Regulation of SAMHD1 antiviral activity

最近发现的人类限制性因子SAMHD 1的表达是感染的原因 阻断由原代巨噬细胞、树突细胞和巨噬细胞对慢病毒如HIV-1、HIV-2和SIVmac的作用。 静息CD4 + T细胞。SAMHD1通过阻止逆转录的发生来阻断慢病毒感染。 SIVmac和HIV-2颗粒中含有的病毒辅助蛋白Vpx克服了SAMHD 1逆转 通过诱导SAMHD 1降解来阻断转录。SAMHD 1是一种dGTP调节的脱氧核苷酸 三磷酸水解酶是一种降低三磷酸脱氧核苷酸（dNTP）的细胞水平的三磷酸水解酶。有趣的是， 循环和非循环细胞表达SAMHD 1;然而，SAMHD 1的抗病毒活性仅在非循环细胞中观察到。 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性表型相关 与SAMHD 1的磷酸化和S-谷胱甘肽化状态有关。这一提议将检验以下假设： SAMHD1抗病毒活性受磷酸化和S-谷胱甘肽化调节。以下具体目标 将被用来解决这个假设。Aim1将探索SAMHD 1磷酸化在逆转录病毒中的作用 限制.目的2探讨S-谷胱甘肽化在逆转录病毒限制性酶切中的作用。目标3将探讨 SAMHD 1在I型IFN应答中的作用。总的来说，这项提案将建立SAMHD 1抗病毒药物的监管， 活动了解SAMHD 1的调控有助于开发新的抗HIV-1药物 疫苗策略，因为克服SAMHD 1增加了感染期间的适应性免疫应答， 树突细胞和巨噬细胞。

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.