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: 10249120
• 负责人: Michael Aaron Mandell
• 金额: $ 25.13万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249120
• 关键词: AIDS/HIV problem; Address; Affect; 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; Infection; Inflammation; Inflammatory; Innate Immune Response; Life Cycle Stages; Metabolism; Molecular; Pathway interactions; Pattern recognition receptor; Pharmaceutical Preparations; Pharmacology; Play; Predisposition; Protein Family; Proteins; Regulation; Rhesus; 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限制因子的相对能力干扰病毒生命周期 有助于宿主对感染的敏感性水平。限制因子的药理增强 功效将是治疗艾滋病毒感染的一种新方法。但是，HIV阻塞的机械基础 通过限制因素，尚未完全理解妨碍基于员工限制因素的主机的努力 定向疗法。蛋白质的三方图案（修剪）家族由人类的70多名成员组成， 其中一些已被确定为抗病毒限制因素。在这个角色中，修剪会减少病毒 直接通过对病毒生命周期干扰或通过微调细胞先天免疫来直接复制 回答。 Trim家族成员TRIM5α完成了这两个：首先，它防止了逆转录病毒感染 通过隐藏的无法解释的机制细胞。其次，TRIM5α也充当模式识别受体， 通过激活炎症信号通路来促进抗病毒细胞状态 逆转录病毒识别。 尽管装饰似乎是抗逆转录病毒防御中的多种方法，但一种非常普遍的方法 修剪家族中的特征是，许多修剪都参与了法规和执行 自噬。除了它是针对细胞内病原体的已知防御机制（包括 HIV-1），自噬也越来越被认为是减少或微调注射的一种手段。这里， 我们建议检验以下假设：自噬是保护细胞免受HIV-1的修剪作用的基础 感染并调节依赖性炎症信号传导。这里提出的研究有 几个总体目标。首先，他们寻求提高我们对分子机制的理解 RhesusTrim5α都调节自噬并指导传入的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制是否影响trim5α依赖性 慢病毒感染时促炎信号的激活。最后，他们将解决人类是否 限制HIV的TRIM5α以外的其他修剪也采用了自噬在其抗病毒作用中（AIM 2）。我们有 组建了一个自噬和艾滋病毒专家团队，以解决这些问题。 我们的研究有可能发现几种已知的抗逆转录病毒蛋白和 为我们理解修剪家庭如何积极和负面影响奠定基础 炎。我们希望这些研究表明自噬是潜水员修剪行动的统一方面 艾滋病毒防御。由于可以通过药物操纵自噬，因此我们的发现可能表明 自噬的调节可能是处理与修剪相关疾病的治疗方法 艾滋病毒/艾滋病。我们在修剪和自噬方面的专业知识，以及财务和机构支持 前提是如果毛申请资助，将确保成功完成这些目标。