Antiviral host defense through selective translational inhibition

通过选择性翻译抑制进行抗病毒宿主防御

• 批准号: 8329334
• 负责人: MICHAEL DAVID
• 金额: $ 29.44万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8329334
• 关键词: AIDS/HIV problem; ATP phosphohydrolase; Affect; Alternative Splicing; Anti-Retroviral Agents; Antigens; Antiviral Agents; Antiviral Response; Area; Attenuated; Binding; Biogenesis; Biological Process; Caenorhabditis elegans; Cells; Charge; Codon Nucleotides; Communicable Diseases; DNA; Development; Diagnostic; Disease; Dominant-Negative Mutation; Drosophila genus; ERG gene; Employee Strikes; Event; Family; Generations; Genes; Genetic Transcription; Goals; HIV; HIV Infections; Homologous Gene; Host Defense; Human; IRF3 gene; Immune response; Infection; Infection prevention; Influenza; Interferon-alpha; Interferon-beta; Interferons; Kinetics; Length; Light; Location; Mediating; Messenger RNA; Molecular; Molecular Mechanisms of Action; Multi-Drug Resistance; Mus; N-terminal; Nucleic Acid Binding; Organism; Pathway interactions; Pharmaceutical Preparations; Positioning Attribute; Poxviridae; Process; Production; Protein Binding; Protein Biosynthesis; Protein Inhibition; Protein Isoforms; Protein Synthesis Inhibition; Proteins; RNA Helicase; Reporting; Retroviridae; Reverse Transcription; Role; Shapes; Specificity; Staging; System; Testing; Therapeutic; Therapeutic Intervention; Transfer RNA; Translational Repression; Viral; Viral Proteins; Virus; Yeasts; base; member; microbial; novel; pathogen; preference; prognostic; prospective; protein expression; protein function; tool; viral RNA

DESCRIPTION (provided by applicant): HIV continues to be one of the most prevalent infectious diseases in this world. Our discovery of a novel cellular factor that inhibits the production of HIV by infected cells provides a new target for the development of a novel class of anti-viral drugs and may additionally carry diagnostic and prognostic value. Furthermore, based on the molecular basis of the antiviral activity we hypothesize that other viruses such as Influenza will also be subject to inhibition by huSlfn11. PUBLIC HEALTH RELEVANCE: Compelling evidence indicates that imunological 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 interferon (IFN) system as wel as cel-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 nove pharmacological strategies for therapeutic intervention during these infectious disease processes, to develop diagnostic tools or to prevent infection. Significantly more is known about the cellular factors that modulate the early steps in retroviral infection than about those that target the late stages in the viral replication cycle such as those governing virus production (which is also evidenced by the absence of antiviral drugs acting at this point in the viral replication cycle). Interferons exert their antiviral effects through the induction of Interferon Stimulated early response Genes (ISGs). An expanding family of such ISGs are the Schlafen (Slfn) genes, which in addition to IFN are also directly induced by pathogen contact with the cells. In our quest to define the biological function of Slfn proteins we discovered that huSlfn11 potently inhibits the production of retroviruses including HIV. Our studies revealed huSlfn11 expression had no effect on the early steps of the infection cycle, but that huSlfn11 protein acts at the very late stages of replication where new viral proteins are synthesized. A striking hallmark of huSlfn11 function is the selective inhibition of the synthesis of virus-encoded proteins, whereas production host cell proteins are apparently unhindered. The studies proposed in this application aim to determine the specificity of huSlfn11 function, to define and characterize the functional domains of huSlfn11, and to elucidate its mechanism of action in the inhibition of retroviral proteins synthesis inhibition. These molecular processes potentially not only affect HIV replication per se, but might also impact the natural variability of HIV and thus limit the generation of multidrug-resistant HIV strains. The anticipated results will not only shed light onto a novel area of the innate antiviral response against HIV and other retroviruses, but will also provide the necessary understanding of Slfn protein function required to exploit their prospective diagnostic and therapeutic value.

描述(申请人提供)：艾滋病毒仍然是世界上最流行的传染病之一。我们发现了一种新的细胞因子，可以抑制感染细胞产生HIV，为开发新型抗病毒药物提供了新的靶点，并可能另外具有诊断和预后价值。此外，根据抗病毒活性的分子基础，我们假设其他病毒，如流感，也将受到huSLfn11的抑制。 公共卫生相关性：令人信服的证据表明，逆转录病毒感染后早期的免疫学事件是影响例如艾滋病毒/艾滋病病程的关键决定因素。先天免疫反应是一种古老的防御系统，由功能不同的子系统组成，这些子系统已经进化出来，以对抗微生物病原体的感染，包括艾滋病毒等逆转录病毒。先天免疫反应不是抗原特异性的，而是由干扰素系统以及基于细胞的抗病原体对策组成的，这些系统限制了病原体的复制。了解先天免疫反应和促进或限制HIV感染不同阶段动力学的途径，对于设计新的药理学策略在这些传染病过程中进行治疗干预、开发诊断工具或预防感染至关重要。人们对调节逆转录病毒感染早期步骤的细胞因素的了解远远多于针对病毒复制周期后期阶段的因素，如控制病毒生产的因素(这也从病毒复制周期的这一点上缺乏抗病毒药物来证明)。干扰素通过诱导干扰素刺激的早期反应基因(ISGs)发挥抗病毒作用。这类ISG的一个不断扩大的家族是Schlafen(Slfn)基因，除了干扰素外，这种基因也是由病原体与细胞接触直接诱导的。在我们寻求确定slfn蛋白的生物学功能的过程中，我们发现huslfn11有效地抑制了包括HIV在内的逆转录病毒的产生。我们的研究表明，huslfn11的表达对感染周期的早期步骤没有影响，但huslfn11蛋白在复制的非常后期阶段发挥作用，在那里合成新的病毒蛋白。HuSLfn11功能的一个显著特点是选择性地抑制病毒编码蛋白的合成，而产生宿主细胞蛋白显然不受阻碍。本研究旨在确定huslfn11功能的特异性，确定并鉴定huslfn11的功能结构域，并阐明其抑制逆转录病毒蛋白合成抑制的作用机制。这些分子过程不仅可能影响艾滋病毒复制本身，还可能影响艾滋病毒的自然变异性，从而限制耐多药艾滋病毒毒株的产生。预期的结果不仅会让 这不仅有助于揭示针对艾滋病毒和其他逆转录病毒的先天抗病毒反应的一个新领域，而且还将提供对SLFN蛋白功能的必要了解，以开发其预期的诊断和治疗价值。