Persistent KSHV infection increases EBV-associated tumor formation in vivo via enhanced EBV lytic gene expression. KSHV/EBV co-infection and tumorigenesis

The human tumor viruses Epstein Barr virus (EBV) and Kaposi Sarcoma associated herpesvirus (KSHV) establish persistent infections in B cells and can cause primary effusion lymphoma (PEL) upon dual infection. So far, no in vivo model exists to study KSHV persistence and associated lymphomagenesis. Here, we report that EBV/KSHV dual infection of mice with reconstituted human immune system components enhanced KSHV persistence and tumorigenesis with plasma cell-like gene expression similar to PELs. KSHV persisted in EBV transformed B cells and was associated with early lytic EBV gene expression, resulting in increased tumor formation. Evidence of lytic EBV replication was also found in EBV/KSHV dually infected lymphoproliferative disorders of patients. Our data suggest that KSHV augments EBV-associated tumorigenesis via stimulation of lytic EBV replication.