(A) EBV is amplified by permissive epithelial cells (lytic infection) and infects mucosal naive B cells. The viral default pathway in B cells is latent infection, where EBV persists as an episome (red circle). A minority of infected B cells are transformed (TrB). In infectious mononucleosis, a significant expansion of transformed lymphoblastoid cells occurs. Anti-EBV antigen CD4⁺ and CD8⁺ T cells control the proliferation of transformed cells. EBV persists in B lymphocytes, as part of the long-lived memory B cell pool (MeB). (B) Early events during KSHV infection are less established. It is uncertain whether B cells become infected after amplification of KSHV in epithelium. Data presented in this issue suggest that KSHV induces significant spontaneous lytic replication ex vivo in tonsillar-derived B cells (2). This lytic infection is suppressed when infected B cells come in contact with activated CD4⁺ T cells. The suppression of spontaneous viral lytic cycle entry in B cells is MHC unrestricted and not dependent on killing of target cells. New data also suggest that the primary target for KSHV in tonsillar explants could be IgM⁺ memory B cells (3). The majority of KSHV latent infected B cells after exposure of tonsillar explants to virus express IgMλ. KSHV induces plasmablastic differentiation of these IgMλ⁺ cells. An enrichment of IgMλ-expressing plasmablasts also occurs in inducible vFLIP knockin mice, targeting vFLIP to different stages of B cell proliferation (4). Such IgMλ⁺ infected plasmablasts are thought to cause KSHV-related MCD. Lytic infected cells are indicated by disrupted nuclear membranes.