TRIM-directed autophagy in HIV restriction and control of inflammation

TRIM 引导的自噬在 HIV 限制和炎症控制中的作用

• 批准号: 9207191
• 负责人: Michael Aaron Mandell
• 金额: $ 30.71万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9207191
• 关键词: AIDS/HIV problem; Address; Affect; Alpha Cell; Amino Acid Motifs; Anti-Retroviral Agents; Antiviral Agents; Autophagocytosis; Capsid; Cell physiology; Cells; Centers of Research Excellence; Defense Mechanisms; Disease; Ensure; Family; Family member; Funding; Goals; HIV; HIV Infections; HIV-1; Human; Income; Infection; Inflammation; Inflammatory; Innate Immune Response; Life Cycle Stages; Macaca mulatta; Metabolism; Molecular; Pathway interactions; Pattern recognition receptor; Pharmaceutical Preparations; Pharmacology; Play; Predisposition; Protein Family; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; TRIM Motif; Testing; Therapeutic; Viral; Virus Replication; base; improved; member; negative affect; novel strategies; pathogen; prevent

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.

概括 细胞自主HIV-1限制因子干扰病毒生命周期的相对能力 有助于提高宿主对感染的易感性水平。 疗效将是治疗艾滋病毒感染的新方法。然而，艾滋病毒阻断的机制基础。 限制因素尚未被完全理解，阻碍了采用基于限制因素的主机的努力 人类的三重基序 (TRIM) 蛋白家族由 70 多个成员组成， 其中一些已被确定为抗病毒限制因子，TRIM 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 TRIM 家族成员 TRIM5α 实现了这两点：首先，它可以防止逆转录病毒感染。 其次，TRIM5α 还充当模式识别受体， 通过激活炎症信号通路促进抗病毒细胞状态的建立 逆转录病毒识别后。 尽管 TRIM 似乎在抗逆转录病毒防御中采用了多种方法，但其中一种非常常见 TRIM家族的一个特点是，许多（如果不是全部）TRIM都参与了监管和执行 自噬除了作为已知的针对细胞内病原体（包括）的防御机制的作用之外。 HIV-1），自噬也越来越被认为是减少或微调炎症的一种手段。 我们建议检验以下假设：自噬是 TRIM 保护细胞免受 HIV-1 侵害的作用的基础 感染和调节 TRIM 依赖性炎症信号传导。 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，又指导传入的 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 TRIM5α 依赖性。 最后，他们将解决慢病毒感染时促炎症信号的激活问题。 除 TRIM5α 之外，限制 HIV 的 TRIM 也在其抗病毒作用中利用自噬（目标 2）。 组建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 TRIM 作为一个家庭如何产生积极和消极影响奠定基础 我们期望这些研究表明自噬是多种 TRIM 作用的统一方面。 HIV 防御。由于自噬可以通过药物控制，我们的研究结果可能表明： 自噬的调节可能是治疗 TRIM 相关疾病的一种治疗方法，包括 HIV/艾滋病。我们在 TRIM 和自噬方面的专业知识，以及财务和机构支持。 如果 COBRE 申请获得资助，将确保成功完成这些目标。