UL34 AND HERPES SIMPLEX VIRUS INFECTION

单纯疱疹病毒(HSV)是一种广泛分布的人类病原体。血清学研究表明，至少50%的美国成年人口对这两种单纯疱疹病毒中的至少一种有抗体，这表明在某个时候会受到感染。疾病的严重程度从无症状到致命不等，这取决于感染者的年龄和免疫能力。通过了解病毒编码蛋白的功能以及这些产物在受感染细胞中的调节机制，可以改善对单纯疱疹病毒和相关疱疹病毒的控制。这里提出的研究将鉴定必要的UL34基因产物的功能。初步研究表明，UL34蛋白是一种膜相关蛋白，其合成的时间和在细胞中的定位表明其具有包膜或出口的功能。这些研究将需要构建和鉴定UL34缺陷病毒，以及鉴定与UL34蛋白相互作用并受UL34蛋白调控的细胞蛋白。这些结果反过来应该阐明由US11和US3蛋白介导的调节事件的功能，它们调节UL34基因的这些产物。这项拟议的研究是新颖的，从几个角度来看可能具有很高的医学意义。(I)UL34基因产物在包括水痘带状疱疹病毒(VZV)在内的甲型疱疹病毒中保守，很可能是在细胞培养和人类宿主中复制所必需的病毒基因产物。因此，它的功能代表了一个潜在的治疗靶点。(Ii)UL34基因产物的功能明显受磷酸化的调节，而UL34又似乎调节细胞蛋白质的磷酸化。调节磷酸化是一种控制广泛细胞过程的普遍策略，这些研究很可能揭示病毒调节细胞磷酸化的新例子。(3)UL34基因座受US11 RNA结合蛋白调控。与US11介导的UL34基因转录本的调控一样，特定的RNA-蛋白质相互作用在调控许多对控制细胞增殖至关重要的过程中(包括癌基因活性的调控)，以及在调控嗜淋巴逆转录病毒的感染方面是至关重要的。这些研究将有助于理解RNA-蛋白质相互作用产生调控效应的方式。

Herpes simplex viruses (HSVs) are widely distributed human pathogens. Serological studies suggest that at least 50 percent of the american adult population have antibodies to at least one of the two herpes simplex viruses, indicating infection at some time. The severity of disease ranges from asymptomatic to lethal, depending upon the age and immune competence of the infected individual. Control of herpes simplex viruses and related herpesviruses can be improved by understanding the functions of the virus-encoded proteins, and the mechanisms by which those products are regulated in the infected cell. The research proposed here will identify the function of the product of the essential UL34 gene. Preliminary studies have shown that the UL34 protein is a membrane associated protein whose timing of synthesis and localization in the cell suggest a function in envelopment or egress. These studies will entail the construction and characterization of UL34-deficient viruses, and identification of cellular proteins that interact with, and are regulated by the UL34 protein. These results should, in turn, illuminate the function of the regulatory events mediated by the US11 and US3 proteins, which regulate these products of the UL34 gene. The proposed research is novel and likely to be highly medically significant from several points of view. (i) The UL34 gene product is conserved among alphaherpesviruses including varicella zoster virus (VZV) and is very likely an essential virus gene product for replication in cell culture and in the human host. Its function, therefore, represents a potential therapeutic target. (ii) The function of the UL34 gene product is apparently regulated by phosphorylation, and UL34, in turn appears to regulate the phosphorylation of cellular proteins. Regulation of phosphorylation is a ubiquitous strategy for controlling a wide range of cellular processes, and these studies are likely to expose a novel example of viral regulation of cellular phosphorylation. (iii) The UL34 locus is regulated by the US11 RNA binding protein. Specific RNA-protein interactions like that involved in US11-mediated regulation of transcripts from the UL34 gene are critical in regulating many processes important to the control of cell proliferation (including regulation of oncogene activity), and in regulating the infection of lymphotropic retroviruses. These studies will contribute to the understanding of the ways in which RNA-protein interactions give rise to regulatory effects.