High-Risk Human Papillomaviruses Repress Constitutive Kappa Interferon Transcription via E6 To Prevent Pathogen Recognition Receptor and Antiviral-Gene Expression

Reiser, J; Hurst, José; Voges, Maike; Krauss, Peter; Münch, P; Iftner, Thomas; Stubenrauch, Frank

doi:10.1128/jvi.05279-11

Cited by 136 publications

(200 citation statements)

References 45 publications

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“…Plasmid pENTR4-IFN-was constructed by subcloning a BglII fragment from pSG-IFN- (15) into the BamHI site of a modified pENTR4 plasmid (Invitrogen). The pInducer 20-IFN-plasmid was constructed by in vitro recombination of pInducer20 (17) with pENTR4-IFN-.…”

Section: Methodsmentioning

confidence: 99%

“…The inhibition of IFN-expression is caused by the hr-HPV E6 oncoprotein and involves the induction of DNA methylation at the IFN-promoter (15,16). This raises the question of whether HPV prevent IFN-expression because it displays anti-HPV activity by regulating ISGs in keratinocytes.…”

mentioning

confidence: 99%

“…The reduction of ISG expression in HPV-positive keratinocytes correlates with the inhibition of IFN-, which is an unusual member of the type I IFN family as it is constitutively expressed at high levels in normal keratinocytes and only weakly responds to inducers of IFN-␣s and -␤ (13)(14)(15)(16). The inhibition of IFN-expression is caused by the hr-HPV E6 oncoprotein and involves the induction of DNA methylation at the IFN-promoter (15,16).…”

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confidence: 99%

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Interferon Kappa Inhibits Human Papillomavirus 31 Transcription by Inducing Sp100 Proteins

Habiger

Jäger²,

Walter³

et al. 2016

J Virol

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High-risk human papillomaviruses (hr-HPV IMPORTANCEHigh-risk HPV can establish persistent infections which may progress to anogenital cancers. hr-HPV interfere with the expression of interferon (IFN)-stimulated genes (ISGs), which is due to reduced levels of IFN-, an IFN that is constitutively expressed in human keratinocytes. This study reveals that IFN-rapidly inhibits HPV transcription and that this is due to the induction of Sp100 proteins. Thus, Sp100 represents an ISG for hr-HPV. P ersistent infections with high-risk human papillomaviruses (hr-HPV) are a necessary risk factor for the development of anogenital and oropharyngeal cancers (1). HPV have circular double-stranded DNA (dsDNA) genomes of ϳ8,000 bp and infect keratinocytes of the basal layer of mucosal and cutaneous epithelium. In undifferentiated cells, HPV genomes replicate as extrachromosomal elements at a low copy number and express only early viral genes such as those for the oncoproteins E6 and E7 and the replication proteins E1, E2, and E8^E2C (2). hr-HPV E6 and E7 interact with critical regulators of the cell cycle such as p53 and retinoblastoma family members to ensure continuous proliferation of infected cells (3).Transcriptome studies have shown that interferon (IFN)-stimulated genes (ISGs) are expressed at lower levels in hr-HPV-positive cell lines than in their uninfected counterparts (4-6). Type I IFNs such as IFN-␣ subtypes or IFN-␤ are induced upon viral infection and then secreted into the extracellular space (7). Secreted IFNs bind to the respective receptor on infected and neighboring cells, and kinases are activated, which results in the nuclear translocation of transcription factors such as STAT1 which then induce several hundred ISGs, many of which have direct antiviral activities (8).The treatment of cell lines that maintain persistently replicating extrachromosomal HPV16 or -31 genomes with recombinant IFN-␤ resulted in growth retardation and the induction of apoptosis, which did not occur with HPV-negative keratinocytes (9, 10). A detailed analysis of the HPV16 copy number and transcription upon IFN-␤ treatment indicated that first the viral copy number is decreased, followed by a reduction of viral transcription (10). HPV31-positive CIN612-9E cells have reduced levels of STAT1, which is both an ISG and also a crucial transcription factor of the IFN signal transduction cascade. Reexpression of STAT1 resulted in a reduction of viral genomes (11). Taken together, these data strongly suggest that IFNs induce ISGs that inhibit the replication of HPV. In line with this, the ISG IFIT1 (or ISG56) directly interacts with the E1 helicases of HPV11 and -18, which results in the inhibition of the replication of the viral origin (12).

