Abstract Gammaherpesviruses establish life-long infections in >95% of adults worldwide and are associated with B cell lymphomas. Gammaherpesvirus-driven cancers develop in both immunocompromised and immunocompetent individuals; prevention of such cancers is currently impossible due to absence of vaccines, curative antivirals, and defined risk factors for lymphomagenesis. Manipulation of B cell differentiation lies at the heart of chronic gammaherpesvirus infection and pathogenesis. Specifically, gammaherpesviruses use natural proliferative capacity of germinal center B cells to amplify latent viral reservoir. Further, germinal center B cells are believed to be the target of viral transformation, as a majority of gammaherpesvirus-driven B cell lymphomas are germinal center-derived. Despite the importance of germinal center response for chronic infection and lymphomagenesis, very few factors that control infection of germinal center B cells have been defined. Interferon Regulatory Factor 3 (IRF-3) is a transcription factor that targets many cellular genes, including interferon (IFN) β. We discovered that, contrary to the predicted role of IRF-3 as an antiviral factor, IRF-3 supports latent gammaherpesvirus infection of germinal center B cells. The proposed studies test the hypothesis that IRF-3 is usurped by gammaherpesvirus to facilitate latent infection of germinal center B cells, with subsequent generation of memory B cells that host life-long latent viral reservoir. This is achieved through IRF-3-dependent regulation of cellular and viral target genes. Successful completion of the proposed studies will offer an insight into the mechanism by which the virus usurps a classical innate antiviral factor for the viral benefit.

Narrative: Over 95% of adults are infected with gammaherpesviruses that are known to drive development of B cell lymphomas. Unfortunately, very little is known about the viral and host factors that influence the development of gammaherpesvirus-driven lymphomas. This proposal will determine how a classical antiviral factor of the host is usurped by gammaherpesviruses to establish life-long infection.