Persistent KSHV infection increases EBV associated PEL-like tumorigenesis in vivo

The human tumor viruses Epstein Barr virus (EBV) and Kaposi Sarcoma associated herpesvirus (KSHV) establish persistence in B cells1,2 and cause primary effusion lymphoma (PEL) by co-infection3. So far no in vivo model exists for long-term KSHV persistence in B cells and associated lymphomagenesis. Here we report that double-infection of KSHV and EBV of mice with reconstituted human immune system components (huNSG mice) leads to KSHV persistence and increased B cell lymphomagenesis. Double-infected tumor cell lines can be rescued from these animals and display plasma cell differentiation similar to PELs. KSHV transactivates lytic EBV replication during double infection and this is required for increased tumorigenesis in double-infected animals. This elevated lytic EBV replication was also found in KSHV and EBV double-infected B cell lymphomas of patients. Thus, KSHV infection persists due to EBV transformation and may transactivate lytic EBV replication for increased horizontal spread of dual infected B cells. Thus, PEL like Kaposi sarcoma could be targeted by inhibition of lytic herpesvirus infection.