Kaposi’s Sarcoma-Associated Herpesvirus Increases PD-L1 and Proinflammatory Cytokine Expression in Human Monocytes

ABSTRACT Kaposi’s sarcoma-associated herpesvirus (KSHV) is associated with the human malignancy Kaposi’s sarcoma and the lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman’s disease. KSHV establishes lytic infection of monocytes in vivo, which may represent an importa...

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Autores principales:	Kurtis M. Host, Sarah R. Jacobs, John A. West, Zhigang Zhang, Lindsey M. Costantini, Charles M. Stopford, Dirk P. Dittmer, Blossom Damania
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Kaposi’s sarcoma-associated herpesvirus PD-1 PD-L1 human herpesvirus innate immunity Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1500b2e7ba7f4ffa9862cea2aac65852
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spelling	oai:doaj.org-article:1500b2e7ba7f4ffa9862cea2aac658522021-11-15T15:51:50ZKaposi’s Sarcoma-Associated Herpesvirus Increases PD-L1 and Proinflammatory Cytokine Expression in Human Monocytes10.1128/mBio.00917-172150-7511https://doaj.org/article/1500b2e7ba7f4ffa9862cea2aac658522017-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00917-17https://doaj.org/toc/2150-7511ABSTRACT Kaposi’s sarcoma-associated herpesvirus (KSHV) is associated with the human malignancy Kaposi’s sarcoma and the lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman’s disease. KSHV establishes lytic infection of monocytes in vivo, which may represent an important cellular reservoir during KS disease progression. KS tumors consist of latently infected endothelial cells; however, lytic phase gene products are important for KS onset. Early KS lesion progression is driven by proinflammatory cytokines supplied by immune cell infiltrates including T cells and monocytes. KSHV-infected monocytes may supply the lytic viral products and the inflammatory milieu conducive to KS tumor progression. To establish successful infection, KSHV extensively modulates the host immune system. KSHV antigens activate both innate and adaptive immune responses including KSHV-specific T cells, but lifelong infection is still established. Programmed death ligand 1 (PD-L1) is a prosurvival cell surface protein that suppresses T-cell-mediated killing. PD-L1 is variably present on various tumor cells and is a targetable marker for cancer treatment. We show that KSHV infection of human monocytes increases PD-L1 expression and transcription in a dose-dependent manner. We also saw evidence of lytic gene expression in the KSHV-infected monocytes. Intact KSHV is needed for full PD-L1 response in human monocytes. KSHV induces a general proinflammatory cytokine milieu including interleukins 1α, 1β, and 6, which have been implicated in early KS lesion progression. KSHV-mediated PD-L1 increase may represent a novel mechanism of KSHV-mediated immune modulation to allow for virus survival and eventually malignant progression. IMPORTANCE KSHV is the etiologic agent of Kaposi’s sarcoma and the lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman’s disease. Programmed death ligand 1 (PD-L1) is an immunosuppressive cell surface marker that inhibits T cell activation. We report that KSHV infection of primary human monocytes upregulates PD-L1 transcription and protein expression. Analysis of the cytokine and chemokine milieu following KSHV infection of monocytes revealed that KSHV induces interleukins 1α, 1β, and 6, all of which have been implicated in KS development. Our work has identified another potential immune evasion strategy for KSHV and a potential target for immunotherapy of KSHV-derived disease.Kurtis M. HostSarah R. JacobsJohn A. WestZhigang ZhangLindsey M. CostantiniCharles M. StopfordDirk P. DittmerBlossom DamaniaAmerican Society for MicrobiologyarticleKaposi’s sarcoma-associated herpesvirusPD-1PD-L1human herpesvirusinnate immunityMicrobiologyQR1-502ENmBio, Vol 8, Iss 5 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Kaposi’s sarcoma-associated herpesvirus PD-1 PD-L1 human herpesvirus innate immunity Microbiology QR1-502
