B cell-intrinsic IRF-1 and conserved gammaherpesvirus protein kinase cooperate to promote murine gammaherpesvirus-driven germinal center response and splenic latent reservoir

Gammaherpesviruses infect >90% of adults and are associated with B cell lymphomas. These viruses drive the expansion and differentiation of germinal center B cells to amplify latent viral reservoir and ensure life-long infection of memory B cells. Additionally, infected germinal center B cells seed viral lymphomagenesis. We previously demonstrated that global deficiency of Interferon Regulatory Factor-1 (IRF-1), a classically antiviral transcription factor, results in increased murine gammaherpesvirus-driven germinal center response and latent viral reservoir. In contrast, B cell-specific loss of IRF-1 expression attenuates murine gammaherpesvirus chronic infection and germinal center response. All gammaherpesviruses encode a conserved protein kinase. We previously showed that the murine gammaherpesvirus protein kinase antagonizes the antiviral activity of global IRF-1 expression to support the establishment of chronic infection. Intriguingly, in this study, we show cooperation between the gammaherpesvirus protein kinase and B cell-intrinsic IRF-1 expression that supported optimal establishment of splenic latent viral reservoir and murine gammaherpesvirus-driven germinal center response. Both viral protein kinase and B cell-intrinsic IRF-1 expression supported the survival and proliferation of germinal center B cells during chronic gammaherpesvirus infection. Elevated DNA damage response or Fas/FasL expression was not observed, failing to account for elevated apoptosis of IRF-1-deficient germinal center B cells. However, B cell-intrinsic IRF-1 deficiency led to decreased MHC-II expression by germinal center B cells during chronic gammaherpesvirus infection. In summary, the results of this study illustrate the critical role of the cell type in defining the functional outcome of the host-viral interaction.IMPORTANCEGammaherpesviruses are highly prevalent pathogens that uniquely target B cells for the establishment of life-long infection. This study demonstrates cooperation between a conserved gammaherpesvirus protein kinase and B cell-intrinsic IRF-1, a classical host antiviral factor. We show that this cooperation is critical to support proliferation and survival of germinal center B cells, a subset of B cells that is latently infected by gammaherpesviruses and is critical for both the establishment of chronic infection and viral lymphomagenesis.