Defining mechanisms of gammaherpesvirus-driven genomic instability in B cells

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PROJECT SUMMARY Gammaherpesviruses (GHVs) establish lifelong chronic infections that place the host at risk for numerous cancers. During chronic infection, GHVs express viral gene products that stimulate host-cell proliferation and differentiation, processes thought to facilitate long-term latent persistence and contribute to tumorigenesis. However, GHVs are not acutely transforming, and cancer is rare given the high incidence of infection among adult humans, estimated at more than 95% for Epstein-Barr virus (EBV). This suggests that host cells are equipped with an intrinsic resistance to GHV-driven proliferation and cellular immortalization. In work performed during the previous funding period, we identified the tumor suppressor p53 as a protein that is activated during the establishment of GHV latent infection. p53 is frequently considered a “guardian of the genome”, working downstream of multiple mutagenic pathways to halt cell-cycle progression, stimulate DNA repair, or promote apoptosis. p53 is frequently mutated in human cancers, including endemic Burkitt lymphoma, an EBV-associated lymphoma that is characterized by a chromosomal translocation between the immunoglobulin heavy-chain promoter and cellular proto-oncogene c-myc. It is hypothesized that EBV synergizes with malaria, to promote the survival of cells that harbor IgH/c-myc translocations. Using murine gammaherpesvirus 68 (MHV68) infection of mice as a small animal model to enable a multi-system analysis GHV pathogenesis, we demonstrated that p53 limits cellular proliferation, especially of germinal center (GC) cells. We also found that p53 inhibits IgH/c- myc translocations in B cells of infected mice, an event that correlates with enhanced B cell lymphoma development in p53-deficient mice infected with MHV68. Moreover, we provide preliminary data indicating that co-infection of mice with MHV68 and a murine malaria parasite also promotes IgH/c-myc translocations. Experiments proposed in this competing renewal will build on our previous progress, harnessing the powerful mouse and MHV68 genetic systems, to (i) define viral genes and molecular pathways that promote genomic instability and lymphoma development, (ii) identify viral and host-factor dependencies in GHV-driven lymphomas, and (iii) determine the mechanisms through which MHV68 and murine Plasmodium parasites facilitate chromosomal translocations. In addition to providing a better understanding of how GHVs cause disease, we anticipate that results of this work will inform new therapeutic approaches that target lymphoma dependencies and reduce the mutagenic potential of GHVs and related co-infections.