Characterization of Super Restriction Factors and Prediction of Host-HIV Interfaces

超级限制因子的表征和宿主-HIV 界面的预测

基本信息

批准号：
10229575
负责人：
Michael Emerman
金额：
$ 48.92万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-27 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10229575
关键词：
Affinity Amino Acids Antiviral Agents Binding Biochemical Biological Biology Catalogs Cell Line Cells Complement Complex Conflict (Psychology)Cytidine Deaminase Data Dimerization Engineering Evolution Genes Genetic Genetic Recombination Genetic Screening Genome HIV Human Human Genome In Vitro Integration Host Factors Lentivirus Libraries Mammals Mutation Nature Primates Property Proteins Proteomics Race Recurrence Research Personnel Resistance Reverse Transcriptase Polymerase Chain Reaction Sampling Site Structure Testing Therapeutic Intervention Time Ursidae Family Variant Viral Viral Proteins Virus anti-viral efficacy arm base enhancing factor fitness gene replacement genome database genome-wide in vivo innovation interest mutant new therapeutic target novel pathogen protein complex protein protein interaction vif Gene Products whole genome

项目摘要

The human genome has evolved a constellation of antiviral genes with the potential to target HIV. However, the efficacy of these antiviral proteins fluctuates dynamically in evolutionary terms; evolution of the viruses triggers evolution of host components and vice-versa. For instance, HIV has adapted to grow in human cells, in part, because it has adapted to escape human antiviral inhibition. In this project, the evolutionary signatures of past interactions of lentiviruses with their primate hosts will be used to guide functional and structural studies of HIV-host protein interactions. In particular, this project exploits genetic innovation at the host-virus interface, characterized by signatures of recurrent Darwinian selection, or positive selection. We use evolutionary signatures of such genetic innovation to derive “super restriction factors” that are more potent at inhibiting HIV and less susceptible to antagonism by viral proteins. By testing libraries of host restriction factors with random amino acid changes at the sites of positive selection, host proteins with novel properties can be derived. Finally, using the criterion of positive selection, a whole genome catalog will be created that will be used to prioritize candidate host proteins identified as part of genome-wide genetic screens or protein-protein interaction studies for further biochemical studies in other Projects in this application by providing a means of assessing if these interactions have been involved in past evolutionary conflicts with pathogens.

人类基因组进化了一个抗病毒基因的星座，具有靶向HIV的潜力。然而，这些抗病毒蛋白的效率以进化术语动态波动。病毒的进化触发主机组件的演变，反之亦然。例如，艾滋病毒已适应人类细胞中的生长，在某种程度上，因为它适应了逃避人类抗病毒抑制作用。在这个项目中，进化签名慢病毒与灵长类动物宿主的过去相互作用将用于指导功能和结构研究 HIV宿主蛋白相互作用的。特别是，该项目利用了主机病毒界面的遗传创新，其特征是复发性达尔文人选择或肯定选择。我们使用这种遗传创新的进化签名得出“超级限制因素”，这些因素在抑制艾滋病毒方面具有更大潜力，并且不太容易受到对抗的影响病毒蛋白。通过测试宿主限制因子的库，并在阳性选择，具有新型特性的宿主蛋白。最后，使用正面标准选择，将创建整个基因组目录，用于优先考虑候选宿主蛋白被确定为全基因组遗传筛选或蛋白质 - 蛋白质相互作用研究的一部分，以进一步生化通过提供评估这些互动是否已经进行的方法，在本应用程序中的其他项目中的研究涉及过去与病原体的进化冲突。