HIV 感染的定量遗传互作图谱
A Quantitative Genetic Interaction Map of HIV Infection.
机构信息
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA; Gladstone Institutes, San Francisco, CA 94158, USA.
School of Biomolecular and Biomedical Science and Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland; Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
出版信息
Mol Cell. 2020 Apr 16;78(2):197-209.e7. doi: 10.1016/j.molcel.2020.02.004. Epub 2020 Feb 20.
We have developed a platform for quantitative genetic interaction mapping using viral infectivity as a functional readout and constructed a viral host-dependency epistasis map (vE-MAP) of 356 human genes linked to HIV function, comprising >63,000 pairwise genetic perturbations. The vE-MAP provides an expansive view of the genetic dependencies underlying HIV infection and can be used to identify drug targets and study viral mutations. We found that the RNA deadenylase complex, CNOT, is a central player in the vE-MAP and show that knockout of CNOT1, 10, and 11 suppressed HIV infection in primary T cells by upregulating innate immunity pathways. This phenotype was rescued by deletion of IRF7, a transcription factor regulating interferon-stimulated genes, revealing a previously unrecognized host signaling pathway involved in HIV infection. The vE-MAP represents a generic platform that can be used to study the global effects of how different pathogens hijack and rewire the host during infection.
我们开发了一个使用病毒感染力作为功能读数的定量遗传互作作图平台，并构建了一个与 HIV 功能相关的 356 个人类基因的病毒宿主互作图谱（vE-MAP），包含超过 63000 对的基因干扰。vE-MAP 提供了 HIV 感染背后遗传依赖性的广阔视角，可用于鉴定药物靶点和研究病毒突变。我们发现 RNA 去腺苷酸化复合物 CNOT 是 vE-MAP 的核心组成部分，并表明 CNOT1、10 和 11 的敲除通过上调先天免疫途径抑制原代 T 细胞中的 HIV 感染。该表型可通过删除转录因子 IRF7（调节干扰素刺激基因的转录因子）得到挽救，揭示了一种以前未被识别的宿主信号通路，该通路参与了 HIV 感染。vE-MAP 代表了一个通用平台，可用于研究不同病原体在感染过程中如何劫持和重编宿主的全局效应。
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