Systematic analysis of human cytomegalovirus immune evasion

Human cytomegalovirus (HCMV) causes significant morbidity and mortality in immunosuppressed people, and congenitally-acquired HCMV is a major cause of birth defects worldwide. HCMV encodes >100 proteins to manipulate cellular immunity and enhance viral persistence. Studying these proteins has uncovered numerous factors influencing the outcome of infection with HCMV, as well as other viruses. Nonetheless, most of them remain uncharacterised. We have developed unique multiplexed proteomic approaches to determine how viruses modulate host cells. We will now combine these approaches with whole-HCMV mutagenesis, functional immune studies, host genome-scale screens and machine learning, to comprehensively characterise and rank the most critical mechanisms of viral immune-evasion and persistence. We will: 1.Define which HCMV proteins are innate/intrinsic immune evasins; 2.Characterise how each evasin modulates the host proteome; 3.Elucidate the mechanisms of the most potent evasins and their host targets; 4.Determine how HCMV immune evasion can be exploited for biological understanding and clinical benefit. These studies will transform our understanding of HCMV’s pathogenesis and persistence, and provide multiple new insights into human antiviral immunity and the vulnerabilities viruses exploit to undermine host defences. These discoveries will enable us to stratify risk of disease from diverse viruses, and develop new therapies for HCMV and other pathogens.