Exploring the molecular factors that determine the fate of human cytomegalovirus infection: From cellular factors to viral targets, from the bench-side to the bed-side

Abstract

Human cytomegalovirus (HCMV) is a ubiquitous viral pathogen that infects the majority of the world’s population. Following a mild primary infection in healthy immunocompetent hosts, the virus persists indefinitely in a latent state which is never fully eradicated. Periodic reactivation of HCMV from latency in immunocompetent individuals rarely lead to disease due to an effective immune response. However reactivation during immunosuppression often leads to the development of serious, life-threatening diseases. Prevention of HCMV disease has remained an elusive goal, and there is currently no licensed vaccine, nor anti-viral therapy that is able to target latent virus, and the molecular basis of latency and reactivation remain very poorly understood. In this thesis, both cellular and viral factors that may play a role in determining the fate of HCMV infection were examined. Firstly, the possible role of the cellular transcriptional repressor Cut-like homeobox protein (CUX1) in influencing the outcome of HCMV infection was investigated. Secondly, a region of the HCMV genome (UL108-UL110) was characterised in the various contexts of the HCMV life-cycle by using viral genome manipulation and models of infection. Finally, the overall HCMV transcriptome during clinical reactivation in allogeneic hematopoietic stem cell transplants (HSCT) patients was examined.