ABSTRACT
Epidermodysplasia verruciformis (EV) is a rare genetic skin disorder that is characterized by the development of papillomavirus-induced skin lesions that can progress to squamous cell carcinoma (SCC). Certain high-risk, cutaneous ß-genus human papillomaviruses (ß-HPVs), in particular HPV5 and HPV8, are associated with inducing EV in individuals who have a homozygous mutation in one of three genes tied to this disease: EVER1, EVER2, or CIB1. EVER1 and EVER2 are also known as TMC6 and TMC8, respectively. Little is known about the biochemical activities of EVER gene products or their roles in facilitating EV in conjunction with ß-HPV infection. To investigate the potential effect of EVER genes on papillomavirus infection, we pursued in vivo infection studies by infecting Ever2-null mice with mouse papillomavirus (MmuPV1). MmuPV1 shares characteristics with ß-HPVs including similar genome organization, shared molecular activities of their early, E6 and E7, oncoproteins, the lack of a viral E5 gene, and the capacity to cause skin lesions that can progress to SCC. MmuPV1 infections were conducted both in the presence and absence of UVB irradiation, which is known to increase the risk of MmuPV1-induced pathogenesis. Infection with MmuPV1 induced skin lesions in both wild-type and Ever2-null mice with and without UVB. Many lesions in both genotypes progressed to malignancy, and the disease severity did not differ between Ever2-null and wild-type mice. However, somewhat surprisingly, lesion growth and viral transcription was decreased, and lesion regression was increased in Ever2-null mice compared with wild-type mice. These studies demonstrate that Ever2-null mice infected with MmuPV1 do not exhibit the same phenotype as human EV patients infected with ß-HPVs.IMPORTANCEHumans with homozygous mutations in the EVER2 gene develop epidermodysplasia verruciformis (EV), a disease characterized by predisposition to persistent ß-genus human papillomavirus (ß-HPV) skin infections, which can progress to skin cancer. To investigate how EVER2 confers protection from papillomaviruses, we infected the skin of homozygous Ever2-null mice with mouse papillomavirus MmuPV1. Like in humans with EV, infected Ever2-null mice developed skin lesions that could progress to cancer. Unlike in humans with EV, lesions in these Ever2-null mice grew more slowly and regressed more frequently than in wild-type mice. MmuPV1 transcription was higher in wild-type mice than in Ever2-null mice, indicating that mouse EVER2 does not confer protection from papillomaviruses. These findings suggest that there are functional differences between MmuPV1 and ß-HPVs and/or between mouse and human EVER2.
Subject(s)
Epidermodysplasia Verruciformis , Mice, Knockout , Papillomavirus Infections , Animals , Mice , Epidermodysplasia Verruciformis/virology , Epidermodysplasia Verruciformis/genetics , Epidermodysplasia Verruciformis/pathology , Papillomavirus Infections/virology , Papillomavirus Infections/pathology , Membrane Proteins/genetics , Membrane Proteins/metabolism , Papillomaviridae/genetics , Papillomaviridae/pathogenicity , Betapapillomavirus/genetics , Betapapillomavirus/pathogenicity , Humans , Disease Susceptibility , Female , Mice, Inbred C57BL , Disease Models, Animal , Skin Neoplasms/virology , Skin Neoplasms/pathology , Skin Neoplasms/geneticsABSTRACT
CONTEXT.: There have been exceedingly few reports of epidermodysplasia verruciformis (EV) or EV-like lesions in the vulva. We describe the first observation of vulvar lesions displaying synchronous EV-like histology and conventional high-grade squamous intraepithelial lesion (HSIL), a finding hitherto unreported in medical literature. OBJECTIVES.: To describe this novel vulvar lesion with hybrid features of HSIL and EV, attempt to confirm the hypothesis of coinfection with α and ß human papillomavirus (α-HPV and ß-HPV) genotypes, and describe relevant underlying genetic mutations. DESIGN.: Cases were retrospectively selected from our institutional archive. Detailed review of clinical information, histologic examination, and whole genome sequencing (WGS) were performed. RESULTS.: Five samples from 4 different patients were included. Three of 4 patients had a history of either iatrogenic immune suppression or prior immune deficiency, and all 3 featured classic HSIL and EV changes within the same lesion. One patient had no history of immune disorders, presented with EV-like changes and multinucleated atypia of the vulva, and was the sole patient without conventional HSIL. By WGS, several uniquely mappable reads pointed toward infection with multiple HPV genotypes, including both α-HPVs and ß-HPVs. Mutations in genes implicated in cell-mediated immunity, such as DOCK8, CARMIL2, MST1, and others, were also found. CONCLUSIONS.: We provide the first description of vulvar lesions harboring simultaneous HSIL and EV features in the English-language literature, a phenomenon explained by coinfection with α-HPV and ß-HPV genotypes. The finding of EV-like changes in a vulvar specimen should prompt assessment of the patient's immune status.
