BAFF Receptor Deficiency Limits Gammaherpesvirus Infection

Lymphocyte colonization by gammaherpesviruses (HVs) is an important target for cancer prevention. However, how it works is not clear. Epstein-Barr virus drives autonomous B cell proliferation in vitro but in vivomay more subtly exploit the prolifera-tive pathways provided by lymphoid germinal centers (GCs). Murid herpesvirus 4 (MuHV-4), which realistically infects inbred mice, provides a useful tool with which to understand further how a HV colonizes B cells in vivo. Not all HVs necessarily be-have the same, but common events can withMuHV-4 be assigned an importance for host colonization and so a potential as ther-apeutic targets. MuHV-4-driven B cell proliferation depends quantitatively on CD4 T cell help. Here we show that it also de-pends on T cell-independent survival signals provided by the B cell-activating factor (BAFF) receptor (BAFF-R). B cells could be infected in BAFF-R/mice, but virus loads remained low. This corresponded to a BAFF-R-dependent defect in GC coloniza-tion. The close parallels between normal, antigen-driven B cell responses and virus-infected B cell proliferation argue that in vivo, HVsmostly induce infected B cells into normal GC reactions rather than generating large numbers of autonomously pro-liferating blasts. IMPORTANCE HVs cause cancers by driving the proliferation of infected cells. B cells are a particular target. Thus, we need to know how virus-driven B cell proliferation works. Controversy exists as to whether viral genes drive it directly or less directly orchestrate the en