Gammaherpesviruses cause lifelong infection and are associated with various diseases, particularly in immune deficient hosts. The human gammaherpesviruses, Epstein Barr virus (EBV) and Kaposi's sarcoma associated virus, are associated with a number of malignancies, including lymphoproliferative disease and lymphomas. Murine gammaherpesvirus-68 is a genetically and biologically conserved with the human gammaherpesviruses, and naturally infects mice. We recently identified that gammaherpesvirus-68 infection of mice unresponsive to the cytokine interferon-gamma results in significant angiocentric inflammation in the lung with variable progression to frank lymphoma within five to nine months of infection. The inflammatory lesions in these individuals are rich in B cells and in virus-infected cells, and the resulting lymphomas are composed primarily of virus-infected B cells. These lesions and lymphomas bear striking similarity to human pulmonary lymphomas associated with chronic virus infection (including EBV). In this proposal for a pilot study, our goal is to extend our initial characterization of these immunodeficiency-associated lymphomas. First, we propose to finalize basic characterization of full cohorts of interferon-gamma unresponsive mice that are mock treated or infected with gammaherpesvirus for up to one year. We will determine tumor-free survival, tumor cell type and virus infection status of lymphoma cells. Second, we will characterize clonality, cell type composition, and virus gene expression of these immunodeficiency- associated lymphomas. Our long-term goal for these studies is the development of a small animal model for immunodeficiency-associated lymphomagenesis that will elucidate the molecular mechanisms that contribute to chronic infection-associated malignancies, to gain new insights into similar human neoplasms and facilitate translational studies.
Characterization of an animal model of chronic infection and disease. Chronic virus infection and immune defects can lead to variable disease outcomes. This pilot study will provide a valuable model system to further our understanding of human pulmonary lymphomas. This study of inflammation and lymphoma associated with chronic virus infection will set the stage for future studies to define the genetic and environmental risks for these tumors, the viral and host contributors to tumor progression, and the critical pathways that could be disrupted for successful therapies.
