Latency-Associated Expression of Human Cytomegalovirus US28 Attenuates Cell Signaling Pathways To Maintain Latent Infection

ABSTRACT Reactivation of human cytomegalovirus (HCMV) latent infection from early myeloid lineage cells constitutes a threat to immunocompromised or immune-suppressed individuals. Consequently, understanding the control of latency and reactivation to allow targeting and killing of latently infected...

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Autores principales:	Benjamin A. Krishna, Emma L. Poole, Sarah E. Jackson, Martine J. Smit, Mark R. Wills, John H. Sinclair
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	cytomegalovirus immunotherapy latent infection virology Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/2437e0f55249499d8a17eee25ae87f04
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spelling	oai:doaj.org-article:2437e0f55249499d8a17eee25ae87f042021-11-15T15:51:56ZLatency-Associated Expression of Human Cytomegalovirus US28 Attenuates Cell Signaling Pathways To Maintain Latent Infection10.1128/mBio.01754-172150-7511https://doaj.org/article/2437e0f55249499d8a17eee25ae87f042017-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01754-17https://doaj.org/toc/2150-7511ABSTRACT Reactivation of human cytomegalovirus (HCMV) latent infection from early myeloid lineage cells constitutes a threat to immunocompromised or immune-suppressed individuals. Consequently, understanding the control of latency and reactivation to allow targeting and killing of latently infected cells could have far-reaching clinical benefits. US28 is one of the few viral genes that is expressed during latency and encodes a cell surface G protein-coupled receptor (GPCR), which, during lytic infection, is a constitutive cell-signaling activator. Here we now show that in monocytes, which are recognized sites of HCMV latency in vivo, US28 attenuates multiple cell signaling pathways, including mitogen-activated protein (MAP) kinase and NF-κB, and that this is required to establish a latent infection; viruses deleted for US28 initiate a lytic infection in infected monocytes. We also show that these monocytes then become potent targets for the HCMV-specific host immune response and that latently infected cells treated with an inverse agonist of US28 also reactivate lytic infection and similarly become immune targets. Consequently, we suggest that the use of inhibitors of US28 could be a novel immunotherapeutic strategy to reactivate the latent viral reservoir, allowing it to be targeted by preexisting HCMV-specific T cells. IMPORTANCE Human cytomegalovirus (HCMV) is a betaherpesvirus and a leading cause of morbidity and mortality among immunosuppressed individuals. HCMV can establish latent infection, where the viral genome is maintained in an infected cell, without production of infectious virus. A number of genes, including US28, are expressed by HCMV during latent infection. US28 has been shown to activate many cellular signaling pathways during lytic infection, promoting lytic gene expression and virus production. As such, the role of US28 remains unclear and seems at odds with latency. Here, we show that US28 has the opposite phenotype in cells that support latent infection—it attenuates cellular signaling, thereby maintaining latency. Inhibition of US28 with a small-molecule inhibitor causes HCMV latent infection to reactivate, allowing latently infected cells to be detected and killed by the immune system. This approach could be used to treat latent HCMV to clear it from human transplants.Benjamin A. KrishnaEmma L. PooleSarah E. JacksonMartine J. SmitMark R. WillsJohn H. SinclairAmerican Society for Microbiologyarticlecytomegalovirusimmunotherapylatent infectionvirologyMicrobiologyQR1-502ENmBio, Vol 8, Iss 6 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	cytomegalovirus immunotherapy latent infection virology Microbiology QR1-502
spellingShingle	cytomegalovirus immunotherapy latent infection virology Microbiology QR1-502 Benjamin A. Krishna Emma L. Poole Sarah E. Jackson Martine J. Smit Mark R. Wills John H. Sinclair Latency-Associated Expression of Human Cytomegalovirus US28 Attenuates Cell Signaling Pathways To Maintain Latent Infection
description	ABSTRACT Reactivation of human cytomegalovirus (HCMV) latent infection from early myeloid lineage cells constitutes a threat to immunocompromised or immune-suppressed individuals. Consequently, understanding the control of latency and reactivation to allow targeting and killing of latently infected cells could have far-reaching clinical benefits. US28 is one of the few viral genes that is expressed during latency and encodes a cell surface G protein-coupled receptor (GPCR), which, during lytic infection, is a constitutive cell-signaling activator. Here we now show that in monocytes, which are recognized sites of HCMV latency in vivo, US28 attenuates multiple cell signaling pathways, including mitogen-activated protein (MAP) kinase and NF-κB, and that this is required to establish a latent infection; viruses deleted for US28 initiate a lytic infection in infected monocytes. We also show that these monocytes then become potent targets for the HCMV-specific host immune response and that latently infected cells treated with an inverse agonist of US28 also reactivate lytic infection and similarly become immune targets. Consequently, we suggest that the use of inhibitors of US28 could be a novel immunotherapeutic strategy to reactivate the latent viral reservoir, allowing it to be targeted by preexisting HCMV-specific T cells. IMPORTANCE Human cytomegalovirus (HCMV) is a betaherpesvirus and a leading cause of morbidity and mortality among immunosuppressed individuals. HCMV can establish latent infection, where the viral genome is maintained in an infected cell, without production of infectious virus. A number of genes, including US28, are expressed by HCMV during latent infection. US28 has been shown to activate many cellular signaling pathways during lytic infection, promoting lytic gene expression and virus production. As such, the role of US28 remains unclear and seems at odds with latency. Here, we show that US28 has the opposite phenotype in cells that support latent infection—it attenuates cellular signaling, thereby maintaining latency. Inhibition of US28 with a small-molecule inhibitor causes HCMV latent infection to reactivate, allowing latently infected cells to be detected and killed by the immune system. This approach could be used to treat latent HCMV to clear it from human transplants.
format	article
author	Benjamin A. Krishna Emma L. Poole Sarah E. Jackson Martine J. Smit Mark R. Wills John H. Sinclair
author_facet	Benjamin A. Krishna Emma L. Poole Sarah E. Jackson Martine J. Smit Mark R. Wills John H. Sinclair
author_sort	Benjamin A. Krishna
title	Latency-Associated Expression of Human Cytomegalovirus US28 Attenuates Cell Signaling Pathways To Maintain Latent Infection
title_short	Latency-Associated Expression of Human Cytomegalovirus US28 Attenuates Cell Signaling Pathways To Maintain Latent Infection
title_full	Latency-Associated Expression of Human Cytomegalovirus US28 Attenuates Cell Signaling Pathways To Maintain Latent Infection
title_fullStr	Latency-Associated Expression of Human Cytomegalovirus US28 Attenuates Cell Signaling Pathways To Maintain Latent Infection
title_full_unstemmed	Latency-Associated Expression of Human Cytomegalovirus US28 Attenuates Cell Signaling Pathways To Maintain Latent Infection
title_sort	latency-associated expression of human cytomegalovirus us28 attenuates cell signaling pathways to maintain latent infection
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/2437e0f55249499d8a17eee25ae87f04
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Latency-Associated Expression of Human Cytomegalovirus US28 Attenuates Cell Signaling Pathways To Maintain Latent Infection

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