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

系统鉴定参与人巨细胞病毒复制、组装和流出的宿主蛋白。

• 批准号: MR/N001796/1
• 负责人: Finn Grey
• 金额: $ 51.11万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN001796%2F1
• 关键词: Systematic; identification; host; proteins; involved

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.

人类巨细胞病毒（HCMV）是一种重要的人类病原体，会给移植患者带来严重问题，感染会增加器官排斥的速度和严重程度，并由于患者的免疫抑制而导致严重的疾病。它也是出生缺陷的主要原因。目前还没有有效的疫苗，可用的抗病毒疗法存在副作用和耐药性等重大问题。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重中之重。自更昔洛韦获得许可以来，很少有抗 HCMV 药物被开发用于对抗 HCMV，而且这些药物都针对相同的病毒基因，从而降低了这些药物对抗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涉及针对病毒成功复制所需的宿主基因。病毒基因组的稳定性相对较低，导致直接针对病毒基因的抗病毒药物的耐药株迅速发展。即使在治疗之前，病毒群体也常常含有突变株，使其对此类药物产生抗药性。相比之下，对针对宿主基因的药物产生耐药性会复杂得多，因为病毒需要获得突变来补偿所需细胞基因的损失。在许多情况下，此类突变可能不存在。通过抑制单个宿主基因，我们已经鉴定出参与人类巨细胞病毒复制的多个宿主基因。我们已经证明，这些宿主基因之一 VCP 对于 HCMV 复制的最早步骤之一至关重要。通过一种名为 NMS-873 的药物抑制该基因，可以完全抑制病毒复制，验证了这种抗病毒发现策略，并表明 NMS-873 可能是未来治疗 HCMV 感染的有效选择。在本申请中，我们的目标是进一步表征 VCP 如何参与 HCMV 复制，并表征可能成为 HCMV 治疗潜在药物靶点的其他宿主因素。这些发现将对新型抗病毒治疗的开发、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产生重要影响。

项目成果

Human cytomegalovirus evades ZAP detection by suppressing CpG dinucleotides in the major immediate early genes

人类巨细胞病毒通过抑制主要立即早期基因中的 CpG 二核苷酸来逃避 ZAP 检测

• DOI: 10.1101/2020.01.07.897132
• 发表时间: 2020
• 作者: Lin Y

Asparagine deprivation causes a reversible inhibition of Human Cytomegalovirus acute virus replication

天冬酰胺剥夺会导致人巨细胞病毒急性病毒复制的可逆抑制

• DOI: 10.1101/690016
• 发表时间: 2019
• 作者: Lee C

Discovering antiviral restriction factors and pathways using genetic screens.

• DOI: 10.1099/jgv.0.001603
• 发表时间: 2021-05
• 期刊: The Journal of general virology
• 作者: Jones CE;Tan WS;Grey F;Hughes DJ
• 通讯作者: Hughes DJ

Identification of Host Factors Involved in Human Cytomegalovirus Replication, Assembly, and Egress Using a Two-Step Small Interfering RNA Screen.

• DOI: 10.1128/mbio.00716-18
• 发表时间: 2018-06-26
• 期刊: mBio
• 影响因子: 6.4
• 作者: McCormick D;Lin YT;Grey F
• 通讯作者: Grey F

Does the Zinc Finger Antiviral Protein (ZAP) Shape the Evolution of Herpesvirus Genomes?

• DOI: 10.3390/v13091857
• 发表时间: 2021-09-17
• 期刊: Viruses
• 作者: Lin YT;Chau LF;Coutts H;Mahmoudi M;Drampa V;Lee CH;Brown A;Hughes DJ;Grey F
• 通讯作者: Grey F