Mechanisms of SAMHD1-mediated HIV-1 restriction in dendritic cells

树突状细胞中 SAMHD1 介导的 HIV-1 限制机制

• 批准号: 8542053
• 负责人: Li Wu
• 金额: $ 36.07万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-17 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8542053
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Antiviral Agents; CD4 Positive T Lymphocytes; Cell Nucleus; Cells; Cessation of life; Coculture Techniques; Communicable Diseases; Cytoplasm; Dendritic Cells; Dendritic cell activation; Environment; Goals; HIV-1; HIV-2; Hereditary Disease; Human; Immune; Immune response; Immunity; Immunosuppression; In Vitro; Infection; Inflammatory; Inflammatory Response; Interferons; Interleukin-6; Intervention; Kinetics; Measures; Mediating; Molecular; Mutation; Myelogenous; Myeloid Cells; Names; Natural Immunity; Nuclear Protein; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Play; Process; Proteins; Regulation; Right-On; Role; SAM Domain; SIV; Signal Pathway; Small Interfering RNA; Symptoms; Syndrome; T-Cell Proliferation; TNF gene; Testing; Text; Virus; Virus Diseases; cytokine; design; driving force; immune activation; in vivo; insight; macrophage; monocyte; novel; public health relevance; response; transmission process

DESCRIPTION (provided by applicant): Immune activation is the driving force of HIV-1 replication in vivo, which facilitates viral infection in target cells and fundamentally contribute to AIDS pathogenesis. Myeloid cells, including monocytes, dendritic cells (DCs) and macrophages, play a critical role in innate immunity against viral infection. Our long-term goal is to define th mechanisms regulating immune activation of myeloid cells during HIV-1 infection. SAMHD1 is a recently identified HIV-1 restriction factor in myeloid cells. SAMHD1 a nuclear protein involved in innate immunity and has been proposed to act as a negative regulator of the interferon response. However, the role of SAMHD1 in regulating immune activation of myeloid cells remains unknown. The molecular mechanisms of SAMHD1-mediated HIV-1 restriction in DCs are not fully understood. In this project, we aim to study the mechanisms of SAMHD1-mediated HIV-1 restriction in primary DCs and the role of SAMHD1 in regulating immune activation of DCs. In our preliminary studies, we observed that HIV-1 infection of DCs significantly up-regulated the release of some early pro-inflammatory cytokines. Intriguingly, we found that HIV-1 infection of DCs resulted in the translocation of SAMHD1 from the nucleus to the cytoplasm. Our central hypotheses are: HIV-1 infection of DCs triggers SAMHD1 cytoplasmic translocation, which is important for HIV-1 restriction and immune suppression of DCs. As a result, HIV-1 restriction by SAMHD1 in DCs negatively regulates DC-mediated activation of CD4+ T-cells and HIV-1 transmission, which sets up a less permissive environment for HIV-1 spreading. We propose two specific aims to test these novel hypotheses. Aim 1. To examine the role of SAMHD1 in suppression of immune activation of DCs during HIV-1 infection; and Aim 2. To define the mechanisms of SAMHD1-mediated HIV-1 restriction in DCs. Our proposed studies will reveal the unique role of SAMHD1 in regulating immune activation of myeloid DCs during HIV-1 infection and define the precise mechanisms of SAMHD1-mediated HIV-1 restriction in primary DCs. Accomplishing the proposed studies will also elucidate the mechanisms by which SAMHD1 negatively regulates DC-mediated HIV-1 trans-infection and activation of CD4+ T-cells. Overall, our results will provide new insights into intrinsic immunity against HIV-1 infectin in myeloid DCs, which can help us to develop novel interventions to block HIV-1 infection and transmission.

描述（申请人提供）：免疫激活是HIV-1在体内复制的驱动力，促进病毒感染靶细胞，从根本上促进艾滋病发病。髓系细胞包括单核细胞、树突状细胞和巨噬细胞，在抗病毒感染的先天性免疫中起关键作用。我们的长期目标是确定HIV-1感染过程中骨髓细胞免疫激活的调节机制。SAMHD 1是最近在骨髓细胞中鉴定的HIV-1限制因子。SAMHD 1是一种核蛋白， 先天性免疫，并被认为是干扰素应答的负调节剂。然而，SAMHD 1在调节骨髓细胞免疫活化中的作用仍然未知。SAMHD 1介导的HIV-1在DC中限制的分子机制尚未完全了解。本课题旨在研究SAMHD 1介导的HIV-1在原代DC中的限制性表达机制及其在调节DC免疫激活中的作用。在我们的初步研究中，我们观察到，HIV-1感染的DC显着上调释放一些早期促炎细胞因子。有趣的是，我们发现HIV-1感染DC导致SAMHD 1从细胞核易位到细胞质。我们的主要假设是：DC感染HIV-1后，SAMHD 1发生胞质转位，这对DC的HIV-1限制和免疫抑制具有重要意义。因此，DC中SAMHD 1对HIV-1的限制负调节DC介导的CD 4 + T细胞活化和HIV-1传播，这为HIV-1传播建立了一个不太允许的环境。我们提出了两个具体的目标来测试这些新的假设。目标1.研究SAMHD 1在HIV-1感染过程中抑制DC免疫激活的作用;目的2.探讨SAMHD 1介导的HIV-1在DC中的限制性表达机制。我们的研究将揭示SAMHD 1在HIV-1感染过程中调节髓样DC免疫激活的独特作用，并确定SAMHD 1介导的HIV-1限制原代DC的确切机制。完成所提出的研究还将阐明SAMHD 1负调控DC介导的HIV-1转感染和CD 4 + T细胞活化的机制。总之，我们的研究结果将为髓样DCs抗HIV-1感染的内在免疫提供新的见解，这可以帮助我们开发新的干预措施来阻断HIV-1感染和传播。