Subject(s)
Alphapapillomavirus , Coinfection , Epidermodysplasia Verruciformis , Genotype , Mutation , Papillomavirus Infections , Humans , Female , Epidermodysplasia Verruciformis/genetics , Epidermodysplasia Verruciformis/virology , Epidermodysplasia Verruciformis/pathology , Papillomavirus Infections/virology , Papillomavirus Infections/genetics , Papillomavirus Infections/complications , Papillomavirus Infections/pathology , Retrospective Studies , Alphapapillomavirus/genetics , Adult , Coinfection/virology , Coinfection/genetics , Coinfection/pathology , Vulvar Neoplasms/virology , Vulvar Neoplasms/genetics , Vulvar Neoplasms/pathology , Middle Aged , Betapapillomavirus/genetics , Vulva/pathology , Vulva/virology , Squamous Intraepithelial Lesions/virology , Squamous Intraepithelial Lesions/pathology , Squamous Intraepithelial Lesions/genetics , Human Papillomavirus VirusesABSTRACT
Persistent infections with high-risk human papillomaviruses (HR-HPV) from the genus alpha are established risk factors for the development of anogenital and oropharyngeal cancers. In contrast, HPV from the genus beta have been implicated in the development of cutaneous squamous cell cancer (cSCC) in epidermodysplasia verruciformis (EV) patients and organ transplant recipients. Keratinocytes are the in vivo target cells for HPV, but keratinocyte models to investigate the replication and oncogenic activities of beta-HPV genomes have not been established. A recent study revealed, that beta-HPV49 immortalizes normal human keratinocytes (NHK) only, when the viral E8^E2 repressor (E8-) is inactivated (T. M. Rehm, E. Straub, T. Iftner, and F. Stubenrauch, Proc Natl Acad Sci U S A 119:e2118930119, 2022, https://doi.org/10.1073/pnas.2118930119). We now demonstrate that beta-HPV8 and HPV38 wild-type or E8- genomes are unable to immortalize NHK. Nevertheless, HPV8 and HPV38 express E6 and E7 oncogenes and other transcripts in transfected NHK. Inactivation of the conserved E1 and E2 replication genes reduces viral transcription, whereas E8- genomes display enhanced viral transcription, suggesting that beta-HPV genomes replicate in NHK. Furthermore, growth of HPV8- or HPV38-transfected NHK in organotypic cultures, which are routinely used to analyze the productive replication cycle of HR-HPV, induces transcripts encoding the L1 capsid gene, suggesting that the productive cycle is initiated. In addition, transcription patterns in HPV8 organotypic cultures and in an HPV8-positive lesion from an EV patient show similarities. Taken together, these data indicate that NHK are a suitable system to analyze beta-HPV8 and HPV38 replication. IMPORTANCE High-risk HPV, from the genus alpha, can cause anogenital or oropharyngeal malignancies. The oncogenic properties of high-risk HPV are important for their differentiation-dependent replication in human keratinocytes, the natural target cell for HPV. HPV from the genus beta have been implicated in the development of cutaneous squamous cell cancer in epidermodysplasia verruciformis (EV) patients and organ transplant recipients. Currently, the replication cycle of beta-HPV has not been studied in human keratinocytes. We now provide evidence that beta-HPV8 and 38 are transcriptionally active in human keratinocytes. Inactivation of the viral E8^E2 repressor protein greatly increases genome replication and transcription of the E6 and E7 oncogenes, but surprisingly, this does not result in immortalization of keratinocytes. Differentiation of HPV8- or HPV38-transfected keratinocytes in organotypic cultures induces transcripts encoding the L1 capsid gene, suggesting that productive replication is initiated. This indicates that human keratinocytes are suited as a model to investigate beta-HPV replication.
