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

• 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
• 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

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.

项目总结/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。艾滋病毒的成功是 这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，该蛋白与细胞蛋白结合， 宿主抗病毒因子和篡夺宿主细胞机制。理解这些相互作用对于 我们与艾滋病的斗争。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它们的生命周期。我假设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检测异常的DNA和RNA 结构，并可直接影响细胞内稳态。 HIV属于一个称为慢病毒的病毒家族，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，我将确定病毒辅助蛋白Vpr 所有现存的慢病毒都有，已经进化到通过两种途径参与宿主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 我将专门测试Vpr直接导致DNA损伤的假设，以激活这种细胞， 反应此外，我将确定参与DNA损伤反应是否是保守的， 因此重要的是，它对所有慢病毒都有功能，或者它对HIV-1有特异性，因此对适应和 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： 确定新的HIV-1调节因子，它们也参与了这种细胞反应。我要进行进化- 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 点击具体的实验来阐明他们的作用。这些研究将确定DNA损伤反应， HIV-1和相关慢病毒的重要调节因子。他们将阐明慢病毒的进化， 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 潜在的抗病毒靶点。