Regulation of SAMHD1 antiviral activity

新近发现的人类限制因子SAMHD1的表达与感染有关 原代巨噬细胞、树突状细胞和巨噬细胞对慢病毒如HIV-1、HIV-2和SIVmac的阻断 静息的CD4+T细胞。SAMHD1通过阻止反转录的发生来阻止慢病毒的感染。 病毒辅助蛋白VPX包含在SIVmac和HIV-2颗粒中，克服了SAMHD1逆转 通过诱导SAMHD1降解来阻断转录。SAMHD1是dGTP调控的脱氧核苷酸 降低细胞内三磷酸脱氧核苷酸(DNTPs)水平的三磷酸水解酶。有趣的是， 周期和非周期细胞表达SAMHD1；然而，SAMHD1‘S抗病毒活性仅在非周期细胞中观察到 循环细胞。我们的初步发现与在非周期细胞中观察到的慢病毒限制表型相关 与SAMHD1的磷酸化和S谷胱甘肽基化状态有关。这项提议将检验这样一个假设： SAMHD1的抗病毒活性受磷酸化和S谷胱甘肽的调节。以下是具体目标 将被用来解决这一假说。Aim1将探讨SAMHD1磷酸化在逆转录病毒中的作用 限制。目的2探讨S谷胱甘肽基化在逆转录病毒限制性内切酶中的作用。目标3将探讨 SAMHD1在I型干扰素应答中。总体而言，该提案将建立对SAMHD1抗病毒药物的监管 活动。了解SAMHD1的调控机制有助于开发新型抗HIV-1药物 攻克SAMHD1后的疫苗策略提高了感染期间的获得性免疫反应 树突状细胞和巨噬细胞。

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.