Subject(s)
Human Papillomavirus Viruses , Keratinocytes , Oncogene Proteins, Viral , Papillomavirus Infections , Humans , Epidermodysplasia Verruciformis/virology , Keratinocytes/virology , Neoplasms, Squamous Cell/virology , Oncogene Proteins, Viral/genetics , Oncogene Proteins, Viral/metabolism , Human Papillomavirus Viruses/genetics , Genome, ViralABSTRACT
A transgender female in her 40s with history of HIV and testicular cancer status post-genital X-irradiation presented with a perianal mass and pruritic rash across her chest. Physical examination revealed a bulky, verrucous tumor protruding outward from the anus involving the medial buttocks. Examination of the chest and arms showed numerous guttate, pink, flat-topped papules coalescing into plaques. Clinically and histologically the lesions were consistent with Buschke-Löwenstein condyloma (BLC) and acquired epidermodysplasia verruciformis (AEDV). Buschke-Löwenstein condyloma incisional biopsy tested negative for common low- and high-risk human papillomavirus (HPV) subtypes, including 6, 11, 16, and 18, possibly implicating beta HPV subtype or a less common pathogenic subtype. The patient underwent abdominoperineal resection of the BLC, which tested positive for low-risk HPV subtypes, suggesting the possibility of multiple implicated HPV subtypes in the same tumor. This case demonstrates a possible role of beta HPV or rarer HPV subtypes in the pathogenesis of verrucous carcinoma, particularly in the setting of immunosuppression.
Subject(s)
Anus Neoplasms/virology , Buschke-Lowenstein Tumor/virology , Epidermodysplasia Verruciformis/virology , HIV Infections/complications , Immunocompromised Host , Papillomaviridae , Papillomavirus Infections/complications , Transgender Persons , Anus Neoplasms/pathology , Buschke-Lowenstein Tumor/pathology , Epidermodysplasia Verruciformis/pathology , Exanthema , Female , Humans , Male , Middle Aged , Testicular NeoplasmsABSTRACT
Human papillomaviruses (HPVs) are responsible for cutaneous and mucosal lesions. Persistent HPV infection remains a leading cause of uterine cancer in women, but also of cutaneous squamous cell carcinoma in patients with epidermodysplasia verruciformis (EV), and of rare and devastating benign tumors, such as 'tree-man' syndrome. HPV infections are usually asymptomatic or benign in the general population. Severe manifestations in otherwise healthy subjects can attest to inherited immunodeficiencies. The human genetic dissection of these cases has identified critical components of the immune response to HPVs, including the non-redundant roles of keratinocyte-intrinsic immunity in controlling ß-HPVs, and of T cell-dependent adaptive immunity for controlling all HPV types. A key role of the CD28 T-cell costimulation pathway in controlling common warts due to HPVs was recently discovered. This review summarizes the state of the art in the human genetics of HPV infection, focusing on two key affected cell types: keratinocytes and T cells.