spellingShingle	Kaposi’s sarcoma-associated herpesvirus PD-1 PD-L1 human herpesvirus innate immunity Microbiology QR1-502 Kurtis M. Host Sarah R. Jacobs John A. West Zhigang Zhang Lindsey M. Costantini Charles M. Stopford Dirk P. Dittmer Blossom Damania Kaposi’s Sarcoma-Associated Herpesvirus Increases PD-L1 and Proinflammatory Cytokine Expression in Human Monocytes
description	ABSTRACT Kaposi’s sarcoma-associated herpesvirus (KSHV) is associated with the human malignancy Kaposi’s sarcoma and the lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman’s disease. KSHV establishes lytic infection of monocytes in vivo, which may represent an important cellular reservoir during KS disease progression. KS tumors consist of latently infected endothelial cells; however, lytic phase gene products are important for KS onset. Early KS lesion progression is driven by proinflammatory cytokines supplied by immune cell infiltrates including T cells and monocytes. KSHV-infected monocytes may supply the lytic viral products and the inflammatory milieu conducive to KS tumor progression. To establish successful infection, KSHV extensively modulates the host immune system. KSHV antigens activate both innate and adaptive immune responses including KSHV-specific T cells, but lifelong infection is still established. Programmed death ligand 1 (PD-L1) is a prosurvival cell surface protein that suppresses T-cell-mediated killing. PD-L1 is variably present on various tumor cells and is a targetable marker for cancer treatment. We show that KSHV infection of human monocytes increases PD-L1 expression and transcription in a dose-dependent manner. We also saw evidence of lytic gene expression in the KSHV-infected monocytes. Intact KSHV is needed for full PD-L1 response in human monocytes. KSHV induces a general proinflammatory cytokine milieu including interleukins 1α, 1β, and 6, which have been implicated in early KS lesion progression. KSHV-mediated PD-L1 increase may represent a novel mechanism of KSHV-mediated immune modulation to allow for virus survival and eventually malignant progression. IMPORTANCE KSHV is the etiologic agent of Kaposi’s sarcoma and the lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman’s disease. Programmed death ligand 1 (PD-L1) is an immunosuppressive cell surface marker that inhibits T cell activation. We report that KSHV infection of primary human monocytes upregulates PD-L1 transcription and protein expression. Analysis of the cytokine and chemokine milieu following KSHV infection of monocytes revealed that KSHV induces interleukins 1α, 1β, and 6, all of which have been implicated in KS development. Our work has identified another potential immune evasion strategy for KSHV and a potential target for immunotherapy of KSHV-derived disease.
format	article
author	Kurtis M. Host Sarah R. Jacobs John A. West Zhigang Zhang Lindsey M. Costantini Charles M. Stopford Dirk P. Dittmer Blossom Damania
author_facet	Kurtis M. Host Sarah R. Jacobs John A. West Zhigang Zhang Lindsey M. Costantini Charles M. Stopford Dirk P. Dittmer Blossom Damania
author_sort	Kurtis M. Host
title	Kaposi’s Sarcoma-Associated Herpesvirus Increases PD-L1 and Proinflammatory Cytokine Expression in Human Monocytes
title_short	Kaposi’s Sarcoma-Associated Herpesvirus Increases PD-L1 and Proinflammatory Cytokine Expression in Human Monocytes
title_full	Kaposi’s Sarcoma-Associated Herpesvirus Increases PD-L1 and Proinflammatory Cytokine Expression in Human Monocytes
title_fullStr	Kaposi’s Sarcoma-Associated Herpesvirus Increases PD-L1 and Proinflammatory Cytokine Expression in Human Monocytes
title_full_unstemmed	Kaposi’s Sarcoma-Associated Herpesvirus Increases PD-L1 and Proinflammatory Cytokine Expression in Human Monocytes
title_sort	kaposi’s sarcoma-associated herpesvirus increases pd-l1 and proinflammatory cytokine expression in human monocytes
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/1500b2e7ba7f4ffa9862cea2aac65852
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Kaposi’s Sarcoma-Associated Herpesvirus Increases PD-L1 and Proinflammatory Cytokine Expression in Human Monocytes

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