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; Robert E. White; Martin J. Allday; Gerald Niedobitek; David J. Blackbourn; Adam Grundhoff; Christian Münz

doi:10.1016/j.chom.2017.06.009

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^*

^*Corresponding author for this work

Medical Sciences

Research output: Contribution to journal › Article › peer-review

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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 language	English
Pages (from-to)	61-73.e7
Journal	Cell Host and Microbe
Volume	22
Issue number	1
DOIs	https://doi.org/10.1016/j.chom.2017.06.009
Publication status	Published - 12 Jul 2017

Bibliographical note

Funding 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.

Publisher Copyright:
© 2017 Elsevier Inc.

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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McHugh, D., Caduff, N., Barros, M. H. M., Rämer, P. C., Raykova, A., Murer, A., Landtwing, V., Quast, I., Styles, C. T., Spohn, M., Fowotade, A., Delecluse, H. J., Papoudou-Bai, A., Lee, Y. M., Kim, J. M., Middeldorp, J., Schulz, T. F., Cesarman, E., Zbinden, 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, 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

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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",

note = "Funding 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. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

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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

N1 - Funding 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. Publisher Copyright: © 2017 Elsevier Inc.

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

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ER -

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

Abstract

Bibliographical note

Keywords

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