HIV-1 Vpr disrupts the IFN-TET-ISG pathway to promote HIV-1 infection and persistence

HIV-1 Vpr 破坏 IFN-TET-ISG 通路，促进 HIV-1 感染和持续存在

• 批准号: 10015198
• 负责人: Lishan Su
• 金额: $ 27.04万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2020-10-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10015198
• 关键词: Antiviral Agents; Binding; Cell Cycle Arrest; Cells; Chromatin; DNA; DNA Methylation; Dioxygenases; Disease; Epigenetic Process; G2/M Arrest; Gene Expression Regulation; Genes; Genetic; Goals; HIV; HIV Infections; HIV-1; Host Defense; Human; Immune; Immune response; Immunology; Impairment; Infection; Inflammation; Inflammatory Response; Interferon Type I; Interferons; Investigation; Lead; Ligase; Link; Mediating; Methylation; Pathogenesis; Pathway interactions; Play; Production; Proteins; RBX1 gene; RNA; Regulation; Role; Series; Signal Transduction; T-Cell Depletion; Testing; Tetanus Helper Peptide; Ubiquitin; Viral; Virus; Virus Diseases; base; cell type; chronic infection; demethylation; fight against; humanized mouse; immune activation; in vivo; insight; lymphoid organ; novel; recruit; transcription factor; ubiquitin-protein ligase; virology; vpr Gene Products

PROJECT SUMMARY The long-term goal of this investigation is to elucidate the mechanisms by which HIV-1 accessory protein Vpr alters host defense pathway to enhance HIV-1 persistent infection and pathogenesis. This investigation is proposed based on five key findings we made recently. (1) HIV-1 infection induces efficient production of type I interferons (IFN-I) by activating pDC, which fails to control HIV-1 infection but rather contributes to HIV-1 diseases. (2) HIV accessory protein Vpr plays an important role to counteract the effect of IFN-I to promote HIV-1 infection. (3) TET methylcytosine dioxygenases are monoubiquitylated by the VprBP-DDB1-CUL4-ROC1 (CRL4VprBP) E3 ligase which promotes TET binding to chromatin. (4) TET2 is recruited by sequence-specific transcription factors (TFs) to and activates the expression of specific target genes, including a subset of interferon (IFN)-stimulated genes (ISGs) and viral-defense genes. (5) Vpr interacts with both VprBP and TET and reprograms CRL4VprBP ligase to catalyze polyubiquitylation of TET2, resulting in TET2 degradation and inhibition of TET2-mediated induction of ISGs, including three HIV restriction factors. We propose that there exists an IFN-JAK-STAT-TET-ISG pathway that modulates IFN signaling and the expression of a subset of ISGs. The Vpr-mediated degradation of TET disrupts this pathway and counteracts the anti-HIV effect of IFN in human cells but not the IFN induction pathway, thereby promoting HIV-1 infection and persistence in the presence of IFN-I, which contributes to HIV-induced inflammation and pathogenesis. We propose four specific aims to test this hypothesis. Aim 1 will determine the function and mechanism Vpr- mediated TET degradation. Aim 2 is to determine the mechanism of the IFN-JAK-STAT-TET-ISG pathway. Aim 3 will study how Vpr and the IFN-STAT-TET pathway modulate HIV-1 infection and persistence in vivo, including the establishment and rebound of HIV-1 reservoir during cART. Aim 4 will investigate how Vpr disrupts the IFN-TET pathway to contribute to HIV-induced inflammation and T cell depletion/impairment. Combining the expertise of the two PIs in HIV virology and immunology, ubiquitin pathway and TET-mediated epigenetic control and motivated by a series of recent key findings, this investigation will establish the IFN- JAK-STAT-TET-ISG pathway in HIV-1 target cells and determine how Vpr disrupts this pathway to lead to persistent HIV infection and the HIV-associated inflammation. This investigation will also gain insights into DNA de/methylation as a mechanism in dynamic gene regulation and immune response, identify novel viral and host targets for developing HIV-1 “cure” treatments, and establish a paradigm on how this novel pathway is involved in the general anti-viral mechanism against other human viruses. 1

项目概要 这项研究的长期目标是阐明 HIV-1 辅助蛋白 Vpr 的机制 改变宿主防御途径以增强 HIV-1 持续感染和发病机制。 (1) HIV-1感染诱导I型的有效产生 通过激活 pDC 来产生干扰素 (IFN-I)，pDC 无法控制 HIV-1 感染，反而会促进 HIV-1 (2) HIV辅助蛋白Vpr在抵消IFN-I促进的作用中起重要作用 (3) TET 甲基胞嘧啶双加氧酶被 VprBP-DDB1-CUL4-ROC1 单泛素化。 (CRL4VprBP) E3 连接酶，促进 TET 与染色质结合 (4) TET2 通过序列特异性招募。 转录因子 (TF) 并激活特定靶基因的表达，包括 干扰素 (IFN) 刺激基因 (ISG) 和病毒防御基因 (5) Vpr 与 VprBP 和 TET 相互作用。 并重新编程CRL4VprBP连接酶以催化TET2的多泛素化，导致TET2降解并 抑制 TET2 介导的 ISG 诱导，包括三个 HIV 限制因子。 我们认为存在调节 IFN 信号传导的 IFN-JAK-STAT-TET-ISG 途径 Vpr 介导的 TET 降解破坏了该途径并抵消了 ISG 子集的表达。 IFN在人体细胞中发挥抗HIV作用，但不影响IFN诱导途径，从而促进HIV-1感染 IFN-I 的持续存在，会导致 HIV 诱发的炎症和发病机制。 我们提出具体目标来检验这一假设，目标 1 将确定 Vpr- 的功能和机制。 目的 2 是确定 IFN-JAK-STAT-TET-ISG 途径的机制。 目标 3 将研究 Vpr 和 IFN-STAT-TET 通路如何调节 HIV-1 感染和体内持续存在， 包括 cART 期间 HIV-1 储存库的建立和反弹，目标 4 将研究 Vpr 如何进行。 破坏 IFN-TET 通路，导致 HIV 诱导的炎症和 T 细胞耗竭/损伤。 结合两位 PI 在 HIV 病毒学和免疫学、泛素途径和 TET 介导方面的专业知识 在表观遗传控制和一系列最近的关键发现的推动下，这项研究将建立 IFN- HIV-1 靶细胞中的 JAK-STAT-TET-ISG 通路，并确定 Vpr 如何破坏该通路以导致 这项研究还将深入了解 DNA 的持续感染和 HIV 相关炎症。 去/甲基化作为动态基因调控和免疫反应的机制，识别新型病毒和宿主 开发 HIV-1“治愈”疗法的目标，并建立关于如何参与这一新途径的范例 在针对其他人类病毒的一般抗病毒机制中。 1