Regulation of SAMHD1 antiviral activity

SAMHD1 抗病毒活性的调节

基本信息

批准号：
9355206
负责人：
Felipe Diaz-Griffero
金额：
$ 44.13万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
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/9355206
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 Heritability Histidine Human Immune In Vitro Individual Infection Infection prevention Interferon Type I Interferons Label Mass Spectrum Analysis Metabolic Molecular Conformation Mus Mutate Mutation Nucleotides Partner in relationship 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 immune response blocking factor cofactor deoxyguanosine triphosphate experimental study interest macrophage mimetics novel particle prevent pseudotoxoplasmosis syndrome response sensor tripolyphosphate

项目摘要

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联带有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-谷氨酸化的调节。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。