Roles and regulation of polyamines during HCMV infection

人巨细胞病毒（HCMV）可导致免疫系统功能低下的患者发生危及生命的疾病，以及宫内感染婴儿的长期神经功能缺损。在HCMV有效复制所需的许多宿主细胞因子中，有一种称为多胺（PA）的小碱性分子。在它们的无数活动中，PA与细胞中的蛋白质合成机器结合。同样，它们也是制造一种被称为eIF5A的蛋白质所必需的，这种蛋白质是将氨基酸连接在一起以制造某些蛋白质所必需的。尽管几十年来人们已经知道PA对于HCMV有效繁殖是至关重要的，并且HCMV感染会增加PA的细胞内浓度，但需要PA的原因以及病毒用于确保细胞中有足够量的PA的机制尚不清楚。从控制PA水平的几种宿主细胞蛋白的研究中出现的有趣数据表明，PA和eIF5A可能控制一些HCMV基因的表达，特别是一种称为gpUL4的迷人基因。先前的研究表明，gpUL4的产生受到极大的抑制，因为制造它的机器被困在信使RNA上，因为一个特定的氨基酸序列被连接在一起。这些和其他结果表明，gpUL4，其功能已被谜了几十年，可能有助于控制在HCMV感染过程中的PA积累。使用影响gpUL4产生的各种HCMV突变体沿着用于改变PA和eIF5A丰度的遗传和药理学工具，Aim 1将揭示PA和eIF5A是否以及如何改变病毒感染期间的捕获机制。目的2将首先检验gpUL4单独和在HCMV感染期间调节细胞中PA浓度的特定假设。另一项实验将测试HCMV是否能在PA水平较低的情况下以某种方式适应繁殖。虽然这些研究集中在HCMV，特别是gpUL4，但这些结果将对理解可能受类似机制调控的其他病毒和细胞基因的控制具有广泛的意义。

Human cytomegalovirus (HCMV) causes life-threatening diseases in patients with poorly functioning immune systems as well as long-lasting neurological deficits in infants infected in utero. Among the many host cell factors that are needed by HCMV to replicate efficiently are small alkaline molecules called polyamines (PAs). Among their myriad activities, PAs bind to the protein synthesizing machinery in the cell. As well, they are necessary to make a protein, known as eIF5A, that is required for linking together amino acids to make certain proteins. Although it has been known for decades that the PAs are critical for HCMV to reproduce efficiently and that HCMV infection increases the intracellular concentration of PAs, the reasons why PAs are needed and the mechanisms the virus uses to ensure that there are sufficient amounts of PAs in the cells are unknown. Intriguing data emerging from studies of several host cell proteins that control the levels of PAs suggest that PAs and eIF5A might control expression of some HCMV genes, in particular a fascination one called, gpUL4. Prior studies showed that the production of gpUL4 is greatly repressed because the machinery for making it becomes trapped on the messenger RNA as a particular sequence of amino acids are being linked together. These and other results suggest that gpUL4, the function of which has been enigmatic for decades, might contribute to the control of PAs accumulation during HCMV infection. Using various HCMV mutants that affect the production of gpUL4 along with genetic and pharmacological tools for altering PA and eIF5A abundance, Aim 1 will reveal if and how PA and eIF5A alter the trapping mechanism during viral infection. Aim 2 will first test the specific hypothesis that gpUL4, alone and during HCMV infection, regulates the concentration of PAs in the cells. Another experiment will test whether HCMV can somehow adapt to reproduce well even when PA levels are low. While these studies focus on HCMV, and especially gpUL4, the results will have broad implications for understanding control of other viral and cells genes that are likely regulated by a similar mechanism.