An integrated quantitative virological and immunological approach to optimise treatment and define correlates of immune protection against cytomegalovirus in allograft recipients. (360G-Wellcome-078332_Z_05_Z)

In a unique collaboration with transplant clinicians we have produced a paradigm shift in understanding the pathogenesis of HCMV infection. Specifically, we have shown that: a) this virus replicates with rapid dynamics; b) it causes disease in individuals once a critical threshold value of viral load has been reached in the blood; c) patients with rapid replication have a HCMV-specific CD8+ immune defect ("specific interferon gamma impairment; SIGI") which precedes the onset of viraemia. These novel findings will be taken forward in four ways: i) we will conduct randomised controlled trials to optimise treatment based on real time measurement of HCMVviral load; ii) we will determine if SIGI explains why some patients have a slow response to treatment; iii) we will determine if reinfection with a different strain of HCMV can induce SIGI; iv) we will systematically extend immunological studies to determine if other specific immune responses against additional HCMV proteins, restricted by class I and class II HLA molecules, also correlate with full control of HCMV replication.