CHARACTERIZATION OF HCMV UL84

人巨细胞病毒(HCMV)是一种普遍存在的疱疹病毒，可引起免疫功能正常的成年人的轻度或亚临床疾病。然而，在免疫功能低下的人中可能会遇到严重的并发症。巨细胞病毒是一种全身性感染，可能会感染体内的几个部位，包括视网膜、胃肠道、肺、肝脏和中枢神经系统。最初的研究表明，人类巨细胞病毒(HCMV)需要11个不同的基因位点进行依赖于来源的DNA复制。后来的研究表明，在最初描述的11个基因座中，UL84似乎是oriLyt依赖复制所需的唯一非核心复制蛋白。这一事实，再加上在HCMV oriLyt中存在RNA-DNA杂交结构的观察，表明HCMV可能具有一种不同于其他疱疹病毒的DNA复制启动方式。UL84可能是启动HCMV DNA复制的关键因子，因此是控制感染所需化疗药物的理想靶点。为此，这项提议将确定UL84在启动HCMV DNA复制和对细胞过程的影响中的作用。UL84蛋白是复制巨细胞病毒DNA所必需的，正如瞬时检测和病毒突变体所证明的那样。UL84功能的阐明将有助于抗巨细胞病毒药物的开发。我们的假设是UL84通过与复制起始点oriLyt直接相互作用参与了HCMV DNA复制的启动，并参与了宿主细胞RNA加工的调节。

Human cytomegalovirus (HCMV) is a ubiquitous herpes virus causing mild or subclinical disease in immunocompetent adults. However, severe complications may be encountered in immunocompromised individuals. HCMV is a systemic infection that may infect several sites in the body, including the retina, gastrointestinal tract, lungs, liver and central nervous system. Initially it is was shown that human cytomegalovirus (HCMV) required eleven distinct loci for origin-dependent DNA replication. In later studies it was demonstrated that, of the eleven loci originally described, UL84 appeared to be the only non- core replication protein required for oriLyt-dependent replication. This fact, coupled with the observation that RNA-DNA hybrid structures are present within HCMV oriLyt, suggests the possibility that HCMV may have a mode of initiation of DNA replication unlike that of other herpesviruses. UL84 may be the key factor involved in initiation of HCMV DNA replication and, therefore, an ideal target for chemotherapeutic agents needed to control infection. To this end, this proposal will define the role of UL84 in the initiation of HCMV DNA replication and effects on cellular processes. The UL84 protein is required for HCMV DNA replication as demonstrated in transient assays and with a viral mutant. The elucidation of a function for UL84 will allow for the development of anti-HCMV drugs. Our hypothesis is that UL84 is involved in the initiation of HCMV DNA replication by a direct interaction with the origin of replication, oriLyt, and participates in the regulation of host cell RNA processing.