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（由申请人提供）：艾滋病毒仍然是世界上最流行的传染病之一。我们发现了一种抑制受感染细胞产生艾滋病毒的新型细胞因子，为开发一类新型抗病毒药物提供了新的靶点，并且可能还具有诊断和预后价值。此外，根据抗病毒活性的分子基础，我们假设流感等其他病毒也会受到 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事件是影响艾滋病毒/艾滋病等疾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到对抗微生物病原体（包括艾滋病毒等逆转录病毒）的感染。先天免疫反应不是抗原特异性的，由干扰素 (IFN) 系统以及限制病原体复制的基于细胞的抗病原体对策组成。了解先天免疫反应以及促进或限制 HIV 感染不同步骤动力学的途径对于设计新的药理学策略以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子的了解远多于对那些针对病毒复制周期后期的细胞因子的了解，例如那些控制病毒产生的细胞因子（这也可以通过此时缺乏抗病毒药物来证明）在病毒复制周期中）。干扰素通过诱导干扰素刺激早期反应基因（ISG）发挥抗病毒作用。 Schlafen (Slfn) 基因是此类 ISG 的一个不断扩大的家族，除了 IFN 之外，该基因也由病原体与细胞接触直接诱导。在我们探索 Slfn 蛋白的生物学功能的过程中，我们发现 huSlfn11 能有效抑制包括 HIV 在内的逆转录病毒的产生。我们的研究表明 huSlfn11 表达对感染周期的早期阶段没有影响，但 huSlfn11 蛋白在合成新病毒蛋白的复制的最后阶段起作用。 huSlfn11 功能的一个显着特征是选择性抑制病毒编码蛋白的合成，而宿主细胞蛋白的生产显然不受阻碍。本申请提出的研究旨在确定huSlfn11功能的特异性，定义和表征huSlfn11的功能域，并阐明其抑制逆转录病毒蛋白合成的作用机制。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，从而限制多重耐药性艾滋病毒株的产生。预期的结果不仅会落空 揭示了针对 HIV 和其他逆转录病毒的先天抗病毒反应的新领域，同时也将提供对 Slfn 蛋白功能的必要了解，以开发其前瞻性诊断和治疗价值。