Cellular Nucleotide Metabolism in HIV Restriction

HIV 限制中的细胞核苷酸代谢

• 批准号: 9057577
• 负责人: FRED W PERRINO
• 金额: $ 38.31万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9057577
• 关键词: ADAR1; Address; Alleles; Antigen Presentation; Antiviral Agents; Antiviral Response; Autoimmune Diseases; Autoimmunity; Binding; Biochemical; Biochemical Genetics; Biochemistry; Biological Assay; Cell Lineage; Cells; Chemicals; Chronic; Complex; Defense Mechanisms; Degradation Pathway; Enzymes; Family; Gap Junctions; Genes; Genetic; Glean; Goals; HIV; HIV Infections; Health; Homeostasis; Human; Hydrolase; Immune response; Immune system; Infection; Inflammation; Integration Host Factors; Interferons; Ions; Mediating; Methods; Mutation; Myelogenous; Myeloid Cells; Natural Immunity; Neurodegenerative Disorders; Nucleic Acids; Nucleotides; Pathogenesis; Primates; Recombinants; Regulation; Reverse Transcription; Ribonucleases; Roentgen Rays; Role; Series; Specificity; Staging; Structural Biochemistry; Structure; Substrate Specificity; Symptoms; Syndrome; System; TREX1 gene; Variant; Viral; Viral Antigens; Viral Load result; Virus Diseases; Work; adaptive immunity; cell type; deoxyguanosine triphosphate; divalent metal; experience; immune activation; inhibitor/antagonist; innovation; insight; lupus-like; mutant; novel; nucleic acid metabolism; nucleotide metabolism; pathogen; protein function; pseudotoxoplasmosis syndrome; research study; response; screening; structural biology; therapeutic target; vif Gene Products; vpr Gene Products

DESCRIPTION (provided by applicant): Our long-term goal is to understand how host factors function in human cells at the interface of maintaining nucleotide homeostasis and initiating viral defense mechanisms. The battle between viral pathogens like HIV and the primate immune system has placed nucleic acid metabolism center stage. For example, the restriction factors SAMHD1 and APOBEC3D/F/G/H dominantly interfere with HIV replication and are counteracted by viral Vpx and Vif proteins, respectively. Mutations in the SAMHD1 gene cause the autoimmune disease Aicardi-Goutieres syndrome (AGS), a lupus-like neurodegenerative disorder that clinically mimics congenital viral infection. Key insights into the interferon-mediatd innate immune response to nucleic acids have been gleaned from the genetics of AGS. AGS is caused by variations in the nucleic acid metabolizing enzymes SAMHD1, TREX1, the three-subunit RNase H2 complex, and ADAR1. Our work on the biochemistry and structure of SAMHD1 revealed the deoxynucleotide triphosphohydrolase activity and suggested a mechanism by which this enzyme might function at the interface of nucleic acid metabolism and the interferon-mediated antiviral response, serving normally to regulate cellular dNTP levels and during an interferon response to starve HIV of dNTPs required for reverse transcription. However, the details of the mechanism of SAMHD1 action in human cells and in HIV pathogenesis during immune activation are not well understood. In particular, the mechanisms by which this enzyme is regulated and how dysfunctional variants of SAMHD1 trigger nucleic acid-mediated innate immune responses and autoimmune disease have not been defined. In this project we will perform biochemical, genetic, and structural studies to generate a comprehensive understanding of SAMHD1 and its roles in nucleic acid metabolism, antiviral defense, and autoimmunity. Insights into these mechanisms will uncover new opportunities for therapeutic targeting in the antiviral response, autoimmunity, and inflammation.

描述（由申请人提供）：我们的长期目标是了解人类细胞中宿主因子如何在维持核苷酸稳态和启动病毒的界面上发挥作用 防御机制。 HIV等病毒病原体与灵长类动物免疫系统之间的战斗已将核酸代谢置于中心舞台。例如，限制因子 SAMHD1 和 APOBEC3D/F/G/H 主要干扰 HIV 复制，并分别被病毒 Vpx 和 Vif 蛋白抵消。 SAMHD1 基因突变会导致自身免疫性疾病 Aicardi-Goutieres 综合征 (AGS)，这是一种类似狼疮的神经退行性疾病，临床上类似于先天性病毒感染。关于干扰素介导的核酸先天免疫反应的关键见解是从 AGS 遗传学中收集到的。 AGS 是由核酸代谢酶 SAMHD1、TREX1、三亚基 RNase H2 复合物和 ADAR1 的变异引起的。我们对 SAMHD1 的生物化学和结构的研究揭示了脱氧核苷酸三磷酸水解酶的活性，并提出了一种机制，该酶可能在核酸代谢和干扰素介导的抗病毒反应的界面上发挥作用，正常情况下调节细胞 dNTP 水平，并在干扰素反应期间使 HIV 缺乏逆转录所需的 dNTP。然而，SAMHD1 在人体细胞和免疫激活过程中 HIV 发病机制中的作用机制细节尚不清楚。特别是，这种酶的调节机制以及 SAMHD1 的功能失调变体如何触发核酸介导的先天免疫反应和自身免疫性疾病尚未明确。在这个项目中，我们将进行生化、遗传学和结构研究，以全面了解 SAMHD1 及其在核酸代谢、抗病毒防御和自身免疫中的作用。对这些机制的深入了解将揭示抗病毒反应、自身免疫和炎症治疗靶向的新机会。