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. McHugh et al. describe a small animal model of KSHV infection and demonstrate that KSHV collaborates with another human gamma herpes virus, EBV, to establish persistent infection in B cells. The emerging transformed cells resemble primary effusion lymphomas, the malignancies that frequently harbor both viruses in humans.
Bibliographical noteFunding Information:
We dedicate this article to Prof. Martin Allday, who sadly passed away during our collaboration on the presented research. He was an inspiration to us through his profound knowledge of EBV and his friendly and collaborative personality. This study was supported by Cancer Research Switzerland ( KFS-3234-08-2013 ), Worldwide Cancer Research ( 14-1033 ), SPARKS ( 15UOZ01 ), KFSPMS and KFSPHHLD of the University of Zurich , the Sobek Foundation , the Swiss Vaccine Research Institute , and the Swiss National Science Foundation (SNSF) ( 310030_162560 and CRSII3_160708 ) to C.M. D.M. is supported by an MD-PhD fellowship from the SNSF ( 323530_145247 ). T.F.S. is supported by the DFG Collaborative Research Centre 900, project C1. We thank Silvia Behnke of SophistolabAG, Switzerland, for the LANA/LMP1 co-staining in Figure 2 B.
© 2017 Elsevier Inc.
- B cell lymphoma
- Epstein-Barr virus
- humanized mouse model
- Kaposi sarcoma-associated herpesvirus
- lytic EBV replication
- primary effusion lymphoma
- virus-associated lymphoma