scholarly journals Human papillomavirus 16 E2 regulates keratinocyte gene expression relevant to cancer and the viral life cycle

2018 ◽  
Author(s):  
Michael R Evans ◽  
Claire D James ◽  
Molly L Bristol ◽  
Tara J Nulton ◽  
Xu Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Radiation Therapy ◽  
Life Cycle ◽  
Innate Immune ◽  
Host Gene ◽  
Host Gene Expression ◽  
Immune Genes ◽  
E6 And E7 ◽  
Innate Immune Genes

AbstractHuman papillomaviruses (HPV) are causative agents in ano-genital and oropharyngeal cancers. The virus must reprogram host gene expression to promote infection, and E6 and E7 contribute to this via targeting of cellular transcription factors including p53 and pRb, respectively. The HPV16 E2 protein regulates host gene expression in U2OS cells and in this study we extend these observations into TERT immortalized oral keratinocytes (NOKs) that are capable of supporting late stages of the HPV16 life cycle. We observed repression of innate immune genes by E2 that are also repressed by the intact HPV16 genome in NOKs. RNA-seq data identified 167 up and 395 downregulated genes by E2; there was a highly significant overlap of the E2 regulated genes with those regulated by the intact HPV16 genome in the same cell type. siRNA targeting of E2 reversed repression of E2 targeted genes. The ability of E2 to repress innate immune genes was confirmed in an ano-genital immortalized keratinocyte cell line, N/Tert-1. We present analysis of data from The Cancer Genome Atlas (TCGA) for HPV16 positive and negative head and neck cancers (HNC) suggesting that E2 plays a role in regulation of the host genome in cancers. Patients with HPV16 positive HNC with a loss of E2 expression exhibit a worse clinical outcome and we discuss how this could, at least partially, be related to the loss of E2 host gene regulation.ImportanceHPV16 positive tumors that retain expression of E2 have a better clinical outcome than those that have lost E2 expression. It has been suggested that this is due to a loss of E2 repression of E6 and E7 expression but this is not supported by data from tumors where there is not more E6 and E7 expression in the absence of E2. Here we report that E2 regulates host gene expression and place this regulation in context of the HPV16 life cycle and HPV16 positive head and neck cancers (the majority of which retain E2 expression). We propose that this E2 function may play an important part in the increased response of HPV16 positive cancers to radiation therapy. Therefore, host gene regulation by E2 may be important for promotion of the HPV16 life cycle, and also for the response of HPV16 positive tumors to radiation therapy.

scholarly journals Human Papillomavirus 16 E2 Regulates Keratinocyte Gene Expression Relevant to Cancer and the Viral Life Cycle

2018 ◽  
Vol 93 (4) ◽  
Author(s):  
Michael R. Evans ◽  
Claire D. James ◽  
Molly L. Bristol ◽  
Tara J. Nulton ◽  
Xu Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Radiation Therapy ◽  
Life Cycle ◽  
Innate Immune ◽  
Host Gene ◽  
Host Gene Expression ◽  
Human Papillomavirus 16 ◽  
Immune Genes ◽  
E6 And E7 ◽  
Innate Immune Genes

ABSTRACTHuman papillomaviruses (HPVs) are causative agents in ano-genital and oropharyngeal cancers. The virus must reprogram host gene expression to promote infection, and E6 and E7 contribute to this via the targeting of cellular transcription factors, including p53 and pRb, respectively. The HPV16 E2 protein regulates host gene expression in U2OS cells, and in this study, we extend these observations into telomerase reverse transcriptase (TERT) immortalized oral keratinocytes (NOKs) that are capable of supporting late stages of the HPV16 life cycle. We observed repression of innate immune genes by E2 that are also repressed by the intact HPV16 genome in NOKs. Transcriptome sequencing (RNA-seq) data identified 167 up- and 395 downregulated genes by E2; there was a highly significant overlap of the E2-regulated genes with those regulated by the intact HPV16 genome in the same cell type. Small interfering RNA (siRNA) targeting of E2 reversed the repression of E2-targeted genes. The ability of E2 to repress innate immune genes was confirmed in an ano-genital immortalized keratinocyte cell line, N/Tert-1. We present the analysis of data from The Cancer Genome Atlas (TCGA) for HPV16-positive and -negative head and neck cancers (HNC) suggesting that E2 plays a role in the regulation of the host genome in cancers. Patients with HPV16-positive HNC with a loss of E2 expression exhibited a worse clinical outcome, and we discuss how this could, at least partially, be related to the loss of E2 host gene regulation.IMPORTANCEHuman papillomavirus 16 (HPV16)-positive tumors that retain expression of E2 have a better clinical outcome than those that have lost E2 expression. It has been suggested that this is due to a loss of E2 repression of E6 and E7 expression, but this is not supported by data from tumors where there is not more E6 and E7 expression in the absence of E2. Here we report that E2 regulates host gene expression and place this regulation in the context of the HPV16 life cycle and HPV16-positive head and neck cancers (the majority of which retain E2 expression). We propose that this E2 function may play an important part in the increased response of HPV16-positive cancers to radiation therapy. Therefore, host gene regulation by E2 may be important for promotion of the HPV16 life cycle and also for the response of HPV16-positive tumors to radiation therapy.

