TRIM-directed autophagy in HIV restriction and control of inflammation

总结 细胞自主HIV-1限制因子干扰病毒生命周期的相对能力 导致宿主对感染的易感性限制因子的药理学增强 有效性将是治疗HIV感染的新方法。然而，艾滋病毒阻断的机制基础 限制性因子的作用还没有完全理解，这阻碍了采用基于限制性因子的宿主的努力 定向治疗。TRIM蛋白质家族由人类中的70多个成员组成， 其中几种已被鉴定为抗病毒限制因子。在这方面，TRIMs可以减少病毒 通过干扰病毒生命周期直接复制或通过微调细胞先天免疫间接复制 应答TRIM家族成员TRIM 5 α实现了这两点：首先，它可以防止逆转录病毒感染， 一种迄今无法解释的机制。其次，TRIM 5 α也作为模式识别受体， 通过激活炎症信号传导途径促进抗病毒细胞状态的建立 逆转录病毒识别。 尽管TRIMs似乎在抗逆转录病毒防御中采用了多种方法， 与贸易有关的投资措施系列中的一个特点是，许多（如果不是所有的话）与贸易有关的投资措施都涉及以下方面的管理和执行： 自噬除了其作为已知的针对细胞内病原体（包括 自噬也越来越被认为是减少或微调炎症的一种手段。在这里， 我们建议验证自噬是TRIM保护细胞对抗HIV-1的基础的假设 感染和调节TRIM依赖性炎症信号传导。这里提出的研究有 几个首要目标。首先，他们试图提高我们对分子机制的理解， 恒河猴TRIM 5 α既调节自噬，又指导进入的HIV-1衣壳的自噬降解 (Aim 1）。第二，他们将确定自噬途径的调节是否影响TRIM 5 α依赖性细胞因子。 慢病毒感染后促炎信号传导的激活。最后，他们将讨论人类是否 TRIM 5 α以外的限制HIV的TRIMs也在其抗病毒作用中使用自噬（Aim 2）。我们有 组建了一个自噬和艾滋病专家团队来解决这些问题。 我们的研究有可能揭示几种已知抗逆转录病毒蛋白的作用模式， 为我们理解TRIMs作为一个大家庭如何产生积极和消极影响奠定基础 炎症我们希望这些研究表明，自噬是TRIM多种作用的一个统一方面， 艾滋病防御。由于自噬可以被人为操纵，我们的发现可能表明， 调节自噬可能是一种治疗TRIM相关疾病的方法， 艾滋病毒/艾滋病的我们在TRIMs和自噬方面的专业知识，以及沿着的财政和机构支持， 如果COBRE应用程序获得资助，将确保成功完成这些目标。

SUMMARY The relative ability of cell autonomous HIV-1 restriction factors to interfere with the viral life cycle contributes to a host’s level of susceptibility to infection. Pharmacological enhancement of restriction factor efficacy would be a novel approach to treating HIV infection. However, the mechanistic basis for HIV blockage by restriction factors is not completely understood hampering efforts to employ restriction factor-based host directed therapies. The tripartite motif (TRIM) family of proteins consists of more than 70 members in humans, several of which have been identified as antiviral restriction factors. In this role, TRIMs can diminish viral replication directly by interfering with the viral life cycle or indirectly by fine tuning cellular innate immune responses. TRIM family member TRIM5α accomplishes both of these: first, it prevents retroviral infection of cells by a hitherto unexplained mechanism. Second, TRIM5α also acts as a pattern recognition receptor, promoting the establishment of an antiviral cellular state via the activation of inflammatory signaling pathways upon retroviral recognition. Although TRIMs appear to employ multiple approaches in antiretroviral defense, one strikingly common feature among the TRIM family is that many if not all TRIMs are involved in the regulation and execution of autophagy. In addition to its role as a known defense mechanism against intracellular pathogens (including HIV-1), autophagy is also increasingly recognized as a means of reducing or fine tuning inflammation. Here, we propose to test the hypothesis that autophagy underlies TRIM action in protecting cells against HIV-1 infection and in modulating the TRIM-dependent inflammatory signaling. The studies proposed here have several overarching goals. First, they seek to improve our understanding of the molecular mechanism whereby rhesus TRIM5α both regulates autophagy and directs the autophagic degradation of incoming HIV-1 capsids (Aim 1). Second, they will determine if modulations of the autophagy pathway affect TRIM5α-dependent activation of pro-inflammatory signaling upon lentiviral infection. Finally, they will address whether human TRIMs other than TRIM5α that restrict HIV also employ autophagy in their antiviral actions (Aim 2). We have assembled a team of autophagy and HIV experts to address these questions. Our studies have the potential to uncover the mode of action of several known antiretroviral proteins and lay the groundwork for our understanding of how TRIMs as a family can both positively and negatively affect inflammation. We expect these studies to show that autophagy is a unifying aspect of diverse TRIM actions in HIV defense. Since autophagy can be pharmacologically manipulated, our findings may indicate that modulations of autophagy could be a therapeutic approach to dealing with TRIM-related diseases including HIV/AIDS. Our expertise in TRIMs and autophagy, along with the financial and institutional support to be provided should the COBRE application be funded will ensure successful completion of these aims.