MicroRNAs of Epstein-Barr Virus Attenuate T-Cell-Mediated Immune Control <italic toggle="yes">In Vivo</italic>

ABSTRACT The human persistent and oncogenic Epstein-Barr virus (EBV) was one of the first viruses that were described to express viral microRNAs (miRNAs). These have been proposed to modulate many host and viral functions, but their predominant role in vivo has remained unclear. We compared recombin...

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Autores principales:	Anita Murer, Julia Rühl, Andrea Zbinden, Riccarda Capaul, Wolfgang Hammerschmidt, Obinna Chijioke, Christian Münz
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Epstein-Barr virus cytotoxic T cells humanized mice immune escape lymphoma miRNA Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/17ba25af3ced431bb075ce49fd4ca487
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spelling	oai:doaj.org-article:17ba25af3ced431bb075ce49fd4ca4872021-11-15T15:55:13ZMicroRNAs of Epstein-Barr Virus Attenuate T-Cell-Mediated Immune Control <italic toggle="yes">In Vivo</italic>10.1128/mBio.01941-182150-7511https://doaj.org/article/17ba25af3ced431bb075ce49fd4ca4872019-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01941-18https://doaj.org/toc/2150-7511ABSTRACT The human persistent and oncogenic Epstein-Barr virus (EBV) was one of the first viruses that were described to express viral microRNAs (miRNAs). These have been proposed to modulate many host and viral functions, but their predominant role in vivo has remained unclear. We compared recombinant EBVs expressing or lacking miRNAs during in vivo infection of mice with reconstituted human immune system components and found that miRNA-deficient EBV replicates to lower viral titers with decreased frequencies of proliferating EBV-infected B cells. In response, activated cytotoxic EBV-specific T cells expand to lower frequencies than during infection with miRNA-expressing EBV. However, when we depleted CD8+ T cells the miRNA-deficient virus reached similar viral loads as wild-type EBV, increasing by more than 200-fold in the spleens of infected animals. Furthermore, CD8+ T cell depletion resulted in lymphoma formation in the majority of animals after miRNA-deficient EBV infection, while no tumors emerged when CD8+ T cells were present. Thus, miRNAs mainly serve the purpose of immune evasion from T cells in vivo and could become a therapeutic target to render EBV-associated malignancies more immunogenic. IMPORTANCE Epstein-Barr virus (EBV) infects the majority of the human population and usually persists asymptomatically within its host. Nevertheless, EBV is the causative agent for infectious mononucleosis (IM) and for lymphoproliferative disorders, including Burkitt and Hodgkin lymphomas. The immune system of the infected host is thought to prevent tumor formation in healthy virus carriers. EBV was one of the first viruses described to express miRNAs, and many host and viral targets were identified for these in vitro. However, their role during EBV infection in vivo remained unclear. This work is the first to describe that EBV miRNAs mainly increase viremia and virus-associated lymphomas through dampening antigen recognition by adaptive immune responses in mice with reconstituted immune responses. Currently, there is no prophylactic or therapeutic treatment to restrict IM or EBV-associated malignancies; thus, targeting EBV miRNAs could promote immune responses and limit EBV-associated pathologies.Anita MurerJulia RühlAndrea ZbindenRiccarda CapaulWolfgang HammerschmidtObinna ChijiokeChristian MünzAmerican Society for MicrobiologyarticleEpstein-Barr viruscytotoxic T cellshumanized miceimmune escapelymphomamiRNAMicrobiologyQR1-502ENmBio, Vol 10, Iss 1 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Epstein-Barr virus cytotoxic T cells humanized mice immune escape lymphoma miRNA Microbiology QR1-502
spellingShingle	Epstein-Barr virus cytotoxic T cells humanized mice immune escape lymphoma miRNA Microbiology QR1-502 Anita Murer Julia Rühl Andrea Zbinden Riccarda Capaul Wolfgang Hammerschmidt Obinna Chijioke Christian Münz MicroRNAs of Epstein-Barr Virus Attenuate T-Cell-Mediated Immune Control <italic toggle="yes">In Vivo</italic>
description	ABSTRACT The human persistent and oncogenic Epstein-Barr virus (EBV) was one of the first viruses that were described to express viral microRNAs (miRNAs). These have been proposed to modulate many host and viral functions, but their predominant role in vivo has remained unclear. We compared recombinant EBVs expressing or lacking miRNAs during in vivo infection of mice with reconstituted human immune system components and found that miRNA-deficient EBV replicates to lower viral titers with decreased frequencies of proliferating EBV-infected B cells. In response, activated cytotoxic EBV-specific T cells expand to lower frequencies than during infection with miRNA-expressing EBV. However, when we depleted CD8+ T cells the miRNA-deficient virus reached similar viral loads as wild-type EBV, increasing by more than 200-fold in the spleens of infected animals. Furthermore, CD8+ T cell depletion resulted in lymphoma formation in the majority of animals after miRNA-deficient EBV infection, while no tumors emerged when CD8+ T cells were present. Thus, miRNAs mainly serve the purpose of immune evasion from T cells in vivo and could become a therapeutic target to render EBV-associated malignancies more immunogenic. IMPORTANCE Epstein-Barr virus (EBV) infects the majority of the human population and usually persists asymptomatically within its host. Nevertheless, EBV is the causative agent for infectious mononucleosis (IM) and for lymphoproliferative disorders, including Burkitt and Hodgkin lymphomas. The immune system of the infected host is thought to prevent tumor formation in healthy virus carriers. EBV was one of the first viruses described to express miRNAs, and many host and viral targets were identified for these in vitro. However, their role during EBV infection in vivo remained unclear. This work is the first to describe that EBV miRNAs mainly increase viremia and virus-associated lymphomas through dampening antigen recognition by adaptive immune responses in mice with reconstituted immune responses. Currently, there is no prophylactic or therapeutic treatment to restrict IM or EBV-associated malignancies; thus, targeting EBV miRNAs could promote immune responses and limit EBV-associated pathologies.
format	article
author	Anita Murer Julia Rühl Andrea Zbinden Riccarda Capaul Wolfgang Hammerschmidt Obinna Chijioke Christian Münz
author_facet	Anita Murer Julia Rühl Andrea Zbinden Riccarda Capaul Wolfgang Hammerschmidt Obinna Chijioke Christian Münz
author_sort	Anita Murer
title	MicroRNAs of Epstein-Barr Virus Attenuate T-Cell-Mediated Immune Control <italic toggle="yes">In Vivo</italic>
title_short	MicroRNAs of Epstein-Barr Virus Attenuate T-Cell-Mediated Immune Control <italic toggle="yes">In Vivo</italic>
title_full	MicroRNAs of Epstein-Barr Virus Attenuate T-Cell-Mediated Immune Control <italic toggle="yes">In Vivo</italic>
title_fullStr	MicroRNAs of Epstein-Barr Virus Attenuate T-Cell-Mediated Immune Control <italic toggle="yes">In Vivo</italic>
title_full_unstemmed	MicroRNAs of Epstein-Barr Virus Attenuate T-Cell-Mediated Immune Control <italic toggle="yes">In Vivo</italic>
title_sort	micrornas of epstein-barr virus attenuate t-cell-mediated immune control <italic toggle="yes">in vivo</italic>
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/17ba25af3ced431bb075ce49fd4ca487
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MicroRNAs of Epstein-Barr Virus Attenuate T-Cell-Mediated Immune Control <italic toggle="yes">In Vivo</italic>

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