scholarly journals Immune Gene Expression Covaries with Gut Microbiome Composition in Stickleback

mBio ◽  
2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Lauren E. Fuess ◽  
Stijn den Haan ◽  
Fei Ling ◽  
Jesse N. Weber ◽  
Natalie C. Steinel ◽  
...  
Keyword(s):  
Gene Expression ◽  
Microbial Communities ◽  
Gut Microbiome ◽  
Alpha Diversity ◽  
Host Immunity ◽  
Host Gene ◽  
Microbiota Composition ◽  
Host Gene Expression ◽  
Microbiome Composition ◽  
Immune Genes

ABSTRACT Commensal microbial communities have immense effects on their vertebrate hosts, contributing to a number of physiological functions, as well as host fitness. In particular, host immunity is strongly linked to microbiota composition through poorly understood bi-directional links. Gene expression may be a potential mediator of these links between microbial communities and host function. However, few studies have investigated connections between microbiota composition and expression of host immune genes in complex systems. Here, we leverage a large study of laboratory-raised fish from the species Gasterosteus aculeatus (three-spined stickleback) to document correlations between gene expression and microbiome composition. First, we examined correlations between microbiome alpha diversity and gene expression. Our results demonstrate robust positive associations between microbial alpha diversity and expression of host immune genes. Next, we examined correlations between host gene expression and abundance of microbial taxa. We identified 15 microbial families that were highly correlated with host gene expression. These families were all tightly correlated with host expression of immune genes and processes, falling into one of three categories—those positively correlated, negatively correlated, and neutrally related to immune processes. Furthermore, we highlight several important immune processes that are commonly associated with the abundance of these taxa, including both macrophage and B cell functions. Further functional characterization of microbial taxa will help disentangle the mechanisms of the correlations described here. In sum, our study supports prevailing hypotheses of intimate links between host immunity and gut microbiome composition. IMPORTANCE Here, we document associations between host gene expression and gut microbiome composition in a nonmammalian vertebrate species. We highlight associations between expression of immune genes and both microbiome diversity and abundance of specific microbial taxa. These findings support other findings from model systems which have suggested that gut microbiome composition and host immunity are intimately linked. Furthermore, we demonstrate that these correlations are truly systemic; the gene expression detailed here was collected from an important fish immune organ (the head kidney) that is anatomically distant from the gut. This emphasizes the systemic impact of connections between gut microbiota and host immune function. Our work is a significant advancement in the understanding of immune-microbiome links in nonmodel, natural systems.

scholarly journals Modulatory upregulation of an insulin peptide gene by different pathogens in C. elegans

2017 ◽  
Author(s):  
Song-Hua Lee ◽  
Shizue Omi ◽  
Nishant Thakur ◽  
Clara Taffoni ◽  
Jérôme Belougne ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Signaling ◽  
Kinase Inhibitor ◽  
Innate Immune ◽  
Immune Genes ◽  
C Elegans ◽  
Intestinal Infections ◽  
Innate Immune Genes ◽  
Peptide Gene ◽  
Complex Manner

