Restriction of Lentiviruses by SAMHD1

人类进化出了宿主限制因子，以防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，病毒设法绕过了这些限制。艾滋病毒等逆转录病毒抵消宿主细胞限制的一种机制是通过编码辅助蛋白，如VPX，这是一种病毒粒子包装的病毒蛋白，可中和宿主限制因子SAMHD1，诱导其蛋白酶体降解。SAMHD1阻止逆转录病毒在巨噬细胞和树突状细胞中的复制，这两种细胞类型在适应性和先天免疫反应中发挥重要作用，是慢病毒的关键靶标。SAMHD1是一种磷酸水解酶，可以破坏细胞的脱氧核苷三磷酸(DNTP)。因为dNTP是DNA的构建块，所以病毒需要它们在进入目标细胞后复制自己的基因组。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。要做到这一点，将识别与SAMHD1相互作用的细胞蛋白，并将表征该蛋白的翻译后修饰。

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.