Human Papillomavirus 16 E6 and E7 Synergistically Repress Innate Immune Gene Transcription

ABSTRACT Human papillomaviruses (HPV) are causative agents in 5% of all cancers, including the majority of anogenital and oropharyngeal cancers. Downregulation of innate immune genes (IIGs) by HPV to promote the viral life cycle is well documented; E6 and E7 are known repressors of these genes. More...

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Autores principales:	Claire D. James, Christian T. Fontan, Raymonde Otoa, Dipon Das, Apurva T. Prabhakar, Xu Wang, Molly L. Bristol, Iain M. Morgan
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	DNA damage response E6 E7 innate immunity papillomavirus Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/bc3fbafcef0743e69b094470b763b5c5
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spelling	oai:doaj.org-article:bc3fbafcef0743e69b094470b763b5c52021-11-15T15:27:52ZHuman Papillomavirus 16 E6 and E7 Synergistically Repress Innate Immune Gene Transcription10.1128/mSphere.00828-192379-5042https://doaj.org/article/bc3fbafcef0743e69b094470b763b5c52020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00828-19https://doaj.org/toc/2379-5042ABSTRACT Human papillomaviruses (HPV) are causative agents in 5% of all cancers, including the majority of anogenital and oropharyngeal cancers. Downregulation of innate immune genes (IIGs) by HPV to promote the viral life cycle is well documented; E6 and E7 are known repressors of these genes. More recently, we demonstrated that E2 could also repress IIGs. These studies have been carried out in cells overexpressing the viral proteins, and to further investigate the role of individual viral proteins in this repression, we introduced stop codons into E6 and/or E7 in the entire HPV16 genome and generated N/Tert-1 cells stably maintaining the HPV16 genomes. We demonstrate that E6 or E7 individually is not sufficient to repress IIG expression in the context of the entire HPV16 genome; both are required for a synergistic repression. The DNA damage response (DDR) is activated by HPV16 irrespective of E6 and E7 expression, presumably due to viral replication; E1 is a known activator of the DDR. In addition, replication stress was apparent in HPV16-positive cells lacking E6 and E7, manifested by attenuated cellular growth and activation of replication stress genes. These studies led us to the following model. Viral replication per se can activate the DDR following infection, and this activation is a known inducer of IIG expression, which may induce cellular senescence. To combat this, E6 and E7 synergistically combine to manipulate the DDR and actively repress innate immune gene expression promoting cellular growth; neither protein by itself is able to do this. IMPORTANCE The role of human papillomavirus 16 (HPV16) in human cancers is well established; however, to date there are no antiviral therapeutics that are available for combatting these cancers. To identify such targets, we must enhance the understanding of the viral life cycle. Innate immune genes (IIGs) are repressed by HPV16, and we have reported that this repression persists through to cancer. Reversal of this repression would boost the immune response to HPV16-positive tumors, an area that is becoming more important given the advances in immunotherapy. This report demonstrates that E6 and E7 synergistically repress IIG expression in the context of the entire HPV16 genome. Removal of either protein activates the expression of IIGs by HPV16. Therefore, gaining a precise understanding of how the viral oncogenes repress IIG expression represents an opportunity to reverse this repression and boost the immune response to HPV16 infections for therapeutic gain.Claire D. JamesChristian T. FontanRaymonde OtoaDipon DasApurva T. PrabhakarXu WangMolly L. BristolIain M. MorganAmerican Society for MicrobiologyarticleDNA damage responseE6E7innate immunitypapillomavirusMicrobiologyQR1-502ENmSphere, Vol 5, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	DNA damage response E6 E7 innate immunity papillomavirus Microbiology QR1-502
spellingShingle	DNA damage response E6 E7 innate immunity papillomavirus Microbiology QR1-502 Claire D. James Christian T. Fontan Raymonde Otoa Dipon Das Apurva T. Prabhakar Xu Wang Molly L. Bristol Iain M. Morgan Human Papillomavirus 16 E6 and E7 Synergistically Repress Innate Immune Gene Transcription
description	ABSTRACT Human papillomaviruses (HPV) are causative agents in 5% of all cancers, including the majority of anogenital and oropharyngeal cancers. Downregulation of innate immune genes (IIGs) by HPV to promote the viral life cycle is well documented; E6 and E7 are known repressors of these genes. More recently, we demonstrated that E2 could also repress IIGs. These studies have been carried out in cells overexpressing the viral proteins, and to further investigate the role of individual viral proteins in this repression, we introduced stop codons into E6 and/or E7 in the entire HPV16 genome and generated N/Tert-1 cells stably maintaining the HPV16 genomes. We demonstrate that E6 or E7 individually is not sufficient to repress IIG expression in the context of the entire HPV16 genome; both are required for a synergistic repression. The DNA damage response (DDR) is activated by HPV16 irrespective of E6 and E7 expression, presumably due to viral replication; E1 is a known activator of the DDR. In addition, replication stress was apparent in HPV16-positive cells lacking E6 and E7, manifested by attenuated cellular growth and activation of replication stress genes. These studies led us to the following model. Viral replication per se can activate the DDR following infection, and this activation is a known inducer of IIG expression, which may induce cellular senescence. To combat this, E6 and E7 synergistically combine to manipulate the DDR and actively repress innate immune gene expression promoting cellular growth; neither protein by itself is able to do this. IMPORTANCE The role of human papillomavirus 16 (HPV16) in human cancers is well established; however, to date there are no antiviral therapeutics that are available for combatting these cancers. To identify such targets, we must enhance the understanding of the viral life cycle. Innate immune genes (IIGs) are repressed by HPV16, and we have reported that this repression persists through to cancer. Reversal of this repression would boost the immune response to HPV16-positive tumors, an area that is becoming more important given the advances in immunotherapy. This report demonstrates that E6 and E7 synergistically repress IIG expression in the context of the entire HPV16 genome. Removal of either protein activates the expression of IIGs by HPV16. Therefore, gaining a precise understanding of how the viral oncogenes repress IIG expression represents an opportunity to reverse this repression and boost the immune response to HPV16 infections for therapeutic gain.
format	article
author	Claire D. James Christian T. Fontan Raymonde Otoa Dipon Das Apurva T. Prabhakar Xu Wang Molly L. Bristol Iain M. Morgan
author_facet	Claire D. James Christian T. Fontan Raymonde Otoa Dipon Das Apurva T. Prabhakar Xu Wang Molly L. Bristol Iain M. Morgan
author_sort	Claire D. James
title	Human Papillomavirus 16 E6 and E7 Synergistically Repress Innate Immune Gene Transcription
title_short	Human Papillomavirus 16 E6 and E7 Synergistically Repress Innate Immune Gene Transcription
title_full	Human Papillomavirus 16 E6 and E7 Synergistically Repress Innate Immune Gene Transcription
title_fullStr	Human Papillomavirus 16 E6 and E7 Synergistically Repress Innate Immune Gene Transcription
title_full_unstemmed	Human Papillomavirus 16 E6 and E7 Synergistically Repress Innate Immune Gene Transcription
title_sort	human papillomavirus 16 e6 and e7 synergistically repress innate immune gene transcription
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/bc3fbafcef0743e69b094470b763b5c5
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Human Papillomavirus 16 E6 and E7 Synergistically Repress Innate Immune Gene Transcription

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