Global innate immune responses to HIV-1 infection

针对 HIV-1 感染的全球先天免疫反应

• 批准号: 8309456
• 负责人: John A T Young
• 金额: $ 402.44万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8309456
• 关键词: Animals; Antiviral Agents; Antiviral Response; Area; Back; Biological Assay; Biological Models; Biology; Cell Culture System; Cell Line; Clinic; Clinical; Data; Data Set; Foundations; Genetic; Genetic Polymorphism; Genotype; HIV; HIV Infections; HIV-1; Human; Immune; Immune response; Immunologic Receptors; Individual; Infection; Interferons; Kinetics; Lymphoid Cell; Mammalian Cell; Maps; Mediating; Modeling; Molecular; Molecular Virology; Mucosal Immunity; Myeloid Cells; Office of Administrative Management; Outcome; Pathway Analysis; Pathway interactions; Pattern recognition receptor; Principal Investigator; Process; Property; Proteins; Proteomics; RNA; RNA Interference; Regulation; Relative (related person); Research; Role; SIV; Sampling; Screening procedure; Shapes; Signal Induction; Signal Pathway; Signal Transduction; System; Systems Biology; TLR7 gene; Technology; Testing; Validation; Viral; Virus; base; cell type; data management; design; experience; feeding; functional genomics; genetic analysis; insight; multidisciplinary; novel; pathogen; premature; programs; response; sensor; therapeutic vaccine; vif Gene Products

DESCRIPTION (provided by applicant): The focus of this proposal is to dissect the early innate immune response to HIV infection using a systems biology approach. The paradigm for these studies is that HIV infection elicits an immediate innate response involving antiviral factors that are either constitutively expressed or are induced by innate signaling pathways. The activities of some of these factors are in turn blocked by HIV countermeasures including the actions of viral accessory proteins. The ensuing battle between the host innate response and these viral countermeasures is crucial for determining whether the virus establishes a foothold, inducing replication and eliciting subsequent adaptive immune responses. Therefore, a comprehensive systems-level understanding of these immediate virus-host responses is critical for devising strategies to interfere with the initial establishment of HIV infection. This proposal describes a multidisciplinary and highly integrated approach that is designed to obtain this critically important information. The foundation for the proposal is a unique dataset that we have obtained by combining cutting-edge experimental and computational technologies to obtain a systems-level view of the immediate innate response to HIV-1 infection. The team assembled in the program consists of thirteen research groups arranged into six scientific projects and a scientific core. The program will exploit systems-based approaches to understand the complete repertoire of cellular sensors and effectors involved in the innate signaling pathways that respond to HIV-1 infection (Project 1); the rate-limiting components, pathway modules, and emergent properties of these viral-host circuits (Project 6); the kinetic regulation of different steps of HIV-1 infection by these circuits (Project 3); the role of these circuits in regulating primary myeloid and lymphoid cell activities that are relevant during HIV-1 infection (Projects 2 and 4); and the relationship between these circuits and the clinical outcome of infection (Project 5). These projects are supported by the Administrative and Data Management Core (Core A) and the Molecular Virology and Systems Biology Screening Core (Core B). Identifying novel genetic and proteomic networks involved in innate responses to HIV infection, combined with iterative modeling and testing of the relative roles of these networks and their molecular components in shaping innate immune responses will likely identify unique features of the HlV-specific response, revealing ways to develop successful therapeutic and vaccine strategies for HIV infections. PROJECT 1: Global Analysis of Cellular Networks Involved In Restriction of HIV Replication (CHANDA, S) PROJECT 1 DESCRIPTION (provided by applicant): We hypothesize that the host-pathogen interface that mediate the innate immune response to HIV infection is comprised of three fundamental components: (i) recognition and induction of signaling by innate immune receptors, (ii) cellular antiviral responses, and (iii) viral evasion of innate restriction mechanisms. Aspects of these viral-host circuits are beginning to be uncovered, and include innate immune recognition of HIV RNA by the TLR7 pattern recognition receptor, restriction of HIV replication by interferon inducible HIV restriction factors Apobec3G and BST2, and inactivation of the latter two molecules by the HIV-encoded proteins Vif and Vpu, respectively. However, comprehensive insight towards the molecular circuitries that underlies these host and viral responses has yet to be established. Towards this end, we propose to employ a systems based strategy to map signaling networks and host-pathogen interactions that form the basis of innate immune responses to HIV infection. This approach will leverage existing functional genomics and proteomics datasets, and also will rely on novel systems-based studies, including RNAi and protein interaction analysis, to comprehensively delineate these innate and host-pathogen networks. For this purpose, we have assembled a team of two co-PIs with significant experience in the field of systems biology. Dr. Chanda has over 10 years experience in functional genomics and genetic analysis in mammalian cells, and Dr. Krogan brings over 10 years of experience in the areas of large-scale proteomic and network analysis. These studies are expected to provide global molecular insight into cellular and viral processes that regulate early immune responses to HIV infection.

