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


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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Virology
04 Faculty of Medicine > Institute of Experimental Immunology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Microbiology, Parasitology, Virology
Language:English
Date:July 2017
Deposited On:19 Jan 2018 14:29
Last Modified:19 Aug 2018 13:07
Publisher:Cell Press (Elsevier)
ISSN:1931-3128
Funders:Cancer Research Switzerland (KFS-3234-08-2013), Worldwide Cancer Research (14-1033), SPARKS (15UOZ01), KFSPMS and KFSPHHLD of the University of Zurich, Sobek Foundation, Swiss Vaccine Research Institute, 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.
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.chom.2017.06.009
PubMed ID:28704654
Project Information:
  • : Funder
  • : Grant ID
  • : Project TitleCancer Research Switzerland (KFS-3234-08-2013)
  • : Funder
  • : Grant ID
  • : Project TitleWorldwide Cancer Research (14-1033)
  • : Funder
  • : Grant ID
  • : Project TitleSPARKS (15UOZ01)
  • : Funder
  • : Grant ID
  • : Project TitleKFSPMS and KFSPHHLD of the University of Zurich
  • : Funder
  • : Grant ID
  • : Project TitleSobek Foundation
  • : Funder
  • : Grant ID
  • : Project TitleSwiss Vaccine Research Institute
  • : FunderSNSF
  • : Grant ID
  • : Project TitleSwiss National Science Foundation (SNSF) (310030_162560 and CRSII3_160708) to C.M
  • : FunderSNSF
  • : Grant ID
  • : Project TitleD.M. is supported by an MD-PhD fellowship from the SNSF (323530_145247).
  • : Funder
  • : Grant ID
  • : Project TitleT.F.S. is supported by the DFG Collaborative Research Centre 900, project C1.

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