TRIM-directed autophagy in HIV restriction and control of inflammation

摘要 细胞自主HIV-1限制因子干扰病毒生命周期的相对能力 有助于宿主对感染的易感性水平。限制因子的药理作用增强 疗效将是治疗艾滋病毒感染的一种新方法。然而，HIV阻断的机制基础 由于限制因素尚未完全了解，阻碍了使用基于限制因素的宿主的努力 定向治疗。人类三方基序(TRIM)家族由70多个成员组成， 其中几个已被确定为抗病毒限制因子。在这一角色中，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 回应。TRIM家族成员TRIM5α实现了这两个目标：第一，它防止逆转录病毒感染 细胞通过一种迄今尚未解释的机制。其次，TRIM5α还作为模式识别受体， 通过激活炎症信号通路促进抗病毒细胞状态的建立 在逆转录病毒识别之后。 尽管TRIMs似乎在抗逆转录病毒防御中使用了多种方法，但其中一种非常常见 TRIM家族的特点是，即使不是所有TRIM，也有许多TRIM参与调节和执行 自噬。除了作为已知的对细胞内病原体的防御机制(包括 自噬也越来越被认为是减少或微调炎症的一种手段。这里, 我们建议检验这样一种假设，即自噬是保护细胞免受HIV-1感染的修剪作用的基础。 感染和调节依赖TRIM的炎症信号。这里提出的研究有 几个首要目标。首先，他们寻求提高我们对分子机制的理解 恒河猴TRIM5α既调节自噬，又指导进入的HIV-1衣壳的自噬降解 (目标1)。其次，他们将确定自噬途径的调节是否影响TRIM5依赖的α 慢病毒感染时促炎信号的激活。最后，他们将讨论人类是否 除限制艾滋病毒的TRIM5α外，TRIM5以外的TRIMs也在其抗病毒行动中使用自噬(目标2)。我们有 组建了一个由自噬和艾滋病毒专家组成的团队来解决这些问题。 我们的研究有可能揭示几种已知的抗逆转录病毒蛋白的作用模式 为我们理解作为一个家庭的Trims如何产生积极和消极影响奠定了基础 发炎。我们期望这些研究表明，自噬是不同修剪行为的一个统一方面。 爱滋病毒防御。由于自噬可以被药物操纵，我们的发现可能表明 自噬的调节可能是治疗TRIM相关疾病的一种方法，包括 艾滋病毒/艾滋病。我们在TRIMs和自噬方面的专业知识，以及将得到的财政和制度支持 如果Cobre申请得到资助，将确保成功实现这些目标。

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.