The unappreciated role of developing B cells in chronic gammaherpesvirus infections

Abstract

The oncogenic gammaherpesviruses, including human Epstein–Barr virus (EBV; HHV-4), human Kaposi’s sarcoma-associated herpesvirus (KSHV; HHV-8), and murine gammaherpesvirus 68 (MHV68; MuHV-4; γHV68), establish lifelong latency in circulating B cells and directly contribute to the genesis of numerous types of malignancies including B cell lymphomas. Mounting evidence also implicates these viruses in autoimmune diseases such as multiple sclerosis. The prevailing paradigm for gammaherpesvirus biology holds that these viruses initially infect naïve B cells, then drive infected B cells independent of antigen stimulation through germinal center reactions and into the memory B cell compartment, which serves as a stable latency reservoir. However, cumulative findings from both humans and mice provide provocative evidence that suggests that B cells may play a central role in the natural lifestyle of gammaherpesviruses even before these cells reach full maturity. Here, we review the recent advancements in our understanding of the roles of developing B cells during gammaherpesvirus infection and disease and propose a new working model for latency establishment that incorporates developing B cell infection into the textbook paradigm.