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

• 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
• 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

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.

人类基因组已经进化出一系列可能针对HIV的抗病毒基因。然而， 这些抗病毒蛋白的有效性在进化方面动态波动；病毒的进化 触发主体零部件的演变，反之亦然。例如，艾滋病毒已经适应了在人类细胞中的生长， 部分原因是它已经适应了逃避人类抗病毒抑制的能力。在这个项目中，进化签名 过去慢病毒与其灵长类宿主的相互作用将被用来指导功能和结构研究 艾滋病病毒与宿主蛋白的相互作用。 特别是，这个项目利用了宿主-病毒界面的遗传创新，其特征是 反复的达尔文选择，或正向选择。我们使用这种基因创新的进化签名 派生出更有效地抑制艾滋病毒和更不容易受到对抗的“超级限制因子” 病毒蛋白。通过测试具有随机氨基酸变化的寄主限制因子文库 正向选择，可以衍生出具有新性质的宿主蛋白。最后，运用肯定的判断标准 选择时，将创建一个全基因组目录，用于对候选宿主蛋白进行优先排序 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，用于进一步的生化研究 通过提供一种评估这些交互作用是否已被 参与了过去与病原体的进化冲突。