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

Donal McHugh, Nicole Caduff, Mario Henrique M. Barros, Patrick C. Rämer, Ana Raykova, Anita Murer, Vanessa Landtwing, Isaak Quast, Christine T. Styles, Michael Spohn, Adeola Fowotade, Henri Jacques Delecluse, Alexandra Papoudou-Bai, Yong Moon Lee, Jin Man Kim, Jaap Middeldorp, Thomas F. Schulz, Ethel Cesarman, Andrea Zbinden, Riccarda CapaulRobert E. White, Martin J. Allday, Gerald Niedobitek, David J. Blackbourn, Adam Grundhoff, Christian Münz

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52 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)61-73.e7
JournalCell Host & Microbe
Volume22
Issue number1
DOIs
Publication statusPublished - 12 Jul 2017

Keywords

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

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