Interferon-Responsive Genes Are Targeted during the Establishment of Human Cytomegalovirus Latency

ABSTRACT Human cytomegalovirus (HCMV) latency is an active process which remodels the latently infected cell to optimize latent carriage and reactivation. This is achieved, in part, through the expression of viral genes, including the G-protein-coupled receptor US28. Here, we use an unbiased proteom...

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Autores principales:	Elizabeth G. Elder, Benjamin A. Krishna, James Williamson, Eleanor Y. Lim, Emma Poole, George X. Sedikides, Mark Wills, Christine M. O’Connor, Paul J. Lehner, John Sinclair
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	IFI16 US28 viral latency cytomegalovirus interferon response Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/380acf94ae2e407ba81bc144361f8da4
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spelling	oai:doaj.org-article:380acf94ae2e407ba81bc144361f8da42021-11-15T15:54:46ZInterferon-Responsive Genes Are Targeted during the Establishment of Human Cytomegalovirus Latency10.1128/mBio.02574-192150-7511https://doaj.org/article/380acf94ae2e407ba81bc144361f8da42019-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02574-19https://doaj.org/toc/2150-7511ABSTRACT Human cytomegalovirus (HCMV) latency is an active process which remodels the latently infected cell to optimize latent carriage and reactivation. This is achieved, in part, through the expression of viral genes, including the G-protein-coupled receptor US28. Here, we use an unbiased proteomic screen to assess changes in host proteins induced by US28, revealing that interferon-inducible genes are downregulated by US28. We validate that major histocompatibility complex (MHC) class II and two pyrin and HIN domain (PYHIN) proteins, myeloid cell nuclear differentiation antigen (MNDA) and IFI16, are downregulated during experimental latency in primary human CD14+ monocytes. We find that IFI16 is targeted rapidly during the establishment of latency in a US28-dependent manner but only in undifferentiated myeloid cells, a natural site of latent carriage. Finally, by overexpressing IFI16, we show that IFI16 can activate the viral major immediate early promoter and immediate early gene expression during latency via NF-κB, a function which explains why downregulation of IFI16 during latency is advantageous for the virus. IMPORTANCE Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus which infects 50 to 100% of humans worldwide. HCMV causes a lifelong subclinical infection in immunocompetent individuals but is a serious cause of mortality and morbidity in the immunocompromised and neonates. In particular, reactivation of HCMV in the transplant setting is a major cause of transplant failure and related disease. Therefore, a molecular understanding of HCMV latency and reactivation could provide insights into potential ways to target the latent viral reservoir in at-risk patient populations.Elizabeth G. ElderBenjamin A. KrishnaJames WilliamsonEleanor Y. LimEmma PooleGeorge X. SedikidesMark WillsChristine M. O’ConnorPaul J. LehnerJohn SinclairAmerican Society for MicrobiologyarticleIFI16US28viral latencycytomegalovirusinterferon responseMicrobiologyQR1-502ENmBio, Vol 10, Iss 6 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	IFI16 US28 viral latency cytomegalovirus interferon response Microbiology QR1-502
spellingShingle	IFI16 US28 viral latency cytomegalovirus interferon response Microbiology QR1-502 Elizabeth G. Elder Benjamin A. Krishna James Williamson Eleanor Y. Lim Emma Poole George X. Sedikides Mark Wills Christine M. O’Connor Paul J. Lehner John Sinclair Interferon-Responsive Genes Are Targeted during the Establishment of Human Cytomegalovirus Latency
description	ABSTRACT Human cytomegalovirus (HCMV) latency is an active process which remodels the latently infected cell to optimize latent carriage and reactivation. This is achieved, in part, through the expression of viral genes, including the G-protein-coupled receptor US28. Here, we use an unbiased proteomic screen to assess changes in host proteins induced by US28, revealing that interferon-inducible genes are downregulated by US28. We validate that major histocompatibility complex (MHC) class II and two pyrin and HIN domain (PYHIN) proteins, myeloid cell nuclear differentiation antigen (MNDA) and IFI16, are downregulated during experimental latency in primary human CD14+ monocytes. We find that IFI16 is targeted rapidly during the establishment of latency in a US28-dependent manner but only in undifferentiated myeloid cells, a natural site of latent carriage. Finally, by overexpressing IFI16, we show that IFI16 can activate the viral major immediate early promoter and immediate early gene expression during latency via NF-κB, a function which explains why downregulation of IFI16 during latency is advantageous for the virus. IMPORTANCE Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus which infects 50 to 100% of humans worldwide. HCMV causes a lifelong subclinical infection in immunocompetent individuals but is a serious cause of mortality and morbidity in the immunocompromised and neonates. In particular, reactivation of HCMV in the transplant setting is a major cause of transplant failure and related disease. Therefore, a molecular understanding of HCMV latency and reactivation could provide insights into potential ways to target the latent viral reservoir in at-risk patient populations.
format	article
author	Elizabeth G. Elder Benjamin A. Krishna James Williamson Eleanor Y. Lim Emma Poole George X. Sedikides Mark Wills Christine M. O’Connor Paul J. Lehner John Sinclair
author_facet	Elizabeth G. Elder Benjamin A. Krishna James Williamson Eleanor Y. Lim Emma Poole George X. Sedikides Mark Wills Christine M. O’Connor Paul J. Lehner John Sinclair
author_sort	Elizabeth G. Elder
title	Interferon-Responsive Genes Are Targeted during the Establishment of Human Cytomegalovirus Latency
title_short	Interferon-Responsive Genes Are Targeted during the Establishment of Human Cytomegalovirus Latency
title_full	Interferon-Responsive Genes Are Targeted during the Establishment of Human Cytomegalovirus Latency
title_fullStr	Interferon-Responsive Genes Are Targeted during the Establishment of Human Cytomegalovirus Latency
title_full_unstemmed	Interferon-Responsive Genes Are Targeted during the Establishment of Human Cytomegalovirus Latency
title_sort	interferon-responsive genes are targeted during the establishment of human cytomegalovirus latency
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/380acf94ae2e407ba81bc144361f8da4
work_keys_str_mv	AT elizabethgelder interferonresponsivegenesaretargetedduringtheestablishmentofhumancytomegaloviruslatency AT benjaminakrishna interferonresponsivegenesaretargetedduringtheestablishmentofhumancytomegaloviruslatency AT jameswilliamson interferonresponsivegenesaretargetedduringtheestablishmentofhumancytomegaloviruslatency AT eleanorylim interferonresponsivegenesaretargetedduringtheestablishmentofhumancytomegaloviruslatency AT emmapoole interferonresponsivegenesaretargetedduringtheestablishmentofhumancytomegaloviruslatency AT georgexsedikides interferonresponsivegenesaretargetedduringtheestablishmentofhumancytomegaloviruslatency AT markwills interferonresponsivegenesaretargetedduringtheestablishmentofhumancytomegaloviruslatency AT christinemoconnor interferonresponsivegenesaretargetedduringtheestablishmentofhumancytomegaloviruslatency AT pauljlehner interferonresponsivegenesaretargetedduringtheestablishmentofhumancytomegaloviruslatency AT johnsinclair interferonresponsivegenesaretargetedduringtheestablishmentofhumancytomegaloviruslatency
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Interferon-Responsive Genes Are Targeted during the Establishment of Human Cytomegalovirus Latency

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