B cell-intrinsic expression of Interferon Regulatory Factor 1 supports chronic gammaherpesvirus infection

Abstract

Abstract Gammaherpesviruses are ubiquitous pathogens that are associated with multiple cancers, including B cell lymphomas. These viruses infect naïve B cells and drive a robust germinal center response to amplify the latent viral reservoir and establish life-long infection in memory B cells. It is the increase in mutagenic B cell differentiation caused by the robust gammaherpesvirus-driven germinal center response which is thought to be the primary cause of malignant transformation in viral-driven lymphomagenesis. The host and viral factors that selectively impact gammaherpesvirus-driven germinal center response are poorly defined. We found that global deficiency of the antiviral and tumor suppressive Interferon Regulatory Factor 1 (IRF-1) selectively promotes the gammaherpesvirus-driven germinal center response and expansion of the viral latent reservoir. To establish the degree to which the antiviral effects of IRF-1 are B cell-intrinsic, we generated mice with conditional deficiency of IRF-1. Unexpectedly, IRF-1 B cell-intrinsic function supports the establishment of chronic viral infection and the gammaherpesvirus-driven germinal center response. Indicating that the antiviral function of IRF-1 during gammaherpesvirus infection is mediated though its expression in non-B cell populations.