Global Analysis of Cellular Networks Involved In Restriction of HIV Replication

参与限制 HIV 复制的细胞网络的全局分析

• 批准号: 8516987
• 负责人: SUMIT K CHANDA
• 金额: $ 8.65万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516987
• 关键词: Antiviral Response; Area; Biological Assay; Biological Models; Cell Cycle Kinetics; Cell Line; Cells; Complex; Computer Analysis; Data; Data Set; Development; Enzyme-Linked Immunosorbent Assay; Epitopes; Event; Foundations; Genes; HIV; HIV Infections; HIV-1; Human; Immune; Immune response; Immunologic Receptors; Infection; Interferons; Life; Mammalian Cell; Maps; Mass Spectrum Analysis; Measures; Mediating; Molecular; Myeloid Cells; Natural Immunity; Pathway Analysis; Pathway interactions; Pattern; Pattern recognition receptor; Precipitation; Process; Protein Analysis; Proteins; Proteome; Proteomics; RNA; RNA Interference; Renilla Luciferases; Reporter; Sampling; Signal Induction; Signal Transduction; Staging; System; Systems Biology; TLR7 gene; Time; Ubiquitination; Validation; Viral; Western Blotting; Work; base; cell type; experience; functional genomics; genetic analysis; genome-wide; insight; monocyte; nef Genes; network models; novel; novel therapeutics; novel vaccines; pathogen; protein protein interaction; response; vif Gene Products

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 underiies these host and viral responses has yet to be established. Towards this end, we propose to employ a systemsbased 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 eariy immune responses to HIV infection.

我们假设，介导对HIV感染的先天免疫应答的宿主-病原体界面由三个基本组成部分组成：（i）先天免疫受体的信号传导的识别和诱导，（ii）细胞抗病毒应答，和（iii）先天限制机制的病毒逃避。这些病毒-宿主回路的方面开始被发现，并且包括通过TLR 7模式识别受体对HIV RNA的先天免疫识别，通过干扰素诱导的HIV限制因子Apobec 3G和BST 2对HIV复制的限制，以及分别通过HIV编码的蛋白质Vif和Vpu对后两种分子的失活。然而，对这些宿主和病毒反应的分子回路的全面了解尚未建立。为此，我们建议采用以系统为本的 战略映射信号网络和宿主-病原体的相互作用，形成的基础上，先天 对HIV感染的免疫反应。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，并依赖于新的基于系统的研究，包括RNAi和蛋白质相互作用分析，以全面描绘这些先天和宿主-病原体网络。为此，我们组建了一个由两名在系统生物学领域具有丰富经验的合作PI组成的团队。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，Krogan博士在大规模蛋白质组学和网络分析领域拥有10多年的经验。这些研究有望为调节HIV感染早期免疫反应的细胞和病毒过程提供全面的分子见解。