CHARACTERIZATION OF HCMV UL84

人巨细胞病毒（HCMV）是一种普遍存在的疱疹病毒，在免疫功能正常的成年人中引起轻度或亚临床疾病。然而，免疫功能低下的个体可能会遇到严重的并发症。HCMV是一种全身性感染，可感染身体多个部位，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个不同的基因座来进行起源依赖性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，再加上观察到HCMV oriLyt中存在RNA-DNA杂交结构，表明HCMV可能具有与其他疱疹病毒不同的DNA复制启动模式。UL84可能是参与HCMV DNA复制起始的关键因子，因此是控制感染所需化疗药物的理想靶点。为此，本提案将确定UL84在HCMV DNA复制起始中的作用及其对细胞过程的影响。UL84蛋白是HCMV DNA复制所必需的，这在瞬时试验和病毒突变体中得到了证实。阐明UL84的功能将有助于开发抗hcmv药物。我们的假设是UL84通过与复制起点oriLyt的直接相互作用参与HCMV DNA复制的起始，并参与宿主细胞RNA加工的调控。

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.