Title: Optimising a novel antiviral immunotherapy
Funder: Health and Care Research Wales (Welsh Government)

Abstract: Human cytomegalovirus (HCMV) is a virus that spreads through saliva, blood, breast milk, and urine. Nearly everyone becomes infected during their life and following this the virus lives inside them forever. HCMV causes serious complications and even death for those with weakened immune systems, such as transplant recipients. It also causes disease if it spreads from a mother to her unborn baby, leading to permanent disabilities such as intellectual disability, blindness, deafness, or death. HCMV infection of babies is more common than other conditions such as Downs syndrome, occurring in over 5,000 babies per year in the UK, and 44,000 per year in the USA. Drugs exist, but are toxic, are not licensed for use during pregnancy or in new-borns, the virus can rapidly become resistant, and there is no vaccine. Better therapies are urgently needed. Current efforts have focussed on neutralising antibodies – these bind to virions and prevent them from infecting cells. However, HCMV spreads directly between cells in the body, so that neutralising antibodies cannot physically bind it. The virus also changes the cell so that the immune system cannot tell which cells are infected. We therefore developed a novel antibody that marks infected cells, so that they can be detected and destroyed by the immune system. These are the first antibodies that have ever been able to control HCMV spread and are being developed commercially. Yet despite their effectiveness, they suffer from two limitations: • They only mark cells where the virus is actively replicating, but HCMV ‘hides’ in some cells without replicating • The spread of virus is stopped, but even in replicating cells, the virus is not completely eliminated This proposal will investigate why these limitations occur, so that we can develop ways of circumventing them. This will allow us to generate a ‘second generation’ improved immunotherapy.

Lay abstract: Human cytomegalovirus (HCMV) is a virus that spreads through saliva, blood, breast milk, and urine. Nearly everyone becomes infected during their life and following this the virus lives inside them forever. HCMV causes serious complications and even death for those with weakened immune systems, such as transplant recipients. It also causes disease if it spreads from a mother to her unborn baby, leading to permanent disabilities such as intellectual disability, blindness, deafness, or death. HCMV infection of babies is more common than other conditions such as Downs syndrome, occurring in over 5,000 babies per year in the UK, and 44,000 per year in the USA. Drugs exist, but are toxic, are not licensed for use during pregnancy or in new-borns, the virus can rapidly become resistant, and there is no vaccine. Better therapies are urgently needed. Current efforts have focussed on neutralising antibodies – these bind to virions and prevent them from infecting cells. However, HCMV spreads directly between cells in the body, so that neutralising antibodies cannot physically bind it. The virus also changes the cell so that the immune system cannot tell which cells are infected. We therefore developed a novel antibody that marks infected cells, so that they can be detected and destroyed by the immune system. These are the first antibodies that have ever been able to control HCMV spread and are being developed commercially. Yet despite their effectiveness, they suffer from two limitations: • They only mark cells where the virus is actively replicating, but HCMV ‘hides’ in some cells without replicating • The spread of virus is stopped, but even in replicating cells, the virus is not completely eliminated This proposal will investigate why these limitations occur, so that we can develop ways of circumventing them. This will allow us to generate a ‘second generation’ improved immunotherapy.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION