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 由原代巨噬细胞，树突状细胞和 静止的CD4+ T细胞。 SAMHD1通过防止发生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反向 通过诱导SAMHD1降解来转录块。 SAMHD1是DGTP调节的脱氧核苷酸 三磷氢化素酶降低了三磷脱氧核苷酸（DNTPS）的细胞水平。有趣的是， 循环和非循环细胞表达SAMHD1；但是，仅在非 - 循环细胞。我们的初步发现与在非循环细胞中观察到的慢病毒限制表型相关 带有SAMHD1的磷酸化和S-谷胱甘肽态。该提议将检验以下假设 SAMHD1抗病毒活性受磷酸化和S-谷氨酸的调节。以下特定目标 将用于解决这一假设。 AIM1将探索SAMHD1磷酸化在逆转录病毒中的作用 限制。 AIM 2将探索S-谷胱甘肽化在逆转录病毒限制中的作用。 AIM 3将探讨 I型IFN响应中的SAMHD1。总体而言，该建议将建立SAMHD1抗病毒的调节 活动。了解SAMHD1的调节对新型抗HIV-1的发展具有重要作用 自克服SAMHD1以来，疫苗策略增加了感染期间的适应性免疫反应 树突状细胞和巨噬细胞。