ABSTRACTWhen an animal is infected, its innate immune response needs to be tightly regulated across tissues and coordinated with other aspects of organismal physiology. Previous studies with Caenorhabditis elegans have demonstrated that insulin-like peptide genes are differentially expressed in response to different pathogens. They represent prime candidates for conveying signals between tissues upon infection. Here, we focused on one such gene, ins-11 and its potential role in mediating cross-tissue regulation of innate immune genes. While diverse bacterial intestinal infections can trigger the up-regulation of ins-11 in the intestine, we show that epidermal infection with the fungus Drechmeria coniospora triggers an upregulation of ins-11 in the epidermis. Using the Shigella virulence factor OpsF, a MAP kinase inhibitor, we found that in both cases, ins-11 expression is controlled cell autonomously by p38 MAPK, but via distinct transcription factors, STA-2/STAT in the epidermis and HLH-30/TFEB in the intestine. We established that ins-11, and the insulin signaling pathway more generally, are not involved in the regulation of antimicrobial peptide gene expression in the epidermis. The up-regulation of ins-11 in the epidermis does, however, affect intestinal gene expression in a complex manner, and has a deleterious effect on longevity. These results support a model in which insulin signaling, via ins-11, contributes to the coordination of the organismal response to infection, influencing the allocation of resources in an infected animal.

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

mSphere ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Claire D. James ◽  
Christian T. Fontan ◽  
Raymonde Otoa ◽  
Dipon Das ◽  
Apurva T. Prabhakar ◽  
...  
Keyword(s):  
Viral Proteins ◽  
Innate Immune ◽  
Cellular Growth ◽  
Immune Gene ◽  
Human Papillomavirus 16 ◽  
Immune Genes ◽  
Hpv16 Genome ◽  
E6 And E7 ◽  
Innate Immune Genes

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.

scholarly journals Global transcriptomics analyses reveal specialized roles for splicing regulatory proteins in the macrophage innate immune response

2020 ◽  
Author(s):  
KO West ◽  
AR Wagner ◽  
HM Scott ◽  
KJ Vail ◽  
K Carter ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Regulatory Proteins ◽  
Raw 264.7 ◽  
Immune Gene ◽  
Post Translational Modification ◽  
Immune Genes ◽  
Innate Immune Genes

ABSTRACTWhile the signaling cascades and transcription factors that activate gene expression in macrophages following pattern recognition receptor engagement are well known, the role of post-transcriptional RNA processing in modulating innate immune gene expression remains understudied. Recent phosphoproteomics analyses revealed that members of the SR and hnRNP families of splicing regulatory proteins undergo dynamic post-translational modification in infected macrophages. To begin to test if these splicing factors play a privileged role in controlling the innate immune transcriptome, we analyzed steady state gene expression and alternatively spliced isoform production in ten SR/hnRNP knockdown RAW 264.7 macrophage cell lines following infection with the bacterial pathogen Salmonella enterica serovar Typhimurium (Salmonella). We observed that thousands of genes were up or downregulated in SR/hnRNP knockdown cells and differentially expressed genes (DEGs) varied significantly depending on the SR/hnRNP examined. We discovered that a subset of critical innate immune genes (Nos2, Mx1, Il1a) rely heavily on SR/hnRNPs for proper induction and/or repression, while others (Tnf, Il1b) are generally unaffected by splicing factor knockdown. We also discovered that many key immune sensors and signaling molecules are subject to regulation by alternative splicing. While our data does not provide evidence for positive correlation between a transcripts’ reliance of SR/hnRNPs for proper expression and the gene’s induction level, length, or intron/exon architecture, we found that many rapidly induced primary response genes are repressed by SR/hnRNPs. Consistent with SR/hnRNP proteins contributing to innate immune outcomes, knockdown of hnRNP K and U significantly enhanced the ability of RAW 264.7 macrophages to control viral replication. Based on these collective findings, we conclude that many innate immune genes have evolved to rely on one or more splicing regulatory factors to ensure the proper timing and magnitude of their induction, supporting a model wherein pre-splicing is a critical regulatory node in the innate immune response.

scholarly journals The K186E Amino Acid Substitution in the Canine Influenza Virus H3N8 NS1 Protein Restores Its Ability To Inhibit Host Gene Expression

2017 ◽  
Vol 91 (22) ◽  
Author(s):  
Aitor Nogales ◽  
Caroline Chauché ◽  
Marta L. DeDiego ◽  
David J. Topham ◽  
Colin R. Parrish ◽  
...  
Keyword(s):  
Gene Expression ◽  
Amino Acid ◽  
Immune Responses ◽  
Influenza Viruses ◽  
Innate Immune ◽  
Host Gene ◽  
Innate Immune Responses ◽  
Host Gene Expression ◽  
Avian Origin ◽  
Canine Influenza