Subject(s)
Keratinocytes/immunology , Papillomaviridae/pathogenicity , Papillomavirus Infections/genetics , Papillomavirus Infections/immunology , T-Lymphocytes/immunology , Animals , Carcinoma, Squamous Cell/virology , Epidermodysplasia Verruciformis/virology , Female , Humans , Papillomavirus Infections/virology , Skin Neoplasms/virology , Uterine Neoplasms/virologySubject(s)
Carcinoma, Basal Cell/complications , Carcinoma, Squamous Cell/complications , DNA, Viral/isolation & purification , Epidermodysplasia Verruciformis/complications , Epidermodysplasia Verruciformis/pathology , Melanoma/complications , Skin Neoplasms/complications , Adult , Aged , Aged, 80 and over , Epidermodysplasia Verruciformis/virology , Female , Humans , Incidental Findings , Male , Middle Aged , PapillomaviridaeABSTRACT
ABSTRACT: Epidermodysplasia verruciformis (EV) is a rare dermatologic condition that is clinically characterized by flat, cutaneous, verrucous papules, pityriasis versicolor-like lesions, and similar lichenoid papules. There are 2 forms of EV: a classic inherited genodermatosis and a secondary acquired form. EV predisposes individuals to infections with certain types of human papillomavirus virus and subsequently increases the risk of cutaneous squamous cell carcinoma. The acquired form occurs in immunosuppressed patients, particularly in patients infected with HIV; however, it has also been described in patients who have undergone stem cell and solid organ transplantation. We report an additional case of renal transplantation and immunosuppressive therapy-associated acquired EV (AEV) in a 78-year-old man with multiple flesh-colored to violaceous, flat-topped papules distributed on the face and trunk clinically mimicking lichen planus. Biopsy was typical for that of EV, demonstrating enlarged keratinocytes with a blue-gray cytoplasm, a thickened granular layer, acanthosis, and hyperkeratosis. Herein, we discuss an unusual presentation of an AEV-mimicking lichen planus with review of the literature.
Subject(s)
Epidermodysplasia Verruciformis/virology , Immunocompromised Host , Immunosuppressive Agents/adverse effects , Kidney Transplantation/adverse effects , Acitretin/therapeutic use , Adult , Aged , Biopsy , Diagnosis, Differential , Epidermodysplasia Verruciformis/diagnosis , Epidermodysplasia Verruciformis/drug therapy , Epidermodysplasia Verruciformis/immunology , Female , Humans , Lichen Planus/diagnosis , Male , Middle Aged , Treatment Outcome , Young AdultABSTRACT
Human papillomaviruses (HPVs) infect squamous epithelia and can induce hyperproliferative lesions. More than 220 different HPV types have been characterized and classified into five different genera. While mucosal high-risk HPVs have a well-established causal role in anogenital carcinogenesis, the biology of cutaneous HPVs is less well understood.From patients with the rare genetic disorder epidermodysplasia verruciformis (EV) and animal models, evidence is accumulating that cutaneous PV of genus ß synergize with ultraviolet (UV) radiation in the development of cutaneous squamous cell carcinoma (cSCC). In 2009, the International Agency for Research on Cancer (IARC) classified the genus ß-HPV types 5 and 8 as "possible carcinogenic" biological agents (group 2B) in EV disease. Epidemiological and biological studies indicate that genus ß-PV infection may also play a role in UV-mediated skin carcinogenesis in non-EV patients. However, they rather act at early stages of carcinogenesis and become dispensable for the maintenance of the malignant phenotype, compatible with a "hit-and-run" mechanism.This chapter will give an overview on genus ß-PV infections and discuss similarities and differences of cutaneous and genus α mucosal high-risk HPV in epithelial carcinogenesis.
Subject(s)
Papillomaviridae/pathogenicity , Skin Neoplasms/etiology , Skin Neoplasms/virology , Animals , Carcinoma, Squamous Cell/etiology , Carcinoma, Squamous Cell/virology , Epidermodysplasia Verruciformis/etiology , Epidermodysplasia Verruciformis/virology , Humans , Ultraviolet Rays/adverse effectsABSTRACT
The cause of epidermodysplasia verruciformis is infection by human papillomavirus, usually types 5 or 8, and it exhibits a high potential for malignant transformation. The diagnostic histologic features of epidermodysplasia verruciformis are not always present and can be mimicked by non-viral diseases. The purpose of this study was to interrogate such lesions for new potential biomarkers to aid in the diagnostic accuracy. HPV DNA was high copy and localized to the upper half of the lesion in cells with cytologic features that included perinuclear halos, blue-grey cytoplasm, and hyper/parakeratosis. Serial section analyses demonstrated that there was increased expression of importin-ß, exportin-5, Mcl1, p16, Ki67 and PDL1 in 13/13 epidermodysplasia verruciformis lesions. Each of these proteins localized primarily to the less differentiated cells in the parabasal aspect of the lesion. Only Ki67 and exportin-5 were expressed in the normal epithelia, though much less so, in 13/13 aged matched controls. It is concluded that the host response to HPV 5/8 infection in epidermodysplasia verruciformis includes the up regulation of several proteins including p16, Ki67, importin-ß, exportin-5, Mcl1, and PDL1. Thus, these proteins may serve as new biomarkers of this disease that can aid in cases that are equivocal for epidermodysplasia verruciformis on histologic examination.
