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中确定为艾滋病毒复制的限制因素的几个因素将是宿主抗病毒感应机械和/或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感应机制的已知和未知刺激剂。有四个已知的病毒病原体传感分子家族诱导IFN和/或抗病毒反应，其中两个是外胞质受体，收费受体（TLR）和凝集素样受体（LLR），另外两个是细胞质受体，NOD受体（NLG）（NLG）（nlg）（nlg）。但是，关于HIV如何与这些感应途径相互作用，并诱导和/或抑制抗病毒反应，例如具有抗HIV活性的IFN和/或IFN刺激的基因（ISGS），几乎没有知之甚少。我们建议确定进食这些途径的限制因素及其在细胞水平的抗HIV先天免疫反应中所起的作用。此外，我们将研究HIV感染期间这些途径的分子调节及其对HIV抗病毒反应的影响。尽管I型IFN具有公认的抗病毒活性，但仅确定了介导IFN对HIV复制抑制作用的少数特定因素。在与项目1、3、4和6合作的过程中，我们将生成HIV-1先天免疫途径激活图，其中包括该PPG中确定的限制因素，我们还将选择IFN引起的4-5个特定限制因素，以详细研究其抗HIV-HIV-1的活动。为了实现这些目标，我们组建了一个由三个共同投资者组成的团队，在这些先天免疫途径中拥有丰富的经验，他们将负责在下面完成具体目标。 Garcia-Sastre博士在IFN和RLR途径方面拥有超过12年的经验，及其在病毒感染期间的调节经验。 David博士已经与Interferon系统合作了18年，他的实验室发现了通过病毒感染和TLR结扎的IRF-3作为关键的先天免疫反应途径。里德博士是NLR信号领域的领导者。生成的数据将有助于提高对HIV与先天免疫系统相互作用的了解，并将确定抗病毒药反应的新型调节剂，这些调节剂可能是开发治疗策略的未来目标。