Systematic identification of host proteins involved in Human Cytomegalovirus replication, assembly and egress.

人类巨细胞病毒（Human cytomegalovirus， HCMV）是一种重要的人类病原体，在移植患者中引起重大问题，感染可增加器官排斥反应的速度和严重程度，并因患者免疫抑制而本身引起严重疾病。它也是导致出生缺陷的主要传染病。目前没有有效的疫苗，可用的抗病毒疗法存在严重问题，包括副作用和耐药性的产生。因此，开发针对HCMV的新型抗病毒治疗方法是有效控制移植和免疫缺陷患者的当务之急。自更昔洛韦获得许可以来，很少开发出用于HCMV的抗病毒药物，其中针对的是相同的病毒基因，这降低了这些药物对耐药菌株的可能有效性。开发新型抗病毒药物的另一种策略是靶向病毒成功复制所需的宿主基因。病毒基因组相对较低的稳定性导致了对直接靶向病毒基因的抗病毒药物的耐药菌株的快速发展。即使在治疗之前，病毒群中也经常含有突变株，使它们对这些药物产生耐药性。相比之下，对靶向宿主基因的药物产生耐药性要复杂得多，因为病毒需要获得突变来弥补所需细胞基因的损失。在许多情况下，这种突变可能不存在。通过抑制单个宿主基因，我们已经确定了参与人类巨细胞病毒复制的多个宿主基因。我们已经证明，其中一种宿主基因VCP对HCMV复制的最早步骤之一至关重要。一种名为NMS-873的药物对该基因的抑制导致病毒复制的完全抑制，验证了抗病毒发现的这一策略，并表明NMS-873可能是未来治疗HCMV感染的有效选择。在本应用中，我们的目标是进一步表征VCP如何参与HCMV复制，以及表征可能成为HCMV治疗潜在药物靶点的其他宿主因子。这些发现将对开发新的抗病毒治疗方法、了解宿主因子在HCMV复制中的作用以及了解宿主因子本身的功能具有重要意义。

Human cytomegalovirus (HCMV) is an important human pathogen, causing significant problems in transplant patients, where infection can increase the speed and severity of organ rejection as well as causing sever disease in its own right due to immunosuppression of patients. It is also the leading infectious cause of birth defects.There is currently no effective vaccine and available antiviral therapies have significant issues including side effects and development of resistance. The development of new antiviral treatments against HCMV is therefore a high priority for effective control in transplant and immunodeficient patients.Very few antivirals have been developed for use against HCMV since the licensing of Ganciclovir and, of these, the same viral genes are targeted, reducing the likely usefulness of these drugs against resistant strains. An alternative strategy for the development of novel antivirals involves targeting of host genes required by the virus for successful replication. The relatively low stability of viral genomes results in rapid development of resistant strains against antiviral drugs that directly target viral genes. Even before treatment, virus populations often contain strains with mutations that render them resistant to such drugs. In contrast developing resistance against drugs that target host genes would be far more complex, as the virus would need to gain mutations that would compensate for the loss of a required cellular gene. In many cases such mutations may not exist.By inhibiting individual host genes we have identified multiple host genes that are involved in human cytomegalovirus replication. We have shown that one of these host genes, VCP, is essential for one of the earliest steps in HCMV replication. Inhibition of this gene by a drug called NMS-873, resulted in complete inhibition of virus replication, validating this strategy for antiviral discovery and suggesting NMS-873 may be a potent future treatment option for HCMV infections.In this application we aim to further characterise how VCP is involved in HCMV replication as well as characterising additional host factors that may be potential drug targets for HCMV treatment. These findings will have important implications for the development of novel antiviral treatments, understanding the role of host factors in HCMV replication as well as understanding the function of host factors themselves.