Subject(s)
Biomarkers/analysis , Epidermodysplasia Verruciformis/diagnosis , Papillomaviridae/isolation & purification , Papillomavirus Infections/diagnosis , Adolescent , Adult , Aged , Cell Transformation, Neoplastic , Epidermodysplasia Verruciformis/pathology , Epidermodysplasia Verruciformis/virology , Gene Expression Regulation , Humans , Immunohistochemistry , Middle Aged , Papillomaviridae/genetics , Papillomavirus Infections/pathology , Papillomavirus Infections/virology , Young AdultABSTRACT
Two novel human gamma-papillomavirus genomes (HPV_MTS3, and HPV_MTS4) were isolated from the skin of an immunosuppressed, late-onset Epidermodysplasia Verruciformis patient and fully cloned. The L1 open reading frames of HPV_MTS3 and HPV_MTS4 were 77% and 91% identical to their closest HPV full genome isolates w18c39 and EV03c60, which belong to the species gamma-22and gamma-7 of the genus Gammapapillomavirus, respectively.
Subject(s)
Epidermodysplasia Verruciformis/virology , Gammapapillomavirus/classification , Gammapapillomavirus/isolation & purification , Skin/virology , Capsid Proteins/genetics , Gammapapillomavirus/genetics , Genome, Viral , Humans , Immunocompromised Host , Phylogeny , Sequence Analysis, DNA , Sequence HomologyABSTRACT
The vast majority of vulvar human papilloma virus infections are produced by α human papilloma viruses and consist of exophytic or flat warts and classic or "usual" vulvar intraepithelial neoplasia. This report details 2 examples of epidermodysplasia verruciformis-like lesions of the vulva in women who were immunosuppressed. The most consistent morphologic feature was the presence of abnormal mature keratinocytes with large pale open nuclei with small nucleoli and eosinophilic cytoplasm, situated in the upper epithelial layers. In addition to these features, which are commonly seen in epidermodysplasia verruciformis-associated lesions, 1 case displayed in addition more extensively distributed abnormal nuclei, including involvement of both the upper epithelial strata and the epithelial/stromal interface. Both lesions were associated with ß-papilloma virus type 5. The unique aspects of epidermodysplasia verruciformis-like lesions relative to the more common human papilloma virus infections of the vulva are highlighted and these cases illustrate the range of epithelial distribution that might be encountered in lesions involving the vulvar mucosa.
