A systems biology approach to fingerprint HIV immune defense in Elite Controllers

一种在精英控制器中识别 HIV 免疫防御的系统生物学方法

• 批准号: 9204504
• 负责人: Xu Yu
• 金额: $ 85.99万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204504
• 关键词: Algorithms; Allogeneic Bone Marrow Transplantation; Area; Bioinformatics; Biological; Biological Assay; CCR5 gene; CD8B1 gene; Cells; Characteristics; Clinical; Complex; Data; Data Set; Defense Mechanisms; Development; Disease; Disease remission; Effector Cell; Elements; Fingerprint; Gene Expression Profile; Gene Proteins; Genes; Genetic Polymorphism; Genetic Variation; Genomics; Goals; HIV; HIV-1; Hematopoietic stem cells; Immune; Immune response; Immune system; Immunology; Immunology procedure; Individual; Infection; Integration Host Factors; Intervention; Investigation; Knowledge; Lead; Life; Link; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Profiling; Nature; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Persons; Pharmaceutical Preparations; Phenotype; Proteomics; Reporting; Research; Resources; Serum; Sorting - Cell Movement; Stem cell transplant; Study models; System; Systems Biology; T-Lymphocyte; Techniques; Therapeutic; Therapeutic Intervention; Time; Translating; Validation; Virus; Voice; Work; abstracting; adaptive immunity; base; genome-wide; high throughput analysis; high throughput technology; immune function; in vivo; innovation; insight; interest; novel; novel strategies; pathogen; patient population; programs; protein expression; proteomic signature; response; single cell analysis; successful intervention; virology

Abstract While a sterilizing cure of HIV-1 infection has only been reported in a single patient after a stem cell transplant with CCR532 homozygous cells, a spontaneous functional cure of HIV-1 occurs in 0.3-0.5% of all infected persons. These individuals, termed elite controllers (EC), maintain undetectable levels of HIV-1 replication in the absence of treatment, despite the repeated isolation of replication-competent virus from their serum. In this way, these individuals provide living evidence that immune-mediated control of HIV-1 infection is possible, and the identification of effective immune defense mechanisms that are active in these patients holds promise for inducing a functional cure of HIV-1 infection in a broader HIV-1 patient population. Previously, the analysis of such mechanisms has mostly focused on studying individual components of the immune system in an isolated fashion, however, it is now increasingly clear that effective immune defense programs in these patients are likely to involve complex networks of innate and adaptive immune responses and that integrative, iterative analysis steps will be required to mechanistically understand synergistic networks of immune defense in EC. Yet, such integrated programs of immune control can hardly be detected using traditional reductionist approaches that are biased towards specific pre-defined molecules or investigate one specific aspect of immune defense in an isolated fashion. Here, we will employ a multi-step research strategy to identify comprehensive, multi-system programs of immune defense in EC and explore their underlying functional mechanisms. In specific aim 1, we will use novel, high throughput technologies such as genome-wide SNP analysis and multiplexed mRNA, miRNA and protein expression analysis in sorted leukocellular subsets to identify specific genomic, transcriptional and proteomic characteristics uniquely associated with an elite controller phenotype. These assays will be performed in combination with multidimensional immunologic assays to identify functional signatures of innate and adaptive immune responses that are selectively observed in elite controllers (specific aim 2). Subsequently, a number of different biocomputational algorithms will be used to detect connectivity between various aspects of immune defense mechanisms, and identify holistic, integrative and unifying programs that link gene/protein expression, immune responses and clinical development of EC phenotype; these pathways will then be studied in detail using cutting-edge single-cell analysis approaches to identify and characterize the molecular circuits most suitable and promising for therapeutic manipulation (specific aim 3). By comprehensively exploring HIV-1 immune responses in EC in relationship to genetic variation and mRNA/miRNA/protein expression profiles and using this data to develop integrative models of HIV-1 immune defense, the proposed studies will generate unprecedented insights into effective mechanisms of HIV-1 immune control, and may lead to novel clinical strategies to induce a functional cure of HIV-1 in a broader patient population.

摘要 虽然只有一名患者在干细胞移植后获得了无菌治愈HIV-1感染的报道 在CCR5HIV32纯合子细胞中，-1的自发功能治愈比例为0.3-0.5% 人。这些人被称为精英管制员(EC)，他们保持着无法检测到的艾滋病毒1复制水平 缺乏治疗，尽管从他们的血清中反复分离出具有复制能力的病毒。在这 通过这种方式，这些人提供了活生生的证据，表明通过免疫媒介控制艾滋病毒-1感染是可能的，并且 在这些患者中有效的免疫防御机制的识别有望为 在更广泛的HIV-1患者群体中诱导HIV-1感染的功能性治愈。在此之前，对 这种机制主要集中在研究孤立的免疫系统的个别组成部分 然而，现在越来越清楚的是，这些患者的有效免疫防御计划是 可能涉及先天和获得性免疫反应的复杂网络，以及整合的、迭代的 将需要分析步骤来机械地理解EC中免疫防御的协同网络。 然而，使用传统的简化论者很难检测到这种集成的免疫控制程序 偏向于特定的预定义分子或研究特定方面的方法 以隔离方式进行免疫防御。在这里，我们将采用多步骤研究策略来确定 全面的、多系统的EC免疫防御方案及其潜在的功能 机制。在具体目标1中，我们将使用新的、高通量的技术，如全基因组SNP 分析和多重分析分类后的白血病细胞亚群中的mRNA、miRNA和蛋白质表达 确定与精英唯一相关的特定基因组、转录和蛋白质组特征 控制者表型。这些检测将与多维免疫学结合进行。 识别选择性观察的先天和获得性免疫反应的功能特征的分析 精英控制器(特定目标2)。随后，一些不同的生物计算算法将被 用于检测免疫防御机制各个方面之间的连通性，并识别整体、 整合和统一的程序，将基因/蛋白表达、免疫反应和临床联系起来 EC表型的发展；然后将使用尖端的单细胞详细研究这些途径 识别和表征最适合和最有希望的分子电路的分析方法 治疗手法(特定目标3)。通过全面探索EC中的HIV-1免疫应答 与遗传变异和mRNA/miRNA/蛋白质表达谱的关系，并利用这些数据开发 HIV-1免疫防御的综合模型，拟议的研究将产生前所未有的洞察力 HIV-1免疫控制的有效机制，并可能导致新的临床策略，以诱导功能性 在更广泛的患者群体中治愈艾滋病毒-1。