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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要开发治疗 HIV-1 感染的方法的一个关键障碍是细胞内的长寿命病毒库，这是由于许多宿主蛋白通过减少病毒潜伏期来调节 HIV-1 基因表达。细胞内 dNTP 水平，宿主蛋白 SAMHD1 抑制骨髓细胞和静息细胞中的 HIV-1 复制 CD4+ T 细胞，这种细胞类型对于 SAMHD1 纯合子患者的 HIV-1 潜伏期很重要。突变会导致自身免疫性疾病，但SAMHD1的功能和机制在尽管对其机制进行了广泛的研究，但调节炎症和免疫仍不清楚。 SAMHD1 介导的病毒复制限制，目前尚不清楚 SAMHD1 是否以及如何发挥作用在这里，我们的目标是解决两个关键问题：（a）什么是天然免疫反应。 SAMHD1 调节 HIV-1 感染先天免疫反应的机制（b）如何？ SAMHD1 是否影响 HIV-1 基因表达？我们的新发现表明 SAMHD1 抑制对病毒感染的先天免疫反应通过抑制核因子-κB (NF-κB) 激活和 I 型干扰素来抑制炎症刺激 (IFN-I) 通过不同的机制诱导。我们发现 SAMHD1 与关键蛋白相互作用。在 NF-κB 和 IFN-I 通路中，使其能够充当先天免疫的多方面抑制因子我们还发现 SAMHD1 会损害 HIV-1 基因表达和病毒潜伏期的重新激活。初级 CD4+ T 细胞对于 HIV-1 基因转录和病毒转录抑制至关重要。基因表达是 HIV-1 潜伏期的主要机制，我们的中心假设是 SAMHD1。通过抑制 NF-κB 激活、IFN-I 调节 HIV-1 抗病毒免疫和病毒基因表达我们设计了三个具体目标来检验这一假设。阐明 SAMHD1 在 HIV-1 感染中抑制 NF-κB 激活的机制；目标 2。明确 SAMHD1 在 HIV-1 感染期间抑制 IFN-I 诱导的机制；目标 3。研究 SAMHD1 损害 HIV-1 基因表达重新激活的机制。这些研究将揭示 SAMHD1 在 HIV-1 期间的新生理功能。主要靶细胞的感染，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成果，从根本上增强我们的机制了解 SAMHD1 在调节 HIV-1 感染、病毒基因表达和先天抗 HIV 方面的作用免疫反应。