Subject(s)
Epidermodysplasia Verruciformis/diagnosis , Papillomaviridae/isolation & purification , Vulvar Neoplasms/diagnosis , Adult , Epidermodysplasia Verruciformis/pathology , Epidermodysplasia Verruciformis/virology , Female , Humans , Immunocompromised Host , Middle Aged , Vulva/pathology , Vulvar Neoplasms/pathology , Vulvar Neoplasms/virologySubject(s)
Chemokine CXCL12/physiology , Host-Pathogen Interactions , Papillomavirus Infections , Receptors, CXCR4/physiology , Epidermodysplasia Verruciformis/genetics , Epidermodysplasia Verruciformis/immunology , Epidermodysplasia Verruciformis/virology , Genetic Predisposition to Disease , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/immunology , Immunologic Deficiency Syndromes/virology , Mutation , Papillomaviridae/immunology , Papillomaviridae/pathogenicity , Papillomavirus Infections/genetics , Papillomavirus Infections/immunology , Risk Factors , Signal Transduction/genetics , Signal Transduction/immunologyABSTRACT
Patients suffering from Epidermodysplasia verruciformis (EV), a rare inherited skin disease, display a particular susceptibility to persistent infection with cutaneous genus beta-human papillomavirus (beta-HPV), such as HPV type 8. They have a high risk to develop non-melanoma skin cancer at sun-exposed sites. In various models evidence is emerging that cutaneous HPV E6 proteins disturb epidermal homeostasis and support carcinogenesis, however, the underlying mechanisms are not fully understood as yet. In this study we demonstrate that microRNA-203 (miR-203), a key regulator of epidermal proliferation and differentiation, is strongly down-regulated in HPV8-positive EV-lesions. We provide evidence that CCAAT/enhancer-binding protein α (C/EBPα), a differentiation-regulating transcription factor and suppressor of UV-induced skin carcinogenesis, directly binds the miR-203 gene within its hairpin region and thereby induces miR-203 transcription. Our data further demonstrate that the HPV8 E6 protein significantly suppresses this novel C/EBPα/mir-203-pathway. As a consequence, the miR-203 target ΔNp63α, a proliferation-inducing transcription factor, is up-regulated, while the differentiation factor involucrin is suppressed. HPV8 E6 specifically down-regulates C/EBPα but not C/EBPß expression at the transcriptional level. As shown in knock-down experiments, C/EBPα is regulated by the acetyltransferase p300, a well-described target of cutaneous E6 proteins. Notably, p300 bound significantly less to the C/EBPα regulatory region in HPV8 E6 expressing keratinocytes than in control cells as demonstrated by chromatin immunoprecipitation. In situ analysis confirmed congruent suprabasal expression patterns of C/EBPα and miR-203 in non-lesional skin of EV-patients. In HPV8-positive EV-lesions both factors are potently down-regulated in vivo further supporting our in vitro data. In conclusion our study has unraveled a novel p300/C/EBPα/mir-203-dependent mechanism, by which the cutaneous HPV8 E6 protein may expand p63-positive cells in the epidermis of EV-patients and disturbs fundamental keratinocyte functions. This may drive HPV-mediated pathogenesis and may potentially also pave the way for skin carcinogenesis in EV-patients.
Subject(s)
CCAAT-Enhancer-Binding Protein-alpha/metabolism , Cell Transformation, Viral/genetics , Gene Expression Regulation/physiology , Keratinocytes/virology , MicroRNAs/biosynthesis , Oncogene Proteins, Viral/metabolism , Cell Line , Chromatin Immunoprecipitation , Electrophoretic Mobility Shift Assay , Epidermodysplasia Verruciformis/complications , Epidermodysplasia Verruciformis/virology , Humans , Immunoblotting , Immunohistochemistry , In Situ Hybridization , Keratinocytes/metabolism , Papillomavirus Infections/complications , Real-Time Polymerase Chain ReactionABSTRACT
A 75-year-old man with human immunodeficiency virus infection and numerous biopsy-proven warts for 10 years, refractory to cryosurgery, cimetidine, and topical imiquimod, presented with numerous pink to hypopigmented verrucous papules and plaques involving the face, trunk, buttocks, and groin. Laboratory evaluation revealed a CD4 T-cell count of 62 cells per microliter and human immunodeficiency virus viral load of <117 copies per milliliter. Biopsy of a plaque groin lesion was performed. Histopathology revealed vertically oriented anastomosing strands of basaloid epithelium arising from multiple points along the epidermis in a background fibrovascular stroma. Ductal differentiation was identified. Areas of epidermis showed compact orthokeratosis, coarse hypergranulosis, and keratinocytes with abundant steel-blue-gray cytoplasm, indicative of viral cytopathic changes. Cytologic atypia was not identified. Human papillomavirus (HPV) genotyping of this lesion was positive for types 5 and 14. Overall, the findings were consistent with epidermodysplasia verruciformis in association with eccrine syringofibroadenoma (ESFA). The patient was subsequently treated with acitretin and showed clinical improvement. ESFA is an uncommon benign adnexal tumor with unknown pathogenesis. Although its association with HPV has rarely been reported, ESFA in the setting of acquired epidermodysplasia verruciformis has not been described. The development of ESFA in this case may be the result of HPV-induced cellular transformation.
