SAMHD1-mediated regulation of HIV-1 innate immunity and viral gene expression

SAMHD1介导的HIV-1先天免疫和病毒基因表达的调节

• 批准号: 10569509
• 负责人: Li Wu
• 金额: $ 47.64万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569509
• 关键词: Address; Affect; Autoimmune Diseases; Binding; CD4 Positive T Lymphocytes; Cells; Development; Gene Expression; Genetic Transcription; HIV; HIV-1; HIV/AIDS; Human; Hydrolase; I Kappa B-Alpha; Immune signaling; Immunity; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Innate Immune Response; Interdisciplinary Study; Interferon Type I; Interferons; Long Terminal Repeats; Macrophage; Maps; Mediating; Molecular; Mutation; Myeloid Cells; Natural Immunity; Nuclear; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Physiological; Proteins; Regulation; Reporting; Rest; Signal Transduction; Signaling Protein; Site; Stimulus; Terminal Repeat Sequences; Testing; Text; Viral; Viral Genes; Viral reservoir; Virus Activation; Virus Diseases; Virus Latency; Virus Replication; antiretroviral therapy; antiviral immunity; cell type; design; experience; global health; inhibitor; insight; interferon regulatory factor-7; knock-down; monocyte; novel; promoter

Project Summary/Abstract A critical barrier to developing a cure for HIV-1 infection is the long-lived viral reservoir in cells due to viral latency. Many host proteins regulate HIV-1 gene expression and viral latency. By reducing intracellular dNTP levels, the host protein SAMHD1 inhibits HIV-1 replication in myeloid cells and resting CD4+ T-cells, cell types that are important for HIV-1 latency. Patients with homozygous SAMHD1 mutations experience autoimmune diseases, but the functions and mechanisms of SAMHD1 in modulating inflammation and immunity remain unclear. Despite extensive studies of the mechanisms underlying SAMHD1-mediated restriction of virus replication, it is unknown whether and how SAMHD1 regulates antiviral innate immune responses. Here, we aim to address two key questions: (a) What are the mechanisms of SAMHD1 in modulating the innate immune response to HIV-1 infection? (b) How does SAMHD1 affect HIV-1 gene expression? Our new findings demonstrated that SAMHD1 suppresses innate immune responses to viral infections and inflammatory stimuli by inhibiting nuclear factor-kappa B (NF-κB) activation and type I interferon (IFN-I) induction through distinct mechanisms. We discovered that SAMHD1 interacts with key proteins in the NF-κB and IFN-I pathways, allowing it to act as a multifaceted repressor of innate immune signaling. We also found that SAMHD1 impairs HIV-1 gene expression and reactivation of viral latency in primary CD4+ T-cells. NF-κB is critical for HIV-1 gene transcription and transcriptional inhibition of viral gene expression is the main mechanism of HIV-1 latency. Our central hypothesis is that SAMHD1 modulates HIV-1 antiviral immunity and viral gene expression by suppressing NF-κB activation, IFN-I induction, and viral transcription. We designed three specific aims to test this hypothesis. Aim 1. Elucidate the mechanisms by which SAMHD1 suppresses NF-κB activation in HIV-1 infection; Aim 2. Define the mechanisms by which SAMHD1 suppresses IFN-I induction during HIV-1 infection; Aim 3. Investigate the mechanisms by which SAMHD1 impairs reactivation of HIV-1 gene expression. Overall impact. These studies will reveal novel physiological functions of SAMHD1 during HIV-1 infection of primary target cells, which are beyond its known function in restricting virus replication. Furthermore, our interdisciplinary studies will yield new results to fundamentally enhance our mechanistic understanding of SAMHD1 in regulating HIV-1 infection, viral gene expression, and anti-HIV innate immune responses.

项目总结/摘要 开发治疗HIV-1感染的关键障碍是细胞中的长寿病毒库， 病毒潜伏期许多宿主蛋白调节HIV-1基因表达和病毒潜伏期。通过减少 宿主蛋白SAMHD 1抑制HIV-1在骨髓细胞和静息细胞中的复制， CD 4 + T细胞，对HIV-1潜伏期很重要的细胞类型。纯合子SAMHD 1患者 突变经历自身免疫性疾病，但SAMHD 1的功能和机制， 调节炎症和免疫力仍不清楚。尽管对这些机制进行了广泛的研究 潜在的SAMHD 1介导的病毒复制限制，尚不清楚SAMHD 1是否以及如何 调节抗病毒先天免疫反应。在这里，我们的目标是解决两个关键问题：（a）什么是 SAMHD 1在调节HIV-1感染的天然免疫应答中的作用机制？(b)如何 SAMHD 1是否影响HIV-1基因表达？ 我们的新发现表明，SAMHD 1抑制对病毒感染的先天免疫反应。 通过抑制核因子-κ B（NF-κB）活化和I型干扰素 （IFN-I）诱导通过不同的机制。我们发现SAMHD 1与关键蛋白质相互作用， 在NF-κB和IFN-I通路中，使其能够作为先天免疫的多方面抑制剂发挥作用。 信号我们还发现，SAMHD 1损害HIV-1基因的表达和病毒潜伏期的重新激活。 原代CD 4 + T细胞。NF-κB在HIV-1基因转录及病毒转录抑制中的作用 基因表达是HIV-1潜伏的主要机制。我们的中心假设是SAMHD 1 通过抑制NF-κB活化、IFN-Ⅰ、IFN-γ、IFN- 诱导和病毒转录。我们设计了三个具体目标来验证这一假设。目标1. 阐明SAMHD 1抑制HIV-1感染中NF-κB活化的机制;目的2。 定义SAMHD 1抑制HIV-1感染期间IFN-1诱导的机制;目的3。 研究SAMHD 1损害HIV-1基因表达重新激活的机制。 整体影响。这些研究将揭示SAMHD 1在HIV-1过程中的新的生理功能 感染原代靶细胞，这超出了其限制病毒复制的已知功能。 此外，我们的跨学科研究将产生新的成果，从根本上提高我们的机械 了解SAMHD 1在调节HIV-1感染、病毒基因表达和抗HIV先天性 免疫反应。