The Interaction Between Human Papillomaviruses and the Stromal Microenvironment

Woodby, Brittany; Scott, Matthew L.; Bodily, Jason M.

doi:10.1016/bs.pmbts.2016.09.003

Cited by 31 publications

(41 citation statements)

References 519 publications

(734 reference statements)

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“…Differentiation of HPV-positive cells induces the productive phase of the viral life cycle by upregulating viral gene expression, resulting in viral genome amplification and virion morphogenesis (1,4). By restricting viral antigen synthesis to differentiated keratinocytes of the epidermis, HPV life cycle organization promotes viral persistence through facilitating immune evasion (1,5,6). In addition, activities of HPV oncoproteins E5, E6, and E7 can actively inhibit innate and adaptive immune responses, thereby promoting viral persistence (6,7).…”

mentioning

confidence: 99%

Induction of Interferon Kappa in Human Papillomavirus 16 Infection by Transforming Growth Factor Beta-Induced Promoter Demethylation

Woodby

Songock

Scott

et al. 2018

J Virol

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Persistent high-risk human papillomavirus (HPV) infection is the major causal factor in cervical and other anogenital cancers. Because there are currently no therapeutics capable of preventing neoplastic progression of HPV infections, understanding the mechanisms of HPV-mediated persistence, including immune evasion, is a major research priority. The multifunctional growth factor transforming growth factor beta (TGFβ) has been shown to inhibit expression of early viral transcripts from cells harboring integrated HPV genomes or cells infected with retroviruses expressing HPV oncoproteins. However, the mechanism of TGFβ-induced inhibition has not been fully defined. In this study, we have observed a previously uncharacterized ability of TGFβ to repress the differentiation-induced upregulation of late HPV16 gene expression. In addition, interferon kappa (IFN-κ), a keratinocyte-specific, constitutively expressed cytokine suppressed by differentiation, can be transcriptionally induced by TGFβ1. TGFβ-mediated IFN-κ transcription only occurs in cells containing HPV16, and this is due to TGFβ1-mediated reversal of HPV-induced methylation of the IFN-κ promoter through active DNA demethylation mediated by thymine DNA glycosylase (TDG). This novel interaction between growth factor and innate immune signaling may shed light on the mechanisms of HPV persistence and how the virus manipulates both immune and growth factor signaling to promote its life cycle. Persistent infection by high-risk HPVs is the primary risk factor for development of HPV-induced cancers. Persistence involves viral evasion of the immune response, including the IFN response. HPV is also known to suppress TGFβ signaling, which inhibits viral gene expression. Here, we show that the TGFβ and IFN pathways are interrelated in the context of HPV16 infection through the upregulation of IFN-κ by TGFβ. The ability of TGFβ to induce IFN-κ promoter demethylation and transcriptional activation provides a new explanation for why HPV has evolved mechanisms to inhibit TGFβ in infected cells.

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confidence: 99%

Induction of Interferon Kappa in Human Papillomavirus 16 Infection by Transforming Growth Factor Beta-Induced Promoter Demethylation

Woodby

Songock

Scott

et al. 2018

J Virol

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“…HPV carries many tools to suppress IFN responses (9,39). This study reveals two more: that the ability of HPV to suppress IFN responses is not just in the infected cells but also in the stromal microenvironment, and that E5 can serve as an innate immune suppressor.…”

Section: Discussionmentioning

confidence: 95%

“…15) would be consistent with the idea that IFN acts late in the viral life cycle. E6 and E7 are both known to interfere with the IFN response, and both have been shown to regulate the expression of soluble factors that are capable of acting on the stroma (39,48,81). Because E6 and E7 are both expressed at normal levels in E5 Stop cells (34), the suppressive effects of these two oncogenes would still be present.…”

Section: Discussionmentioning

confidence: 99%

“…Work by many investigators has uncovered a complex array of interactions between epithelial cells and fibroblasts, endothelial cells, and immune cells in the tissue stromal microenvironment (35)(36)(37)(38). Interactions between epithelia and stroma are important for immune responses (39), and signals provided by stromal fibroblasts are increasingly recognized as critical elements in cancer development (38,(40)(41)(42). Fibroblasts are the major cell type in dermal stroma; they participate in many signaling pathways, extracellular matrix (ECM) maintenance, and other functions to ensure tissue homeostasis and produce factors important for inflammation, wound healing, and angiogenesis (reviewed in references 37 and 43).…”

