An antiviral role for poly(ADP-ribosyl)ation

聚（ADP-核糖基）化的抗病毒作用

• 批准号: 7407068
• 负责人: Julie Ann Bletz
• 金额: $ 3万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7407068
• 关键词: ADP ribosylation; Acquired Immunodeficiency Syndrome; Address; Amino Acids; Antiviral Agents; Biochemical; Biological Assay; Biology; Candidate Disease Gene; Cells; Complex; Conflict (Psychology); Depth; Development; Endogenous Retroviruses; Evolution; Family member; Gene Family; Gene Proteins; Genes; Genetic; Genome; Genomics; Goals; HIV; HIV Infections; HIV Long Terminal Repeat; Host Defense; Human; Human Genome; Immune system; Immunity; Infection; Life Cycle Stages; Light; Luc Gene; Luciferases; Macaca mulatta; Mammalian Genetics; Measures; Methods; Modeling; Murine leukemia virus; Mutate; Mutation; Nature; Numbers; Orthologous Gene; Pan Genus; Pathway interactions; Primates; Protein Isoforms; Protein Region; Proteins; Public Health; Recording of previous events; Reporter; Research; Retroviridae; Rodent; Role; Scanning; Staging; Surveys; Tertiary Protein Structure; Testing; Therapeutic; Viral; Viral Genes; Virus; Virus Diseases; Virus Replication; Work; Zinc Fingers; base; design; driving force; in vivo; mammalian genome; novel; pathogen; prevent; promoter; tool

DESCRIPTION (provided by applicant): Recent work has demonstrated that viruses have a complex and antagonistic relationship with host cells. Viruses have evolved proteins to exploit host proteins and cellular pathways to guarantee successful infection. In turn, host cells have evolved restriction factors to directly inhibit viral replication. As a result of this ancient and on-going conflict, the host and viral genes at the center of the conflict are evolving under positive selection. By studying the evolutionary history of host genes, we can identify new host antiviral genes and uncover the nature of their interaction with viruses. I have used evolutionary approaches to demonstrate that the gene, Zinc-finger Antiviral Protein, or ZAP, is evolving under positive selection in primates, suggesting it has a role in primate host defense. Further, my work implicates the PARP domain of ZAP as being at the interface of the conflict between ZAP and the virus. My proposal focuses on using functional assays to determine if human ZAP has antiviral activity and more specifically to address the role of the PARP domain in viral restriction. I will test primate ZAP isoforms with and without the PARP domain in cells challenged by MLV or HIV infection. I will also generate a version of human ZAP with a catalytically dead PARP domain to determine whether poly(ADP)ribosylation activity is necessary for restrictive capabilities. These studies will help to elucidate the mechanism by which ZAP restricts viruses and provide a model for poly(ADP)ribosylation in host defense. There are 16 other PARP containing genes and given the role of ZAP in host defense, I have performed a cursory survey of other PARP genes to identify other antiviral candidates. Indeed, 5 of these genes show signatures of positive selection and the other goal of my research plan is to perform a thorough evolutionary analysis of these genes in order to better understand the selective forces driving their evolution. RELEVANCE TO PUBLIC HEALTH Using the power of evolutionary methods and functional assays to explore the host-virus conflict will reveal how viruses successfully infect cells and how host cells are able to prevent viral infection. The results of this work will shed light on efforts to design antiviral therapeutics in the treatment of AIDS and other viral diseases.

描述（由申请人提供）：最近的工作表明，病毒与宿主细胞具有复杂且对抗的关系。病毒已经进化出蛋白质来利用宿主蛋白质和细胞途径来保证成功感染。反过来，宿主细胞进化出限制因子来直接抑制病毒复制。由于这场古老而持续的冲突，处于冲突中心的宿主和病毒基因正在积极选择下不断进化。通过研究宿主基因的进化史，我们可以识别新的宿主抗病毒基因并揭示它们与病毒相互作用的本质。我使用进化方法证明了锌指抗病毒蛋白（ZAP）基因在灵长类动物的正选择下进化，这表明它在灵长类宿主防御中发挥作用。此外，我的工作表明 ZAP 的 PARP 域处于 ZAP 和病毒之间冲突的界面。我的建议重点是使用功能测定来确定人类 ZAP 是否具有抗病毒活性，更具体地说是解决 PARP 结构域在病毒限制中的作用。我将在受到 MLV 或 HIV 感染的细胞中测试带有和不带有 PARP 结构域的灵长类 ZAP 亚型。我还将生成具有催化死亡 PARP 结构域的人类 ZAP 版本，以确定聚 (ADP) 核糖基化活性是否是限制性能力所必需的。这些研究将有助于阐明 ZAP 限制病毒的机制，并为宿主防御中的聚 (ADP) 核糖基化提供模型。还有其他 16 个含有 PARP 的基因，考虑到 ZAP 在宿主防御中的作用，我对其他 PARP 基因进行了粗略的调查，以确定其他抗病毒候选药物。事实上，其中 5 个基因显示出正选择的特征，我的研究计划的另一个目标是对这些基因进行彻底的进化分析，以便更好地了解驱动其进化的选择力。与公共卫生的相关性利用进化方法和功能分析的力量来探索宿主与病毒的冲突，将揭示病毒如何成功感染细胞以及宿主细胞如何能够预防病毒感染。这项工作的结果将有助于设计治疗艾滋病和其他病毒性疾病的抗病毒疗法。