Investigation of gammaherpesvirus-induced lymphoproliferative disorders through sequencing of the B cell receptor repertoire

Human gammaherpesviruses such as the Epstein Barr virus (EBV) or the Kaposi Sarcoma Associated Herpesvirus (KSHV) can be associated with lymphoproliferative disorders (LPD) following transient or prolonged immunosuppression. This is an important public health issue as those viruses infect more than 90% of the world’s population, and as the estimation of mortality of EBV-related cancers goes up to 200,000 cases worldwide annually. Most of those LPD are of B cells origin as both EBV and KSHV establish latency in those cells and impact their normal physiology. In this project, using Murid herpesvirus 4 (MuHV-4), a mouse model of human gammaherpesviruses, we studied B cell dynamics in WT and β2-microglobulin deficient mice displaying a higher risk of developing a LPD due to the lack of control of infected B cells by CD8 T cells. We firstly focused on acute infection (9 and 18 days post-infection) and analyzed the influence of MuHV-4 infection on the B cell immune repertoire. Importantly, we used a flow-FISH cytometry assay that detects cells expressing MuHV-4-encoded small RNAs, allowing rapid identification of MuHV-4-infected cells among the entire B cell population. In the future, we hope that this approach could allow us to better understand the mechanisms behind gammaherpesvirus-induced LPDs and potentially develop strategies to avoid such disorders.