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

几万到几百万年来，病毒一直是灵长类动物环境的一部分，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。最著名的例子之一是灵长类动物对猴(或人类)免疫缺陷病毒(SIV/HIV)和类似艾滋病的疾病的易感性发生了变化。尽管灵长类物种之间的遗传相似性很高，但在大多数自然感染的非人类灵长类动物中，已知的导致人类艾滋病(SIV/HIV)的病毒通常是非致病性的。本研究假设灵长类动物先天免疫系统中存在导致易感性变化的关键变异。为了确定特定的先天免疫系统基因是否与灵长类动物的SIV/HIV致病有关，本研究将对18种灵长类动物中两种病毒识别途径(TLR7/ssRNA诱导的信号通路和rig-I/dsRNA诱导的信号通路)中的10个基因的蛋白质编码区进行测序。物种被选为具有不同程度的关联性和对SIV/HIV感染和艾滋病样疾病的易感性的分类群。目标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是通过寻找跨基因和物种的积极和消极选择的信号来测试适应的迹象。目标3是通过将可变氨基酸映射到翻译蛋白上的特定结合区域来测试这些适应的功能意义。这项研究将进一步了解灵长类免疫系统的进化，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。更广泛地说，该项目将作为一个模型，通过研究生物体--S先天免疫系统和病毒之间的相互作用来理解分子的协同适应，并可能对试图通过为药物开发提供潜在靶点来对抗人类艾滋病毒/艾滋病的生物医学研究有用。这个博士论文改进项目将作为联合研究员-S论文研究，并导致她接受最先进的分子、分析和生物信息学技术的培训。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。作为这项研究的一部分，产生的序列将被注释并提交给GenBank。

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.