Genome wide association analysis of Innate response factors

人类免疫缺陷病毒（HIV）感染宿主细胞启动先天免疫信号通路，导致I型干扰素和促炎细胞因子的表达，干扰病毒的生命周期。这种病毒可以采取措施，不仅使其能够逃避细胞内的检测，而且还可以利用免疫信号通路的成分为自己谋取利益。对HIV逃避抗病毒先天免疫应答机制的研究，为表征可影响宿主信号通路组分的遗传多态性提供了科学动力。我们将进行一项队列研究，以确定通过全基因组功能筛选鉴定出的宿主蛋白是否与HIV/AIDS易感性有关，这些蛋白的生物学作用机制是否合理。我们将研究遗传变异（已知的和以前未知的）与HIV/AIDS易感性之间的关系，使用生物样本和从参加多中心艾滋病队列研究（MACS）的男性中获得的信息。这将使我们能够进行足够样本量的详细研究，以令人信服地区分功能相关因素的拟议影响与无影响。我们的目标是采取一种“整体”方法，系统地检查病毒和抗病毒先天免疫反应如何相交，以发现参与信号通路的遗传变异模式和基因表达差异如何可能导致艾滋病毒疾病。我们的方法的基本原理是，所描述的每一个与宿主相关的因素只与一小部分继续抵抗艾滋病毒/艾滋病的人有关。因此，确定HIV如何破坏先天免疫反应对于系统级理解先天免疫反应和合理设计改进的治疗方法非常重要。我们的具体目标是：区分最有可能影响HIV感染先天免疫反应的系统识别基因网络功能的多态性；并研究候选先天免疫反应基因的遗传多态性与HIV/AIDS易感性之间的关系。通过与其他项目的合作，我们将收集全面的定量数据集，以获得抗病毒先天免疫反应的系统级理解。

Human immunodeficiency virus (HIV) infection of host cells initiates innate immune signaling pathways that result in the expression of type I interferons and pro¿inflammatory cytokines that interfere with the life cycle of the virus. The virus can bring about measures that not only allow it to escape detection within the cell, but also to use the components of the immune signaling pathways for its own advantage. Studies of mechanisms by which HIV evades the antiviral innate immune responses provide the scientific impetus to characterize the genetic polymorphisms that can affect components of the host signaling pathways. We will conduct a cohort study to determine whether the host proteins identified by genome¿wide functional screens for which a plausible biological mechanism of action for the gene is found contributes to HIV/AIDS susceptibility. We will look at the association between genetic variants (both known and previously unknown) and HIV/AIDS susceptibility using biological samples and information obtained from men enrolled in the Multicenter AIDS Cohort Study (MACS). This will allow us to undertake detailed studies of sufficient sample size to distinguish the proposed effect of a factor of functional relevance from no effect convincingly. Our objective is to undertake a "holistic" approach to the systematic examination of how the virus and antiviral innate immune responses intersect to discover how the patterns of genetic variation and differences in gene expression of the factors that are involved in signaling pathways may contribute to HIV disease. The rationale for our approach is that each of the described host¿related factors are relevant to only a small proportion of people who continue to resist HIV/AIDS. Defining how HIV subverts the innate immune response is thus important for systems¿level understanding of the innate immune response and rational design of improved therapies. Our specific aims are to: distinguish polymorphisms most likely to affect function ofthe systematically identified network of genes underlying the innate immune response to HIV infection; and examine the association between genetic polymorphism in the candidate innate immune response genes and HIV/AIDS susceptibility. Through collaboration with the other Projects, we will collect a comprehensive quantitative data set to attain systems¿level understanding of antiviral innate immune responses.