Subject(s)
Epidermodysplasia Verruciformis/complications , HIV Infections/complications , Papillomavirus Infections/complications , Poroma/complications , Sweat Gland Neoplasms/complications , Aged , Cell Transformation, Viral , Epidermodysplasia Verruciformis/pathology , Epidermodysplasia Verruciformis/virology , Humans , Male , Poroma/pathology , Poroma/virology , Sweat Gland Neoplasms/pathology , Sweat Gland Neoplasms/virologyABSTRACT
Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by abnormal susceptibility to cutaneous human beta-papillomavirus infections causing persistent flat warts or pityriasis versicolor-like lesions. This generalized verrucous skin disorder resembles generalized verrucosis, but these 2 conditions are distinguished by differences in clinical manifestation and the human papillomavirus types involved. A breakthrough in our understanding of EV was the discovery that homozygous inactivating mutations in TMC6 (EVER1) and TMC8 (EVER2) determine susceptibility to this disorder; however, they have not solved all EV cases fully. These deficiencies account for 75% of affected individuals, leaving a substantial number of patients without an underlying genetic cause. Recently, it has been revealed that mutations in additional genes (RHOH, MST-1, CORO1A, and IL-7) result in extensive human beta-papillomavirus replication and therefore manifest with an EV-like phenotype. The term "acquired EV" is used to describe an EV-like phenotype that develops in immunocompromised hosts, and the introduction of this entity further aggravates the confusion. Reevaluation of these entities is warranted. Here, we review the available data on this issue, provide up to date information on the major characteristics that differentiate between these seemingly clinically similar disorders, and highlight the different mechanisms involved in each disorder.
Subject(s)
Epidermodysplasia Verruciformis/genetics , Epidermodysplasia Verruciformis/immunology , Epidermodysplasia Verruciformis/virology , Humans , Mutation , Papillomavirus InfectionsABSTRACT
Cutaneous beta-papillomaviruses are associated with non-melanoma skin cancers that arise in patients who suffer from a rare genetic disorder, Epidermodysplasia verruciformis (EV) or after immunosuppression following organ transplantation. Recent studies have shown that the E6 proteins of the cancer associated beta human papillomavirus (HPV) 5 and HPV8 inhibit NOTCH and TGF-ß signaling. However, it is unclear whether disruption of these pathways may contribute to cutaneous HPV pathogenesis and carcinogenesis. A recently identified papillomavirus, MmuPV1, infects laboratory mouse strains and causes cutaneous skin warts that can progress to squamous cell carcinoma. To determine whether MmuPV1 may be an appropriate model to mechanistically dissect the molecular contributions of cutaneous HPV infections to skin carcinogenesis, we investigated whether MmuPV1 E6 shares biological and biochemical activities with HPV8 E6. We report that the HPV8 and MmuPV1 E6 proteins share the ability to bind to the MAML1 and SMAD2/SMAD3 transcriptional cofactors of NOTCH and TGF-beta signaling, respectively. Moreover, we demonstrate that these cutaneous papillomavirus E6 proteins inhibit these two tumor suppressor pathways and that this ability is linked to delayed differentiation and sustained proliferation of differentiating keratinocytes. Furthermore, we demonstrate that the ability of MmuPV1 E6 to bind MAML1 is necessary for papilloma formation in experimentally infected mice. Our results, therefore, suggest that experimental MmuPV1 infection in mice will be a robust and useful experimental system to model key aspects of cutaneous HPV infection, pathogenesis and carcinogenesis.
