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

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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.