Restriction of Lentiviruses by SAMHD1

人类已经进化出宿主限制因子来阻止人类免疫缺陷病毒（HIV）和其他逆转录病毒的复制。不幸的是，病毒已经设法绕过了这些限制。逆转录病毒（如HIV）对抗宿主细胞限制的一种机制是通过编码辅助蛋白（如Vpx）， Vpx是一种病毒粒子包装的病毒蛋白，可对抗宿主限制因子SAMHD1，诱导其蛋白酶体降解。SAMHD1阻断逆转录病毒在巨噬细胞和树突状细胞中的复制，这些细胞类型在适应性和先天免疫应答中起重要作用，是慢病毒的关键靶点。SAMHD1是一种磷酸水解酶，可以破坏细胞中的三磷酸脱氧核苷（dNTP）。由于dNTPs是DNA的组成部分，病毒进入目标细胞后需要dNTPs来复制其基因组。因此，SAMHD1耗尽dNTP池可以保护细胞免受感染。Vpx被包装在病毒中，并在进入时释放。释放后，Vpx与SAMHD1相互作用并引导其进入蛋白酶体降解途径。该项目将研究Vpx破坏SAMHD1的机制，以及细胞如何控制SAMHD1的酶活性和数量。为此，将鉴定与SAMHD1相互作用的细胞蛋白，并对该蛋白的翻译后修饰进行表征。了解SAMHD1在不同细胞类型中的调控将为限制HIV-1的复制和提高宿主对病毒的免疫反应的有效性提供新的策略。

Humans have evolved host restriction factors that prevent the replication of the human immunodeficiency virus (HIV) and other retroviruses. Unfortunately, viruses have managed to circumvent these restrictions. One mechanism by which retroviruses such as HIV counteract host cell restrictions is by encoding accessory protein such as Vpx, a virion-packaged virus protein that counteracts the host restriction factor SAMHD1, inducing its proteasomal degradation. SAMHD1 blocks the replication of retroviruses in macrophages and dendritic cells, cell-types that play an important role in the adaptive and innate immune response and are a key target of lentiviruses. SAMHD1 is a phosphohydrolase that destroys the cells deoxynucleoside triphosphates (dNTP). Because dNTPs are the building blocks for DNA, they are required by viruses to replicate their genome following entry into a target cell. Thus, depletion of the dNTP pool by SAMHD1 protects the cell from becoming infected. Vpx is packaged in the virus and is released upon entry. Upon release, Vpx interacts with SAMHD1 and directs it to the proteasomal degradation pathway. The project will investigate the mechanism by which Vpx destroys SAMHD1 and how the enzymatic activity and amount of SAMHD1 is controlled by the cell. To do this, cellular proteins that interact with SAMHD1 will be identified and post-translational modifications of the protein will be characterized. Understanding the regulation of SAMHD1 in different cell-types will provide novel strategies to limit the replication of HIV-1 and to improve the effectiveness of the host immune response to the virus.