Subject(s)
Oncogene Proteins, Viral/metabolism , Papillomaviridae/metabolism , Receptors, Notch/antagonists & inhibitors , Transforming Growth Factor beta/antagonists & inhibitors , Animals , Cell Differentiation/physiology , Cell Line, Tumor , Cell Proliferation/physiology , Cell Survival/physiology , Epidermodysplasia Verruciformis/virology , HCT116 Cells , Humans , Keratinocytes/physiology , Mice , Mice, Inbred BALB C , Mice, Nude , Nuclear Proteins/metabolism , Oncogene Proteins, Viral/genetics , Phosphorylation , Protein Binding/physiology , Signal Transduction , Skin Neoplasms/virology , Smad2 Protein/metabolism , Smad3 Protein/metabolism , Transcription Factors/metabolism , Transcription, Genetic/physiologyABSTRACT
The beta genus comprises more than 50 beta human papillomavirus (HPV) types that are suspected to be involved, together with ultraviolet (UV) irradiation, in the development of non-melanoma skin cancer (NMSC), the most common form of human cancer. Two members of the genus beta, HPV5 and HPV8, were first identified in patients with a genetic disorder, epidermodysplasia verruciformis (EV), that confers high susceptibility to beta HPV infection and NMSC development. The fact that organ transplant recipients (OTRs) with an impaired immune system have an elevated risk of NMSC raised the hypothesis that beta HPV types may also be involved in skin carcinogenesis in non-EV patients. Epidemiological studies have shown that serological and viral DNA markers are weakly, but significantly, associated with history of NMSC in OTRs and the general population. Functional studies on mucosal high-risk (HR) HPV types have clearly demonstrated that the products of two early genes, E6 and E7, are the main viral oncoproteins, which are able to deregulate events closely linked to transformation, such as cell cycle progression and apoptosis. Studies on a small number of beta HPV types have shown that their E6 and E7 oncoproteins also have the ability to interfere with the regulation of key pathways/events associated with cellular transformation. However, the initial functional data indicate that the molecular mechanisms leading to cellular transformation are different from those of mucosal HR HPV types. Beta HPV types may act only at early stages of carcinogenesis, by potentiating the deleterious effects of other carcinogens, such as UV radiation.
Subject(s)
Betapapillomavirus/genetics , Epidermodysplasia Verruciformis/virology , Oncogene Proteins, Viral/genetics , Papillomavirus E7 Proteins/genetics , Papillomavirus Infections/virology , Skin Neoplasms/virology , Betapapillomavirus/classification , Betapapillomavirus/growth & development , Betapapillomavirus/pathogenicity , DNA, Viral/genetics , DNA, Viral/immunology , Epidermodysplasia Verruciformis/etiology , Epidermodysplasia Verruciformis/immunology , Epidermodysplasia Verruciformis/pathology , Gene Expression , Host-Pathogen Interactions , Humans , Immunocompromised Host , Oncogene Proteins, Viral/immunology , Organ Transplantation , Papillomavirus E7 Proteins/immunology , Papillomavirus Infections/immunology , Papillomavirus Infections/pathology , Skin Neoplasms/etiology , Skin Neoplasms/immunology , Skin Neoplasms/pathology , Transplant Recipients , Ultraviolet Rays/adverse effectsABSTRACT
We present a patient with HPV 70/85-positive widespread cutaneous warts characterized by clinical and histological features atypical for classic generalized verrucosis or epidermodysplasia verruciformis. The cutaneous HPV infection is characterized by verrucous papules or plaques variable in size, number, and distribution depending on the genotype of HPV involved and the immune status of the patient. Human papillomaviruses comprise ï¬ve genera (alpha, beta, gamma, mu, and nu papillomavirus) with different life-cycle characteristics, epithelial tropisms, and disease associations. Epidermodysplasia verruciformis (EV) is a rare, lifelong, autosomal recessive skin disease characterized by persistent cutaneous human papillomavirus infection not necessarily associated with immune system defects. The disease results from an unusual genetic susceptibility to infections with various types of HPVs (especially ß-HPV), some of which cause malignant transformation. Conversely, generalized verrucosis has been more typically associated with generalized warts, which are associated with immunocompromised conditions.