Persistent KSHV Infection Increases EBV-Associated Tumor Formation In Vivo via Enhanced EBV Lytic Gene Expression

• DOI: 10.1016/j.chom.2017.06.009
• Publication Date: 2017-07-12T18:00:21Z
• Authors: Donal McHugh; Nicole Caduff; Mario Henrique M....; Patrick C. Rämer; Ana Raykova; Anita Murer; Vanessa Landtwing; Isaak Quast; Christine T. Styles; Michael Spohn; Adeola Fowotade; Henri-Jacques Del...; Alexandra Papoudo...; Yong-Moon Lee; Jin-Man Kim; Jaap Middeldorp; Thomas F. Schulz; Ethel Cesarman; Andrea Zbinden; Riccarda Capaul; Robert E. White; Martin J. Allday; Gerald Niedobitek; David J. Blackbourn; Adam Grundhoff; Christian Münz
• Keywords: Lytic cycle; Virus latency

The human tumor viruses Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) establish persistent infections in B cells. KSHV is linked to primary effusion lymphoma (PEL), and 90% of PELs also contain EBV. Studies on persistent KSHV infection in vivo and the role of EBV co-infection in PEL development have been hampered by the absence of small animal models. We developed mice reconstituted with human immune system components as a model for KSHV infection and find that EBV/KSHV dual infection enhanced KSHV persistence and tumorigenesis. Dual-infected cells displayed a plasma cell-like gene expression pattern similar to PELs. KSHV persisted in EBV-transformed B cells and was associated with lytic EBV gene expression, resulting in increased tumor formation. Evidence of elevated lytic EBV replication was also found in EBV/KSHV dually infected lymphoproliferative disorders in humans. Our data suggest that KSHV augments EBV-associated tumorigenesis via stimulation of lytic EBV replication.