ABSTRACT Canine influenza viruses (CIVs) are the causative agents of canine influenza, a contagious respiratory disease in dogs, and include the equine-origin H3N8 and the avian-origin H3N2 viruses. Influenza A virus (IAV) nonstructural protein 1 (NS1) is a virulence factor essential for counteracting the innate immune response. Here, we evaluated the ability of H3N8 CIV NS1 to inhibit host innate immune responses. We found that H3N8 CIV NS1 was able to efficiently counteract interferon (IFN) responses but was unable to block general gene expression in human or canine cells. Such ability was restored by a single amino acid substitution in position 186 (K186E) that resulted in NS1 binding to the 30-kDa subunit of the cleavage and polyadenylation specificity factor (CPSF30), a cellular protein involved in pre-mRNA processing. We also examined the frequency distribution of K186 and E186 among H3N8 CIVs and equine influenza viruses (EIVs), the ancestors of H3N8 CIV, and experimentally determined the impact of amino acid 186 in the ability of different CIV and EIV NS1s to inhibit general gene expression. In all cases, the presence of E186 was responsible for the control of host gene expression. In contrast, the NS1 protein of H3N2 CIV harbors E186 and blocks general gene expression in canine cells. Altogether, our results confirm previous studies on the strain-dependent ability of NS1 to block general gene expression. Moreover, the observed polymorphism on amino acid 186 between H3N8 and H3N2 CIVs might be the result of adaptive changes acquired during long-term circulation of avian-origin IAVs in mammals. IMPORTANCE Canine influenza is a respiratory disease of dogs caused by two CIV subtypes, the H3N8 and H3N2 viruses, of equine and avian origins, respectively. Influenza NS1 is the main viral factor responsible for the control of host innate immune responses, and changes in NS1 can play an important role in host adaptation. Here we assessed the ability of H3N8 CIV NS1 to inhibit host innate immune responses and gene expression. The H3N8 CIV NS1 did not block host gene expression, but this activity was restored by a single amino acid substitution (K186E), which was responsible for NS1 binding to the host factor CPSF30. In contrast, the H3N2 CIV NS1, which contains E186, blocks general gene expression. Our results suggest that the ability to block host gene expression is not required for influenza virus replication in mammals but might be important in the long-term adaptation of avian-origin influenza viruses to mammals.

scholarly journals Immune gene expression covaries with gut microbiome composition in stickleback

2020 ◽  
Author(s):  
Lauren Fuess ◽  
Stijn den Haan ◽  
Fei Ling ◽  
Jesse N. Weber ◽  
Natalie C. Steinel ◽  
...  
Keyword(s):  
Gene Expression ◽  
Microbial Communities ◽  
Gut Microbiome ◽  
Alpha Diversity ◽  
Host Immunity ◽  
Host Gene ◽  
Microbiota Composition ◽  
Host Gene Expression ◽  
Microbiome Composition ◽  
Immune Genes

ABSTRACTCommensal microbial communities have immense effects on their vertebrate hosts, contributing to a number of physiological functions as well as host fitness. In particular, host immunity is strongly linked to microbiota composition through poorly understood bi-directional links. Gene expression may be a potential mediator of these links between microbial communities and host function. However few studies have investigated connections between microbiota composition and expression of host immune genes in complex systems. Here we leverage a large study of laboratory-raised fish from the species Gasterosteus aculeatus (three-spined stickleback) to document correlations between gene expression and microbiome composition. First, we examined correlations between microbiome alpha diversity and gene expression. Our results demonstrate robust positive associations between microbial alpha diversity and expression of host immunity. Next, we examined correlations between host gene expression and abundance of microbial taxa. We identified 15 microbial families that were highly correlated to host gene expression. These families were all tightly correlated to host expression of immune genes and processes, falling into one of three categories: those positively correlated, negatively correlated, and neutrally related to immune processes. Furthermore, we highlight several important immune processes that are commonly associated with abundance of these taxons, including both macrophage and B cell functions. Further functional characterization of microbial taxa will help disentangle the mechanisms of the correlations described here. In sum, our study supports prevailing hypotheses of intimate links between host immunity and gut microbiome composition.

