Innate Immunity and HIV Restriction

先天免疫和艾滋病毒限制

• 批准号: 8013192
• 负责人: JOHN C REED
• 金额: $ 97.63万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013192
• 关键词: Activation Analysis; Affect; Antiviral Agents; Antiviral Response; Area; Attenuated; Biological Assay; Biological Process; CD4 Positive T Lymphocytes; Cell Line; Cells; Collaborations; Cytoplasmic Receptors; DNA; Data; Dendritic Cells; Enhancers; Factor Analysis; Family; Future; Gene Expression; Genes; Goals; HIV; HIV Enhancer; HIV Infections; HIV-1; Immune; Immune response; Immune system; Infection; Interferons; Intervention; Kinetics; Knowledge; Laboratories; Lectin; Lectin Receptors; Leucine-Rich Repeat; Libraries; Ligands; Ligation; Maps; Mediating; Mitochondria; Molecular; Natural Immunity; Pathway interactions; Play; Production; Protein Binding; Proteins; RNA; Receptor Signaling; Regulation; Repression; Research Personnel; Reverse Transcription; Role; Screening procedure; Signal Transduction; Small Interfering RNA; System; Testing; Therapeutic; Toll-like receptors; Viral; Viral Genes; Viral Proteins; Virus; Virus Diseases; Work; base; cell type; design; experience; feeding; genome-wide; improved; macrophage; new therapeutic target; novel; pathogen; prophylactic; receptor; research study; response; sensor; vpr Gene Products

We hypothesize that several of the factors identified in Project 1 as restriction factors of HIV replication will be components of the host antiviral sensing machinery and/or of pathways downstream this sensing machinery. Restriction factors may include known and unknown stimulators of the antiviral sensing machinery leading up to the antiviral response. There are four known families of sensing molecules of viral pathogens that induce IFN and/or antiviral responses, two of them are extracytoplasmic receptors, the Tolllike receptors (TLR) and the lectin-like receptors (LLR), and the two other are cytoplasmic receptors, the Nod-like receptors (NLR) and the RlG-1-like receptors (RLR). However, very little is known about how HIV interacts with these sensing pathways and induces and/or represses an antiviral response such as the induction of IFN and/or IFN-stimulated genes (ISGs) with anti-HIV activity. We propose to determine the restriction factors that feed into these pathways and the role they play in the anti-HIV innate immune response at the cellular level. In addition, we will study the molecular regulation of these pathways during HIV infection and their impact in the HIV antiviral response. Despite the recognized antiviral activity of type I IFN, only a few specific factors that mediate the inhibitory effect of IFN on HIV replication have been identified. While in collaboration with Projects 1, 3, 4 and 6 we will generate an HIV-1 innate immune pathway activation map that includes the restriction factors identified in this PPG, we will also select 4-5 specific restrictions factors induced by IFN to study in more detail their anti-HIV-1 activities. To achieve these goals, we have assembled a team of three co-investigators with extensive experience in these innate immunity pathways who will be responsible for accomplishing the specific aims below. Dr. Garcia-Sastre has more than 12 years of experience in IFN and the RLR pathways, and their modulation during viral infection. Dr. David has been working with the interferon system for 18 years, and his lab discovered the activation of IRF-3 by virus infection and TLR ligation as a key innate immune response pathway. Dr. Reed is a leader in the area of NLR signaling. The generated data will aide in improving understanding of the interactions of HIV with innate immune systems, and will identify novel regulators of antiviral responses that may serve as future targets for developing therapeutic strategies.

我们假设项目 1 中确定的 HIV 复制限制因素中的几个因素将是宿主抗病毒传感机制和/或该传感机制下游途径的组成部分。限制因素可能包括导致抗病毒反应的抗病毒传感机制的已知和未知刺激物。有四个已知的病毒病原体传感分子家族可诱导 IFN 和/或抗病毒反应，其中两个是胞质外受体，Toll 样受体 (TLR) 和凝集素样受体 (LLR)，另外两个是胞质受体、Nod 样受体 (NLR) 和 RlG-1 样受体 (RLR)。然而，人们对 HIV 如何与这些传感途径相互作用并诱导和/或抑制抗病毒反应（例如诱导具有抗 HIV 活性的 IFN 和/或 IFN 刺激基因 (ISG)）知之甚少。我们建议确定进入这些途径的限制因素以及它们在细胞水平的抗艾滋病毒先天免疫反应中所发挥的作用。此外，我们还将研究艾滋病毒感染期间这些途径的分子调控及其对艾滋病毒抗病毒反应的影响。尽管 I 型 IFN 的抗病毒活性已得到公认，但仅确定了一些介导 IFN 对 HIV 复制抑制作用的特定因素。在与项目 1、3、4 和 6 合作的同时，我们将生成 HIV-1 先天免疫通路激活图谱，其中包括本 PPG 中确定的限制因素，我们还将选择 IFN 诱导的 4-5 个特定限制因素进行研究更详细地说明其抗 HIV-1 活性。为了实现这些目标，我们组建了一个由三名在这些先天免疫途径方面拥有丰富经验的联合研究人员组成的团队，他们将负责实现以下具体目标。 Garcia-Sastre 博士在 IFN 和 RLR 通路及其在病毒感染过程中的调节方面拥有超过 12 年的经验。 David 博士从事干扰素系统研究已有 18 年，他的实验室发现病毒感染和 TLR 连接激活 IRF-3 是一种关键的先天免疫反应途径。 Reed 博士是 NLR 信号传导领域的领导者。生成的数据将有助于增进对艾滋病毒与先天免疫系统相互作用的理解，并将确定抗病毒反应的新调节因子，这些调节因子可能作为制定治疗策略的未来目标。