Antiviral host defense through selective translational inhibition

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。我们发现了一种新的细胞因子，可以抑制感染细胞产生HIV，这为开发新型抗病毒药物提供了新的靶点，并可能具有诊断和预后价值。此外，基于抗病毒活性的分子基础，我们假设其他病毒如流感病毒也会受到huSlfn 11的抑制。 公共卫生相关性：令人信服的证据表明，在逆转录病毒感染后早期发生的免疫事件是决定艾滋病毒/艾滋病等疾病进程的关键因素。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为对抗微生物病原体（包括逆转录病毒，如HIV）的感染。先天性免疫应答不是抗原特异性的，并且由干扰素（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。了解先天免疫反应和促进或限制HIV感染不同步骤动力学的途径对于在这些感染性疾病过程中设计新的治疗干预药物策略，开发诊断工具或预防感染至关重要。关于调节逆转录病毒感染早期步骤的细胞因子，比那些靶向病毒复制周期后期阶段的细胞因子（如控制病毒产生的细胞因子）了解得更多（这也通过缺乏在病毒复制周期的这一点上起作用的抗病毒药物来证明）。干扰素通过诱导干扰素刺激的早期反应基因（ISG）发挥其抗病毒作用。这种ISG的扩展家族是Schlafen（Slfn）基因，其除了IFN之外还通过病原体与细胞接触直接诱导。在我们寻求定义Slfn蛋白的生物学功能时，我们发现huSlfn 11有效地抑制逆转录病毒（包括HIV）的产生。我们的研究表明，huSlfn 11表达对感染周期的早期阶段没有影响，但huSlfn 11蛋白在复制的晚期阶段起作用，在此阶段合成新的病毒蛋白。huSlfn 11功能的显著标志是选择性抑制病毒编码蛋白的合成，而生产宿主细胞蛋白显然不受阻碍。本申请中提出的研究旨在确定huSlfn 11功能的特异性，定义和表征huSlfn 11的功能结构域，并阐明其在抑制逆转录病毒蛋白合成抑制中的作用机制。这些分子过程不仅可能影响HIV复制本身，而且可能影响HIV的自然变异性，从而限制多药耐药HIV毒株的产生。预期的结果不仅会使 光对艾滋病毒和其他逆转录病毒的先天性抗病毒反应的一个新领域，但也将提供必要的了解Slfn蛋白的功能，需要利用其前瞻性的诊断和治疗价值。

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.