Role of TLR3 pathway in HIV infection

TLR3通路在HIV感染中的作用

• 批准号: 9204258
• 负责人: MICHAEL DAVID
• 金额: $ 22.09万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-17 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204258
• 关键词: AIDS/HIV problem; Ablation; Accounting; Affect; Alleles; Antigens; Antiviral Agents; Binding; Biological Assay; CD4 Positive T Lymphocytes; Cell Surface Receptors; Cells; Communicable Diseases; Complementary DNA; DNA; Dendritic Cells; Development; Diagnostic; Disease; Disease Progression; Double-Stranded RNA; Drug resistance; EP300 gene; Educational process of instructing; Employee Strikes; Event; Exposure to; Failure; Fostering; Generations; Genes; Genetic Polymorphism; Genome; HIV; HIV Infections; HIV-1; Human; IRF3 gene; Immune response; Immune system; Immunologic Surveillance; Individual; Infection; Infection prevention; Integrase Inhibitors; Interferon Type I; Interferon-alpha; Interferon-beta; Interferons; Invaded; Kinetics; Lead; Life Cycle Stages; Ligands; Link; Mediating; Molecular; Natural Immunity; Nucleic Acids; Organism; Outcome; PLK1 gene; Pathway interactions; Pattern recognition receptor; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Process; Production; Proteins; RNA; RNA Viruses; Receptor Signaling; Reporting; Resistance; Retroviridae; Role; Shapes; Signal Pathway; Signal Transduction; Specificity; Staging; Subfamily lentivirinae; System; T-Lymphocyte; TBK1 gene; TLR3 gene; TLR4 gene; TLR7 gene; TLR8 gene; TLR9 gene; Therapeutic Intervention; Toll-like receptors; Up-Regulation; Viral; Viral Load result; Viral reservoir; Virus Diseases; Virus Integration; adaptive immunity; base; ds-DNA; gene induction; macrophage; microbial; novel; nucleic acid structure; pathogen; prevent; prognostic value; protein expression; receptor; research study; response; sensor; tool; transmission process

Rapid recognition of invading pathogens by the host organism is crucial in mounting an effective immune response. Conserved structural features on pathogens termed PAMPs are recognized by the Toll-like cell surface receptors, which are part of the evolutionary conserved innate immune system. Over a decade ago we co-discovered the activation of Interferon Regulatory Factor 3 (IRF3) by TLR ligands, and the ensuing induction of both, type I interferon genes (IFNα/β) and Interferon Stimulated Genes (ISGs). We subsequently characterized many components involved in TLR-mediated IRF3 and IRF7 activation and their role in both innate and adaptive immunity. Compelling evidence indicates that immunological events early after retroviral infection are critical determinants shaping the course of, for instance, HIV/AIDS disease. The innate immune response is an ancient defense system made up of functionally distinct subsystems that have evolved to counter infection by microbial pathogens including retroviruses such as HIV. The innate immune response is not antigen-specific, and is composed of the PAMP/TLR-induced interferon (IFN) system as well as cell-based anti-pathogen countermeasures that restrict the replication of pathogens. Understanding the innate immune response and the pathways that promote or restrict the kinetics of different steps of HIV infection is essential for devising novel pharmacological strategies for therapeutic intervention during these infectious disease processes, to develop diagnostic tools or to prevent infection. The current paradigm of the role of TLR3 and its downstream signaling components TRIF, TBK1 and IRF3/7 teaches that activation of this pathway during viral infection leads to the production of type I interferons, which in turn mediate their antiviral activity via the upregulation of ISGs. As such, this pathway is considered a cornerstone in the defense against RNA viruses, including retroviruses such as HIV. It was therefore a striking and unexpected finding that ablation of TLR3, TRIF or IRF7 lead to a dramatic reduction in HIV infection, rather than an enhancement. Similarly, pharmacological inhibition of TBK1, or the newly implicated polo-like kinases, as well as p300 abolished the completion of the HIV replication cycle. Interestingly, we found that the disruption of the TLR3->IRF7 pathway did not matter once the viral cDNA was integrated into the host cell genome. These observations lead us to the hypothesis that IRF7 activation downstream of TLR3/TRIF promotes generation, stability or integration of the viral cDNA, and that pharmacological inhibition this cascade at the very early stage after exposure to HIV has the potential to prevent the establishment of a viral reservoir similar to RT or integrase inhibitors, with the benefit of a limited likelihood of the emergence of drug resistance.

宿主生物体对入侵病原体的快速识别对于建立有效的免疫至关重要 反应Toll样细胞识别病原体上保守的结构特征，称为PAMPs 表面受体，这是进化保守的先天免疫系统的一部分。十多年前， 共同发现TLR配体对干扰素调节因子3（IRF 3）的激活以及随后的诱导作用 I型干扰素基因（IFNα/β）和干扰素刺激基因（ISG）。我们随后 表征了参与TLR介导的IRF 3和IRF 7激活的许多组分及其在两者中的作用。 先天性和适应性免疫。 令人信服的证据表明，逆转录病毒感染后早期的免疫事件是至关重要的 例如，艾滋病毒/艾滋病的形成过程的决定因素。先天免疫反应是一种 由功能不同的子系统组成的古代防御系统，这些子系统已经进化为通过以下方式对抗感染： 微生物病原体，包括逆转录病毒如HIV。先天免疫反应不是抗原特异性的， 由PAMP/TLR诱导的干扰素（IFN）系统和基于细胞的抗病原体组成 限制病原体复制的对策。了解先天免疫反应和 促进或限制HIV感染的不同步骤的动力学的途径对于设计新的治疗方案是必不可少的。 在这些传染病过程中进行治疗干预的药理学策略， 诊断工具或预防感染。 TLR 3及其下游信号传导组分TRIF、TBK 1和TRIF的作用的当前范例是： IRF 3/7教导了在病毒感染期间该途径的激活导致I型干扰素的产生， 其又通过ISG的上调介导其抗病毒活性。因此，这一途径被认为是一种 在防御RNA病毒，包括逆转录病毒，如艾滋病毒的基石。因此，这是一个惊人的 并且出乎意料地发现，TLR 3、TRIF或IRF 7的消融导致HIV感染的显著减少， 而不是增强。类似地，TBK 1或新涉及的polo样激酶的药理学抑制， 以及p300取消了HIV复制周期的完成。有趣的是，我们发现 一旦病毒cDNA整合到宿主细胞中，TLR 3-> IRF 7途径的破坏就不重要 基因组这些观察结果使我们假设IRF 7在TLR 3/TRIF下游的激活 促进病毒cDNA的产生、稳定性或整合，并且药理学抑制该级联反应 在暴露于艾滋病毒后的早期阶段， 类似于RT或整合酶抑制剂，具有出现耐药性的有限可能性的益处。