Gammaherpesviruses establish life-long infections in >95% of adults worldwide and are associated with B cell lymphomas. Prevention of gammaherpesvirus-driven lymphomas is currently impossible due to absence of vaccines, curative antivirals, and defined risk factors for lymphomagenesis. All gammaherpesviruses encode a protein kinase, a key determinant of chronic infection and pathogenesis. This grant application aims to define the molecular and cellular mechanisms underlying physiologically relevant functions of gammaherpesvirus protein kinases during chronic infection of an intact host. Based on our published and preliminary findings, the proposed studies test the working model that macrophage- intrinsic IFN signaling is antagonized by an enzymatically active viral protein kinase to promote the passage of the virus from myeloid to B cell compartment. Once viral access to B cells is gained, viral kinase supports latent viral gene expression and engages host mechanisms to drive B cell differentiation and establishment of chronic infection. Successful completion of the proposed studies will define molecular and cellular mechanisms underlying functions of the conserved gammaherpesvirus protein kinase during chronic infection of an intact natural host. Such mechanisms are likely to operate during viral lymphomagenesis and may present novel therapeutic targets for the prevention of gammaherpesvirus-driven lymphomas.