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 Capaul & 6 others Robert E. White, Martin J. Allday, Gerald Niedobitek, David J. Blackbourn, Adam Grundhoff, Christian Münz

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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 and 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

Cite this

McHugh, D., Caduff, N., Barros, M. H. M., Rämer, P. C., Raykova, A., Murer, A., ... Münz, C. (2017). Persistent KSHV Infection Increases EBV-Associated Tumor Formation In Vivo via Enhanced EBV Lytic Gene Expression. Cell Host and Microbe, 22(1), 61-73.e7. https://doi.org/10.1016/j.chom.2017.06.009
McHugh, Donal ; Caduff, Nicole ; Barros, Mario Henrique M. ; Rämer, Patrick C. ; Raykova, Ana ; Murer, Anita ; Landtwing, Vanessa ; Quast, Isaak ; Styles, Christine T. ; Spohn, Michael ; Fowotade, Adeola ; Delecluse, Henri Jacques ; Papoudou-Bai, Alexandra ; Lee, Yong Moon ; Kim, Jin Man ; Middeldorp, Jaap ; Schulz, Thomas F. ; Cesarman, Ethel ; Zbinden, Andrea ; Capaul, Riccarda ; White, Robert E. ; Allday, Martin J. ; Niedobitek, Gerald ; Blackbourn, David J. ; Grundhoff, Adam ; Münz, Christian. / Persistent KSHV Infection Increases EBV-Associated Tumor Formation In Vivo via Enhanced EBV Lytic Gene Expression. In: Cell Host and Microbe. 2017 ; Vol. 22, No. 1. pp. 61-73.e7.
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title = "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. 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.",
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",
author = "Donal McHugh and Nicole Caduff and Barros, {Mario Henrique M.} and R{\"a}mer, {Patrick C.} and Ana Raykova and Anita Murer and Vanessa Landtwing and Isaak Quast and Styles, {Christine T.} and Michael Spohn and Adeola Fowotade and Delecluse, {Henri Jacques} and Alexandra Papoudou-Bai and Lee, {Yong Moon} and Kim, {Jin Man} and Jaap Middeldorp and Schulz, {Thomas F.} and Ethel Cesarman and Andrea Zbinden and Riccarda Capaul and White, {Robert E.} and Allday, {Martin J.} and Gerald Niedobitek and Blackbourn, {David J.} and Adam Grundhoff and Christian M{\"u}nz",
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McHugh, D, Caduff, N, Barros, MHM, Rämer, PC, Raykova, A, Murer, A, Landtwing, V, Quast, I, Styles, CT, Spohn, M, Fowotade, A, Delecluse, HJ, Papoudou-Bai, A, Lee, YM, Kim, JM, Middeldorp, J, Schulz, TF, Cesarman, E, Zbinden, A, Capaul, R, White, RE, Allday, MJ, Niedobitek, G, Blackbourn, DJ, Grundhoff, A & Münz, C 2017, 'Persistent KSHV Infection Increases EBV-Associated Tumor Formation In Vivo via Enhanced EBV Lytic Gene Expression', Cell Host and Microbe, vol. 22, no. 1, pp. 61-73.e7. https://doi.org/10.1016/j.chom.2017.06.009

Persistent KSHV Infection Increases EBV-Associated Tumor Formation In Vivo via Enhanced EBV Lytic Gene Expression. / McHugh, Donal; Caduff, Nicole; Barros, Mario Henrique M.; Rämer, Patrick C.; Raykova, Ana; Murer, Anita; Landtwing, Vanessa; Quast, Isaak; Styles, Christine T.; Spohn, Michael; Fowotade, Adeola; Delecluse, Henri Jacques; Papoudou-Bai, Alexandra; Lee, Yong Moon; Kim, Jin Man; Middeldorp, Jaap; Schulz, Thomas F.; Cesarman, Ethel; Zbinden, Andrea; Capaul, Riccarda; White, Robert E.; Allday, Martin J.; Niedobitek, Gerald; Blackbourn, David J.; Grundhoff, Adam; Münz, Christian.

In: Cell Host and Microbe, Vol. 22, No. 1, 12.07.2017, p. 61-73.e7.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Persistent KSHV Infection Increases EBV-Associated Tumor Formation In Vivo via Enhanced EBV Lytic Gene Expression

AU - McHugh, Donal

AU - Caduff, Nicole

AU - Barros, Mario Henrique M.

AU - Rämer, Patrick C.

AU - Raykova, Ana

AU - Murer, Anita

AU - Landtwing, Vanessa

AU - Quast, Isaak

AU - Styles, Christine T.

AU - Spohn, Michael

AU - Fowotade, Adeola

AU - Delecluse, Henri Jacques

AU - Papoudou-Bai, Alexandra

AU - Lee, Yong Moon

AU - Kim, Jin Man

AU - Middeldorp, Jaap

AU - Schulz, Thomas F.

AU - Cesarman, Ethel

AU - Zbinden, Andrea

AU - Capaul, Riccarda

AU - White, Robert E.

AU - Allday, Martin J.

AU - Niedobitek, Gerald

AU - Blackbourn, David J.

AU - Grundhoff, Adam

AU - Münz, Christian

PY - 2017/7/12

Y1 - 2017/7/12

N2 - 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.

AB - 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.

KW - B cell lymphoma

KW - EBV

KW - Epstein-Barr virus

KW - humanized mouse model

KW - Kaposi sarcoma-associated herpesvirus

KW - KSHV

KW - lytic EBV replication

KW - primary effusion lymphoma

KW - virus-associated lymphoma

UR - http://www.scopus.com/inward/record.url?scp=85026903460&partnerID=8YFLogxK

U2 - 10.1016/j.chom.2017.06.009

DO - 10.1016/j.chom.2017.06.009

M3 - Article

VL - 22

SP - 61-73.e7

JO - Cell Host and Microbe

JF - Cell Host and Microbe

SN - 1931-3128

IS - 1

ER -