Cell Host & Microbe
Volume 22, Issue 1, 12 July 2017, Pages 61-73.e7
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Article
Persistent KSHV Infection Increases EBV-Associated Tumor Formation In Vivo via Enhanced EBV Lytic Gene Expression

https://doi.org/10.1016/j.chom.2017.06.009Get rights and content
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Highlights

  • Humanized NSG mice developed as an in vivo model for EBV/KSHV dual infection

  • Latent EBV infection of B cells supports persistent KSHV infection

  • Dual-infected cells display plasma cell-like gene expression similar to human PEL cells

  • Enhanced lymphomagenesis upon dual infection depends on lytic EBV gene expression

Summary

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.

Keywords

Epstein-Barr virus
EBV
Kaposi sarcoma-associated herpesvirus
KSHV
primary effusion lymphoma
humanized mouse model
B cell lymphoma
virus-associated lymphoma
lytic EBV replication

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Present address: Department of Immunology & Pathology, Monash University, Melbourne, Australia

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These authors contributed equally

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