scholarly journals Functional Evolution of the 2009 Pandemic H1N1 Influenza Virus NS1 and PA in Humans

2018 ◽  
Vol 92 (19) ◽  
Author(s):  
Aitor Nogales ◽  
Luis Martinez-Sobrido ◽  
Kevin Chiem ◽  
David J. Topham ◽  
Marta L. DeDiego
Keyword(s):  
Gene Expression ◽  
Influenza Virus ◽  
Amino Acid ◽  
H1n1 Influenza ◽  
Innate Immune ◽  
Host Gene ◽  
Pandemic H1n1 ◽  
Host Gene Expression ◽  
Pandemic H1n1 Influenza ◽  
Nonstructural Protein 1

ABSTRACT In 2009, a pandemic H1N1 influenza A virus (IAV) (pH1N1) emerged in the human population from swine causing a pandemic. Importantly, this virus is still circulating in humans seasonally. To analyze the evolution of pH1N1 in humans, we sequenced viral genes encoding proteins inhibiting general gene expression (nonstructural protein 1 [NS1] and PA-X) from circulating seasonal viruses and compared them to the viruses isolated at the origin of the pandemic. Recent pH1N1 viruses contain amino acid changes in the NS1 protein (E55K, L90I, I123V, E125D, K131E, and N205S), as previously described (A. M. Clark, A. Nogales, L. Martinez-Sobrido, D. J. Topham, and M. L. DeDiego, J Virol 91:e00721-17, 2017, https://doi.org/10.1128/JVI.00721-17), and amino acid changes in the PA-X protein (V100I, N204S, R221Q, and L229S). These amino acid differences between early and more recent pH1N1 isolates are responsible for increased NS1-mediated inhibition of host gene expression and decreased PA-X-mediated shutoff, including innate immune response genes. In addition, currently circulating pH1N1 viruses have acquired amino acid changes in the PA protein (V100I, P224S, N321K, I330V, and R362K). A recombinant pH1N1 virus containing PA, PA-X, and NS1 genes from currently circulating viruses is fitter in replication in cultured cells and in mice and is slightly more pathogenic than the original ancestor pH1N1 virus. These results demonstrate the need to monitor the evolution of pH1N1 in humans for mutations in the viral genome that could result in enhanced virulence. Importantly, these results further support our previous findings suggesting that inhibition of global gene expression mediated by NS1 and PA-X proteins is subject to a balance which can determine virus pathogenesis and fitness. IMPORTANCE IAVs emerge in humans from animal reservoirs, causing unpredictable pandemics. One of these pandemics was caused by an H1N1 virus in 2009, and this virus is still circulating seasonally. To analyze host-virus adaptations likely affecting influenza virus pathogenesis, protein amino acid sequences from viruses circulating at the beginning of the pandemic and those circulating currently were compared. Currently circulating viruses have incorporated amino acid changes in two viral proteins (NS1 and PA-X), affecting innate immune responses, and in the PA gene. These amino acid differences led to increased NS1-mediated and decreased PA-X-mediated inhibition of host gene expression. A recombinant pH1N1 virus containing PA, PA-X, and NS1 genes from recently circulating viruses is fitter in replication in tissue culture cells and in mice, and the virus is more pathogenic in vivo. Importantly, these results suggest that a balance in the abilities of NS1 and PA-X to induce host shutoff is beneficial for IAVs.

scholarly journals Human papillomavirus 16 E6 and E7 synergistically repress innate immune gene transcription

2019 ◽  
Author(s):  
Claire D. James ◽  
Christian T. Fontan ◽  
Raymonde Otoa ◽  
Dipon Das ◽  
Apurva T. Prabhakar ◽  
...  
Keyword(s):  
Viral Proteins ◽  
Innate Immune ◽  
Cellular Growth ◽  
Immune Gene ◽  
Immune Genes ◽  
Hpv16 Genome ◽  
E6 And E7 ◽  
Innate Immune Genes ◽  
Innate Immune Gene

AbstractHuman papillomaviruses 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 over-expressing 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 are 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 the HPV16 positive cells lacking E6 and E7, manifested by attenuated cellular growth and activation of replication stress genes. These studies lead 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 could 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.ImportanceThe role of HPV16 in human cancers is well established; however, to date there are no anti-viral therapeutics that are available for combatting these cancers. To identify such targets, we must enhance 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.

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