Most people carry human cytomegalovirus (HCMV) for life without ever knowing it, but when the immune system weakens—in transplant recipients or people with AIDS—the virus reactivates and can cause serious disease. The problem is that no one fully understands how HCMV hides from the immune system during latency, or how it disarms the body’s first line of defence—interferons—when it reactivates. This project uses new proteomic techniques to track thousands of proteins on the surface of infected cells over time, identifying exactly which antiviral proteins the virus targets and destroys. If the researcher succeeds, the work could reveal new markers for latent infection and pinpoint vulnerable points in the virus’s strategy. That could lead to drugs that block reactivation, or to better ways of monitoring at-risk patients. The research is fundamental science—it asks how a stealthy virus manipulates human cells at the molecular level—but understanding that mechanism is the first step toward designing therapies that keep the virus dormant.
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Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that infects 60-90% of individuals. Following primary infection, HCMV establishes a latent infection under the control of a healthy immune system. Reactivation from viral latency to productive infection causes serious disease in immunocompromised individuals, such as transplant recipients and AIDS patients. The plasma membrane (PM) provides a critical interface between the cell and its environment, and is the initial portal of entry for viruses. Early interactions between virus and cellular sensors trigger synthesis of interferons (IFN), however little is known about HCMV subversion of IFN-mediated immunity during latency and reactivation, and IFN-evasion during productive infection is only partly understood. I have developed novel unbiased quantitative proteomic techniques that identify plasma membrane and intracellular proteins modulated by viral infection. I used 'plasma membrane profiling' (PMP) to discover that HCMV la tency protein UL138 targets cell surface multi-drug resistance protein-1 (MRP1) for degradation, providing a marker and therapeutic target for latent infection. Using new proteomic technology, I developed 'Quantitative Temporal Viromics' to analyse >8,000 proteins including 1,200 PM proteins over time through the entire course of productive HCMV infection. I have filtered these data to identify 17 novel proteins targeted by HCMV that induce or respond to IFN. I now wish to determine: 1.What a re the functional consequences and mechanism of downregulation of IRF3, PARP9 and PARP14 during productive infection? 2.(i).How are these and other IFN-associated antiviral factors subverted by HCMV during experimental latency and reactivation? 2.(ii).Can key targets be validated during natural latency, and what are their functional effects?
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