它是针对 HIV-1 的，那么对于适应和适应至关重要人类的发病机制。此外，我将通过以下方式扩展我们对 DNA 损伤反应在慢病毒生物学中的作用的认识：鉴定出也参与这种细胞反应的 HIV-1 的新调节因子。我将进行一次进化—— 引导筛选以确定候选 DNA 损伤反应蛋白和途径，我将跟进这些通过具体的实验来阐明它们的作用。这些研究将确定 DNA 损伤反应为 HIV-1 和相关慢病毒的重要调节因子。他们将揭示慢病毒进化、细胞对感染的反应以及 DNA 损伤反应的多方面作用，同时帮助识别我们抗击艾滋病毒的潜在抗病毒目标。