The Role Of Antibody in Enabling Cell-mediated Control of HCMV Infection

人巨细胞病毒（HCMV）是一个严重的临床问题。如果母亲在怀孕期间感染并传给胎儿，胎儿可能会死亡，或终身残疾，包括耳聋、失明或智力残疾。在英国，每年有超过5,000名婴儿感染巨细胞病毒，而在美国，超过44,000名婴儿将感染它。它还导致免疫系统减弱的患者，如移植受体或艾滋病毒患者的主要问题。该病毒是造成痛苦的主要原因，并给卫生系统带来沉重的财政负担;照顾一个感染CMV的婴儿每年的费用超过330，000美元。目前的治疗方法是抗病毒药物，但这些药物毒性很大，病毒会迅速对药物产生抗药性。对于许多病毒和癌症的研究，通过给予患者可以与细胞结合的抗体，并激活免疫细胞杀死感染或癌细胞，已经取得了巨大的成功。HCMV抗体可以以类似的方式控制感染，但我们对这些抗体结合哪些HCMV蛋白或哪些免疫细胞负责杀死受感染的细胞知之甚少。解决这些问题对于产生最佳疫苗、新疗法以及了解免疫系统如何控制患者的疾病非常重要。我们已经鉴定了感染细胞表面存在的所有HCMV蛋白，并表明抗体可以结合这些蛋白，使它们能够被免疫细胞“看到”。我们现在将利用这些观察结果来确定哪些病毒蛋白最擅长激活免疫细胞，哪些免疫细胞最擅长控制感染。我们还将研究病毒可能试图阻止抗体与受感染细胞结合的方式，以便我们可以绕过这些“逃避”机制。总之，这些数据将使我们能够设计有效的抗体，这些抗体被优化用于控制人类患者的HCMV疾病，并将使更有效的疫苗策略的合理设计成为可能。

Human cytomegalovirus (HCMV) is a serious clinical problem. If a mother catches it during pregnancy and it passes to the foetus, the foetus may die, or it may suffer from lifelong disabilities including deafness, blindness or intellectual disability. In the UK over 5,000 babies contract CMV every year, while in America, over 44,000 babies will catch it. It also causes major problems in patients with weakened immune systems, such as transplant recipients or HIV sufferers. The virus is a major cause of suffering, and places a high financial burden on the health system; caring for a single CMV infected baby costs >$330,000 per year. Current treatment are antivirals, however these can be very toxic, and the virus can rapidly become resistant to the drugs. For many viruses, and in the study of cancer, great success has been achieved by giving patients antibodies that can bind to cells, and activate immune cells to kill infected or cancerous cells. HCMV antibodies can control infection in a similar way, yet we have very little understanding of which HCMV proteins these antibodies are binding, or which immune cells are responsible for killing the infected cells. Answering these questions is important to generating optimal vaccines, novel therapies, and for understanding how the immune system controls disease in patients.We have identified all the HCMV proteins that are present on the surface of infected cells, and shown that antibodies can bind to these proteins, enabling them to be 'seen' by immune cells. We will now exploit these observations to determine which virus proteins are best at activating immune cells, and which immune cells are best at controlling the infection. We will also investigate the ways that the virus might try and prevent antibodies from binding to infected cells, so that we can circumvent these 'evasion' mechanisms. Taken together, this data will enable us to design effective antibodies that are optimised for controlling HCMV disease in human patients, and will enable the rational design of more effective vaccine strategies.