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而拮抗的关系。病毒已进化出蛋白质来利用宿主蛋白和细胞途径以保证成功感染。反过来，宿主细胞具有进化的限制因子，以直接抑制病毒复制。由于这种古老而持续的冲突，冲突中心的寄主和病毒基因正在积极选择下发展。通过研究宿主基因的进化史，我们可以鉴定出新的宿主抗病毒药基因并揭示其与病毒相互作用的性质。我已经使用了进化方法来证明基因，锌指抗病毒蛋白或ZAP在灵长类动物的阳性选择下正在发展，这表明它在灵长类动物的宿主防御中起作用。此外，我的工作意味着ZAP的PARP领域处于ZAP与病毒之间冲突的界面。我的建议着重于使用功能测定来确定人ZAP是否具有抗病毒活性，并且更具体地解决了PARP域在病毒限制中的作用。我将测试有或没有MLV或HIV感染挑战的细胞中具有PARP结构域的灵长类动物ZAP同工型。我还将生成具有催化死亡PARP结构域的人类ZAP版本，以确定poly（ADP）核糖基化活性是否对于限制性功能是必需的。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）核糖化提供模型。还有16个包含基因的PARP，并鉴于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，以识别其他抗病毒药候选。的确，这些基因中的5个显示出肯定选择的特征，而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，以便更好地了解推动其进化的选择性力量。使用进化方法和功能测定的力量探索宿主病毒冲突的功能将揭示病毒如何成功感染细胞以及宿主细胞如何预防病毒感染。这项工作的结果将阐明在治疗艾滋病和其他病毒疾病时设计抗病毒治疗剂的努力。