Doctoral Dissertation Improvement: Primate Innate Immune Defense and Adaptation to SIV/HIV Infection

博士论文改进：灵长类动物先天免疫防御和对SIV/HIV感染的适应

• 批准号: 0648457
• 负责人: Todd Disotell
• 金额: $ 0.9万
• 依托单位: New York University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0648457&HistoricalAwards=false
• 关键词: Doctoral; Dissertation; Improvement; Primate; Innate

Viruses have been part of the primate environment for tens of thousands to millions of years and differences in primate susceptibility to viral infection and disease suggests that some species are better adapted to co-exist with certain viruses.? One of the best-known examples of this is variation in primate susceptibility to simian (or human) immunodeficiency viruses (SIV/HIV) and AIDS-like diseases.? Despite a high level of genetic similarity among primate species, the same viruses that have been known to cause AIDS in humans (SIV/HIV) are generally non-pathogenic in most naturally infected non-human primates.? This research hypothesizes that there is key variation in the primate innate immune system that leads to the observed variation in susceptibility.In order to determine if specific innate immune system genes contribute to SIV/HIV pathogenicity in primates, the protein-coding regions of ten genes involved in one of two viral recognition pathways (TLR7/ssRNA induced signaling pathway and RIG-I/dsRNA induced signaling pathway) will be sequenced in 18 primate species.? Species were chosen to represent taxa with varying degrees of relatedness and susceptibility to SIV/HIV infection and AIDS-like diseases.There are three main objectives to this research.? Objective 1 is to test for signs of adaptation by comparing immune system gene trees to species phylogenies.? Objective 2 is to test for signs of adaptation by looking for signatures of positive and negative selection across loci and species. Objective 3 is to test the functional significance of these adaptations by mapping variable amino acids to particular binding domains on the translated protein.This research will further our understanding of the evolution of the primate immune system and determine if variation in theses genes contribute to variation in a primate species? ability to co-exist with SIV infection.? More generally, the project will serve as a model for understanding molecular co-adaptation by examining interactions between an organism?s innate immune system and viruses and may be useful for biomedical research attempting to combat HIV/AIDS in humans by providing potential targets for drug development.?This doctoral dissertation improvement project will serve as the co-investigator?s thesis research and result in her being trained in state-of-the-art molecular, analytical, and bioinformatics techniques. This research will be published as a dissertation and in scholarly papers, as well as presented at academic conferences.? Sequences generated as part of this research will be annotated and submitted to GenBank.

病毒已经在灵长类动物环境中存在了数万至数百万年，灵长类动物对病毒感染和疾病的易感性差异表明，一些物种更适合与某些病毒共存。这方面最著名的例子之一是灵长类动物对类人猿（或人类）免疫缺陷病毒（SIV/HIV）和艾滋病样疾病的易感性的变化。尽管灵长类物种之间具有高度的遗传相似性，但已知在人类中引起艾滋病的相同病毒（SIV/HIV）在大多数自然感染的非人类灵长类动物中通常是非致病性的。本研究假设灵长类先天免疫系统中存在导致观察到的易感性变化的关键变异。为了确定特异性先天免疫系统基因是否与灵长类动物的SIV/HIV致病性有关，将对18种灵长类动物中涉及两种病毒识别途径（TLR7/ssRNA诱导的信号通路和RIG-I/dsRNA诱导的信号通路）之一的10个基因的蛋白质编码区进行测序。选择的物种代表具有不同程度的亲缘关系和对SIV/HIV感染和艾滋病样疾病的易感性的分类群。这项研究有三个主要目的。目的1是通过比较免疫系统基因树和物种系统发育来测试适应的迹象。目标2是通过寻找基因座和物种之间的正选择和负选择的特征来测试适应的迹象。目的3是通过将可变氨基酸定位到翻译蛋白上的特定结合域来测试这些适应性的功能意义。这项研究将进一步加深我们对灵长类免疫系统进化的理解，并确定这些基因的变异是否会导致灵长类物种的变异。与SIV感染共存的能力。更一般地说，该项目将作为一个模型，通过检查生物之间的相互作用来理解分子的共同适应。通过提供药物开发的潜在靶标，可能对试图对抗人类艾滋病毒/艾滋病的生物医学研究有用。本次博士论文改进项目将作为共同研究者？她的论文研究和结果是在最先进的分子，分析和生物信息学技术方面接受培训。这项研究将以论文和学术论文的形式发表，并在学术会议上发表。作为本研究的一部分产生的序列将被注释并提交给GenBank。