描述（由申请人提供）：该提案的重点是使用系统生物学方法剖析对艾滋病毒感染的早期先天免疫反应。这些研究的范例是，艾滋病毒感染引起了涉及抗病毒因子的直接先天反应，这些反应要么由构成性表达或由先天信号通路诱导。其中一些因素的活动又被HIV对策所阻止，包括病毒辅助蛋白的作用。随之而来的宿主先天反应与这些病毒对策之间的战斗对于确定病毒是否建立立足点，引起复制并引起随后的适应性免疫反应至关重要。因此，对这些即时病毒宿主反应的全面系统级别的理解对于制定策略来干扰最初的艾滋病毒感染至关重要。该提案描述了一种多学科和高度综合的方法，旨在获取这一至关重要的信息。该提案的基础是我们通过结合尖端实验和计算技术来获得的独特数据集，以获得对HIV-1感染的天生反应的系统级别的视图。该计划组装的团队由13个研究小组组成，这些研究小组安排为六个科学项目和一个科学核心。该计划将利用基于系统的方法来了解对HIV-1感染响应的先天信号通路涉及的细胞传感器和效应子的完整曲目（项目1）；这些病毒宿主电路的限制组件，途径模块和新兴特性（项目6）；这些电路对HIV-1感染的不同步骤的动力学调节（项目3）；这些电路在调节HIV-1感染过程中相关的原发性髓样和淋巴样活性中的作用（项目2和4）；这些电路与感染的临床结果之间的关系（项目5）。这些项目得到了行政和数据管理核心（核心A）以及分子病毒和系统生物学筛查核心（Core B）的支持。确定与艾滋病毒感染的先天反应有关的新型遗传和蛋白质组学网络，再加上这些网络及其在塑造先天免疫反应中的相对作用及其分子成分的相对作用的迭代建模和测试可能会确定HLV特异性反应的独特特征，并揭示成功的治疗方法和疫苗策略的方法。 项目1：涉及HIV复制限制的蜂窝网络的全球分析 （Chanda，S） 项目1描述（由申请人提供）：我们假设介导对艾滋病毒感染的先天免疫反应的宿主 - 病原体界面包括三个基本组成部分：（i）识别和识别先天免疫受体的信号传导，（ii）细胞抗病毒反应，以及（iii）对现有限制机制的病毒抗病毒反应。这些病毒宿主电路的各个方面开始被发现，并包括通过TLR7模式识别受体对HIV RNA的先天免疫识别，通过干扰素可限制HIV HIV限制因子Apobec3G和BST2对HIV复制的限制，以及后两种Molecules通过HIV-niv-proted proteed vicue vefuf和vpeee vefuf和Vpue vefus and nive vif和Vpue vefif和v。但是，尚未建立对这些宿主和病毒反应基础的分子电路的全面见解。为此，我们建议采用基于系统的策略来绘制信号网络和宿主 - 病原体相互作用，构成了对HIV感染的先天免疫反应的基础。这种方法将利用现有的功能基因组学和蛋白质组学数据集，还将依靠基于新型的基于系统的研究，包括RNAi和蛋白质相互作用分析，以全面地描述这些先天和宿主 - 疾病的网络。为此，我们组建了一个在系统生物学领域具有丰富经验的两个共同训练的团队。 Chanda博士在哺乳动物细胞的功能基因组学和遗传分析方面拥有10多年的经验，而Krogan博士在大型蛋白质组学和网络分析领域具有10多年的经验。这些研究有望提供对调节早期免疫反应对HIV感染的早期免疫反应的细胞和病毒过程的全球分子见解。