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Interferon Kappa Inhibits Human Papillomavirus 31 Transcription by Inducing Sp100 Proteins

Habiger

Jäger²,

Walter³

et al. 2016

J Virol

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“…Both E6 and E7 have been shown to target the IL-18 receptor directly, to prevent activation of target cells (32). E6 and E7 also prevent the transcription of inflammatory cytokines by targeting antiviral signaling pathways (9,14,35).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, they reduce the production of antiviral interferons by subverting the actions of interferon (IFN) regulatory factors (IRFs) (10,11) and nuclear factor kappa B (NF-B) (12,13). More recently, they have been implicated in the reduced production of type III IFNs (14).…”

mentioning

confidence: 99%

Human Papillomavirus E7 Oncoprotein Increases Production of the Anti-Inflammatory Interleukin-18 Binding Protein in Keratinocytes

Richards

Doble

Wasson

et al. 2014

J Virol

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Human papillomavirus (HPV) can successfully evade the host immune response to establish a persistent infection. We show here that expression of the E7 oncoprotein in primary human keratinocytes results in increased production of interleukin-18 (IL-18) binding protein (IL-18BP). This anti-inflammatory cytokine binding protein is a natural antagonist of IL-18 and is necessary for skin homeostasis. We map increased IL-18BP production to the CR3 region of E7 and demonstrate that this ability is shared among E7 proteins from different HPV types. Furthermore, mutagenesis shows that increased IL-18BP production is mediated by a gamma-activated sequence (GAS) in the IL-18BP promoter. Importantly, the increased IL-18BP levels seen in E7-expressing keratinocytes are capable of diminishing IL-18-mediated CD4 lymphocyte activation. This study provides the first evidence for a virus protein that targets IL-18BP and further validates E7 as a key component of the HPV immune evasion armor. IMPORTANCEInfection with human papillomavirus is a leading cause of morbidity and mortality worldwide. This study demonstrates that the E7 protein increases production of the anti-inflammatory IL-18BP, a major regulator of epithelial homeostasis. A number of E7 proteins can increase IL-18BP production, and a region within the CR3 of E7 is necessary for mediating the increase. A consequence of increased IL-18BP production is a reduction in CD4-positive lymphocyte activation in response to IL-18 costimulation. These findings may shed light on the immune evasion abilities of HPV.

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Integration of high‐risk human papillomavirus into cellular cancer‐related genes in head and neck cancer cell lines

et al. 2017

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Background HPV-positive oropharyngeal cancer is generally associated with excellent response to therapy, but some HPV-positive tumors progress despite aggressive therapy. This study evaluates viral oncogene expression and viral integration sites in HPV16 and HPV18-positive squamous carcinoma cell lines. Methods E6-E7 alternate transcripts were assessed by RT-PCR. Detection of integrated papillomavirus sequences (DIPS-PCR) and sequencing identified viral insertion sites and affected host genes. Cellular gene expression was assessed across viral integration sites. Results All HPV-positive cell lines expressed alternate HPVE6/E7 splicing indicative of active viral oncogenesis. HPV integration occurred within cancer-related genes TP63, DCC, JAK1, TERT, ATR, ETV6, PGR, PTPRN2, and TMEM237 in 8 HNSCC lines but UM-SCC-105 and UM-GCC-1 had only intergenic integration. Conclusions HPV integration into cancer-related genes occurred in 7/9 HPV-positive cell lines and of these six were from tumors that progressed. HPV integration into cancer-related genes may be a secondary carcinogenic driver in HPV-driven tumors.

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High-Risk Human Papillomaviruses Repress Constitutive Kappa Interferon Transcription via E6 To Prevent Pathogen Recognition Receptor and Antiviral-Gene Expression

Cited by 136 publications

References 45 publications

Interferon Kappa Inhibits Human Papillomavirus 31 Transcription by Inducing Sp100 Proteins

Interferon Kappa Inhibits Human Papillomavirus 31 Transcription by Inducing Sp100 Proteins

Human Papillomavirus E7 Oncoprotein Increases Production of the Anti-Inflammatory Interleukin-18 Binding Protein in Keratinocytes

Integration of high‐risk human papillomavirus into cellular cancer‐related genes in head and neck cancer cell lines

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