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confidence: 99%

“…HPVs infect keratinocytes exclusively, but many of the genes regulated by HPV oncogenes are secreted factors such as growth factors, cytokines, and IFNs that have the potential to affect stromal cells (48)(49)(50). Paracrine factors produced by stromal fibroblasts have the potential to impact the growth and invasiveness of HPV-containing epithelia (39,51,52), and changes in stromal fibroblast gene expression have been observed during progression of low-to high-grade cervical lesions (53,54). However, little is understood about how fibroblasts might regulate the HPV life cycle, or vice versa, and how HPV might affect epithelial-stromal communication in general.…”

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confidence: 99%

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Suppression of Stromal Interferon Signaling by Human Papillomavirus 16

Raikhy

Woodby

Scott

et al. 2019

J Virol

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Human papillomaviruses (HPVs) infect squamous epithelia and cause several important cancers. Immune evasion is critical for viral persistence. Fibroblasts in the stromal microenvironment provide growth signals and cytokines that are required for proper epithelial differentiation, maintenance, and immune responses and are critical in the development of many cancers. In this study, we examined the role of epithelial-stromal interactions in the HPV16 life cycle using organotypic (raft) cultures as a model. Rafts were created using uninfected human foreskin keratinocytes (HFKs) and HFKs containing either wild-type HPV16 or HPV16 with a stop mutation to prevent the expression of the viral oncogene E5. Microarray analysis revealed significant changes in gene expression patterns in the stroma in response to HPV16, some of which were E5 dependent. Interferon (IFN)-stimulated genes (ISGs) and extracellular matrix remodeling genes were suppressed, the most prominent pathways affected. STAT1, IFNAR1, IRF3, and IRF7 were knocked down in stromal fibroblasts using lentiviral short hairpin RNA (shRNA) transduction. HPV late gene expression and viral copy number in the epithelium were increased when the stromal IFN pathway was disrupted, indicating that the stroma helps control the late phase of the HPV life cycle in the epithelium. Increased late gene expression correlated with increased late keratinocyte differentiation but not decreased IFN signaling in the epithelium. These studies show HPV16 has a paracrine effect on stromal innate immunity, reveal a new role for E5 as a stromal innate immune suppressor, and suggest that stromal IFN signaling may influence keratinocyte differentiation. IMPORTANCE The persistence of high-risk human papillomavirus (HPV) infections is the key risk factor for developing HPV-associated cancers. The ability of HPV to evade host immunity is a critical component of its ability to persist. The environment surrounding a tumor is increasingly understood to be critical in cancer development, including immune evasion. Our studies show that HPV can suppress the expression of immune-related genes in neighboring fibroblasts in a three-dimensional (3D) model of human epithelium. This finding is significant, because it indicates that HPV can control innate immunity not only in the infected cell but also in the microenvironment. In addition, the ability of HPV to regulate stromal gene expression depends in part on the viral oncogene E5, revealing a new function for this protein as an immune evasion factor.

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The role of the innate and adaptive immune response in HPV‐associated oropharyngeal squamous cell carcinoma

Subbarayan

Arnold

Gomez

et al. 2019

Laryngoscope Investig Oto

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Human papilloma virus (HPV) has been implicated in the development of oropharyngeal squamous cell carcinoma (OPSCC) and is directly attributed to its increasing incidence. The immune microenvironment surrounding HPV‐associated OPSCC tumors is complex and plays a critical role in the carcinogenic process. The neoplastic mechanism includes cells of the innate immunity such as macrophages, and dendritic cells as well as cells of the adaptive immune process such as CD8+ T‐cells. The intricate interactions between these two arms of the immune system allow for a pro‐inflammatory and pro‐tumorigenic environment. Intensive efforts are underway to gain a greater understanding of the mechanisms involved in the immune system's role in tumor development. This study seeks to summarize the current knowledge pertaining to role of the innate and adaptive immune response in HPV‐associated OPSCC. Level of Evidence 3a

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The Interaction Between Human Papillomaviruses and the Stromal Microenvironment

Cited by 31 publications

References 519 publications

Induction of Interferon Kappa in Human Papillomavirus 16 Infection by Transforming Growth Factor Beta-Induced Promoter Demethylation

Induction of Interferon Kappa in Human Papillomavirus 16 Infection by Transforming Growth Factor Beta-Induced Promoter Demethylation

Suppression of Stromal Interferon Signaling by Human Papillomavirus 16

The role of the innate and adaptive immune response in HPV‐associated oropharyngeal squamous cell carcinoma

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