Global Analysis of Cellular Networks Involved In Restriction of HIV Replication

我们假设，介导HIV感染的先天性免疫反应的宿主-病原体界面由三个基本组成部分组成：(I)天然免疫受体对信号的识别和诱导，(Ii)细胞抗病毒反应，以及(Iii)病毒逃避先天性限制机制。这些病毒-宿主回路的一些方面已经开始被发现，包括TLR7模式识别受体对HIV RNA的天然免疫识别，干扰素诱导的HIV限制因子APOBEC3G和BST2对HIV复制的限制，以及后两个分子分别被HIV编码蛋白Vif和VPu灭活。然而，对这些宿主和病毒反应背后的分子电路的全面洞察尚未建立。为此，我们建议采用一种基于 绘制信号网络和宿主-病原体相互作用的策略，形成先天的基础 对艾滋病毒感染的免疫反应。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，并将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，以全面描述这些先天和宿主-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基因分析方面拥有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对艾滋病毒感染的早期免疫反应的细胞和病毒过程提供全球分子洞察。

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.