Regulation of SAMHD1 antiviral activity

SAMHD1 抗病毒活性的调节

• 批准号: 9205960
• 负责人: Felipe Diaz-Griffero
• 金额: $ 45.57万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9205960
• 关键词: Address; Affect; Antiviral Agents; Aspartic Acid; Binding; Biological; C-terminal; CD4 Positive T Lymphocytes; Cell Cycle; Cells; Cysteine; Dendritic Cells; Development; Disease; Exhibits; Genes; Glutathione; HIV-1; HIV-1 vaccine; HIV-2; Histidine; Human; Immune; In Vitro; Individual; Infection; Infection prevention; Interferon Type I; Label; Mass Spectrum Analysis; Mus; Mutate; Mutation; Nucleotides; Phenotype; Phosphorylation; Positioning Attribute; Post-Translational Protein Processing; Production; Proteins; RNA; RNA Binding; Regulation; Rest; Reverse Transcription; Role; SAM Domain; Subfamily lentivirinae; Testing; Threonine; Viral; Work; adaptive immunity; blocking factor; cofactor; deoxyguanosine triphosphate; interest; macrophage; metabolic abnormality assessment; mimetics; novel; particle; prevent; pseudotoxoplasmosis syndrome; research study; response; sensor; tripolyphosphate

Expression of the recently discovered human restriction factor SAMHD1 is responsible for the infection block imposed to lentiviruses such as HIV-1, HIV-2 and SIVmac by primary macrophages, dendritic cells and resting CD4+ T-cells. SAMHD1 blocks lentiviral infection by preventing the occurrence of reverse transcription. The viral accessory protein Vpx, contained in SIVmac and HIV-2 particles, overcomes the SAMHD1 reverse transcription block by inducing SAMHD1 degradation. SAMHD1 is a dGTP-regulated deoxynucleotide triphosphohydrolase that decreases the cellular levels of triphosphodeoxynucleotides (dNTPs). Interestingly, cycling and non-cycling cells express SAMHD1; however, SAMHD1's antiviral activity is only observed in non- cycling cells. Our preliminary findings correlate the lentiviral restriction phenotype observed in non-cycling cells with the phosphorylation and S-glutathionylation state of SAMHD1. This proposal will test the hypothesis that SAMHD1 antiviral activity is regulated by phosphorylation and S-glutathionylation. The following specific aims will be used to address this hypothesis. Aim1 will explore the role of SAMHD1 phosphorylation in retroviral restriction. Aim 2 will explore the role of S-glutathionylation in retroviral restriction. Aim 3 will explore the role of SAMHD1 in the type I IFN response. Overall, this proposal will establish the regulation of SAMHD1 antiviral activity. Understanding the regulation of SAMHD1 is instrumental for the development of novel anti-HIV-1 vaccine strategies since overcoming SAMHD1 increases the adaptive immune response during infection of dendritic cells and macrophages.

最近发现的人类限制因子 SAMHD1 的表达是导致感染的原因 原代巨噬细胞、树突状细胞和细胞对慢病毒（例如 HIV-1、HIV-2 和 SIVmac）的阻断 静息 CD4+ T 细胞。 SAMHD1 通过阻止逆转录的发生来阻止慢病毒感染。 SIVmac 和 HIV-2 颗粒中包含的病毒辅助蛋白 Vpx 克服了 SAMHD1 逆转 通过诱导 SAMHD1 降解来阻断转录。 SAMHD1 是一种 dGTP 调节的脱氧核苷酸 三磷酸水解酶可降低三磷酸脱氧核苷酸 (dNTP) 的细胞水平。有趣的是， 循环和非循环细胞表达 SAMHD1；然而，SAMHD1 的抗病毒活性仅在非 循环细胞。我们的初步研究结果与在非循环细胞中观察到的慢病毒限制表型相关 SAMHD1 的磷酸化和 S-谷胱甘肽化状态。该提案将检验以下假设： SAMHD1 的抗病毒活性受磷酸化和 S-谷胱甘肽化的调节。具体目标如下 将用于解决这个假设。 Aim1 将探讨 SAMHD1 磷酸化在逆转录病毒中的作用 限制。目标 2 将探讨 S-谷胱甘肽化在逆转录病毒限制中的作用。目标 3 将探讨 SAMHD1 在 I 型 IFN 反应中的作用。总体而言，该提案将建立 SAMHD1 抗病毒药物的监管 活动。了解 SAMHD1 的调控有助于开发新型抗 HIV-1 克服 SAMHD1 后的疫苗策略可增加感染期间的适应性免疫反应 树突状细胞和巨噬细胞。