The role of B cell Cul4b in gammaherpesvirus latency and lymphoma

About This Grant

PROJECT SUMMARY Gammaherpesviruses chronically infect more than 90% of all humans worldwide by establishing lifelong latency in B cells. Latent infection is usually asymptomatic, but these viruses can be oncogenic, especially in immunocompromised patients. One example is Epstein Barr Virus (EBV), the cause of Burkitt lymphoma, and the first oncogenic virus ever discovered. No vaccines or antivirals are available to prevent or cure gammaherpesvirus latency, despite the high infection rates and oncogenic potential. One barrier to the development of such interventions is that there is a limited mechanistic understanding of how these viruses establish latency and drive lymphoma. A better understanding of viral and host factors that regulate latency and lymphoma formation would lay the groundwork new vaccines or therapies in the future. A key feature of all gammaherpesviruses is that they infect B cells and drive them through the germinal center activation program before establishing latency in memory B cells. The mouse gammaherpesvirus, MHV68, faithfully reproduces this characteristic, and MHV68 can be used to study viral pathogenesis in vivo. Using this model, we have discovered that the host ubiquitin ligase, Cul4b, is essential for establishment of latency in B cells. Infection of mice that lack Cul4b only in B cells results in a 100-fold reduction in viral latency and also reduces the magnitude of the antiviral humoral response, suggesting that Cul4b is directly needed to support germinal center B cell activation pathways. Our lab is the first to report a role for Cul4b in B cells, but in cell lines and human tumors, Cul4b facilitates proliferation and malignancy. This project will use the MHV68 mouse model of chronic infection and lymphomagenesis to define the role of Cul4b in infected GC B cells, in direct comparison with antigen-activated GC B cells, and we will define the impact of Cul4b on gammaherpesvirus-induced malignancy. The results will shed new light on the understanding of gammaherpesvirus latency establishment, lymphomagenesis, and basic GC B cell biology. This information will be useful for designing strategies to prevent or cure latent infection and gammaherpesvirus induced malignancy, especially in high-risk immunocompromised patients.