Patients with epidermodysplasia verruciformis (EV) and biallelic null mutations of (encoding EVER... more Patients with epidermodysplasia verruciformis (EV) and biallelic null mutations of (encoding EVER1) or (EVER2) are selectively prone to disseminated skin lesions due to keratinocyte-tropic human β-papillomaviruses (β-HPVs), which lack E5 and E8. We describe EV patients homozygous for null mutations of the gene encoding calcium- and integrin-binding protein-1 (CIB1). CIB1 is strongly expressed in the skin and cultured keratinocytes of controls but not in those of patients. CIB1 forms a complex with EVER1 and EVER2, and CIB1 proteins are not expressed in EVER1- or EVER2-deficient cells. The known functions of EVER1 and EVER2 in human keratinocytes are not dependent on CIB1, and CIB1 deficiency does not impair keratinocyte adhesion or migration. In keratinocytes, the CIB1 protein interacts with the HPV E5 and E8 proteins encoded by α-HPV16 and γ-HPV4, respectively, suggesting that this protein acts as a restriction factor against HPVs. Collectively, these findings suggest that the disr...
Myrm.ecia warts induced by human papillomavirus type 1 (HPV1) are characterized by abundant eosin... more Myrm.ecia warts induced by human papillomavirus type 1 (HPV1) are characterized by abundant eosinophilic inclusions associated with HPVl E4 gene products. The 111ajor BPVl E4 proteins are a 17-kilodalton (kDa) EI-E4 fusion protein and a 16-kDa species lacking the five El aminoacids and a few E4 residues. To study the contribution of E4 proteins to the formation of myrmecia inclusions, we used a previously designed transient expression system in the rabbit VX2-R keratinocyte line. We find that the EI-E4 and an E4 protein without the El residues (E4-3200) form eosinophilic inclusions. Ultrastructural and immunoelectron microscopic studies show that the electron-dense, keratohyalin-like myrrn ecia inclusions are recognized by anti-E4 antibodies. They are associated with tonofilament bundles at their periphery in the cytoplasm or free of filaments in the nucleus. The EI-E4 inclusions formed in vitro are also homogeneously electron S ixty-six types of human papillomavirus (HPV) have been identified so far [1,2). Most of these small epitheliotropic DNA viruses induce benign cutaneous or genital tumors of keratinocytes. Certain HPV types are associated with premalignant lesions that may progress to malignancy under the influence of cofactors still little known [3,4). HPVs replicate exclusively in terminally differentiating ker~ti nocytes of the lesions they induce. Vegetative viral DNA replIcation is triggered upon the onset of the differentiation process in the suprabasall~yers and is followed by the.synthes.is of. the L1 and L2 capsid protems and by. the assemb~y o~ vlr~l particles mn~ore superficial layers [5-8). Viral multiplication IS associated With a cytopathic effect recognized by the presence of clear cells in skin warts and koilocytes in genital lesions [9). In HPV1-induced palmo-plantar warts, known also as myrmecia or inclusion warts [10), the cytopathic effect is characterized by the presence of eosinophilic and electron-dense cytoplasmic and nuclear inclusions, usually referred to as keratohyalin [9) or keratohyalin-like granules [7,11, 12). Furthermore, the lack of detection of keratins K1 and K10 [12) , filaggrin, and loricrin (our unpublished observations) indicates that the Manuscript
We identified sequences from two distantly related papillomaviruses in genital warts from two Bur... more We identified sequences from two distantly related papillomaviruses in genital warts from two Burmeister's porpoises, including a PV antigen-positive specimen, and characterized Phocoena spinipinnis papillomavirus type 1 (PsPV-1). The PsPV-1 genome comprises 7879 nt and presents unusual features. It lacks an E7, an E8 and a bona fide E5 open reading frame (ORF) and has a large E6 ORF. PsPV-1 L1 ORF showed the highest percentage of nucleotide identity (54–55 %) with human papillomavirus type 5, bovine papillomavirus type 3 (BPV-3) and Tursiops truncatus papillomavirus type 2 (TtPV-2). This warrants the classification of PsPV-1 as the prototype of the genus Omikronpapillomavirus. PsPV-1 clustered with TtPV-2 in the E6 and E1E2 phylogenetic trees and with TtPV-2 and BPV-3 in the L2L1 tree. This supports the hypothesis that PV evolution may not be monophyletic across all genes.
Human papillomavirus (HPV) DNA sequences coexisting with HPV16 and HPV45 were cloned from an inva... more Human papillomavirus (HPV) DNA sequences coexisting with HPV16 and HPV45 were cloned from an invasive cervical carcinoma. The cloned HPV was shown to be a novel type, named HPV66, and is related to HPV56 (an HPV detected in cervical cancer). After screening 160 anogenital biopsies, four specimens exhibited histological features of intraepithelial neoplasia and contained HPV66 sequences. Of these, three were found to be associated with another HPV type. More than 20 types of human papillomavirus (HPV) are associated with anogenital infections, causing benign prolif-erations (condylomata acuminata) or premalignant lesions (intraepithelial neoplasia) (8). HPV types associated with intraepithelial neoplasia such as HPV16 and HPV18 have been detected in the majority of anogenital invasive carci-nomas (30). Several studies have shown the presence of uncharacterized HPV types in 10 to 30 % of HPV-positive genital lesions (1, 17, 20, 29). These HPVs need to be HPV PROBE 16.18t33 1f 4»:iYP R...
Bulletin de l'Academie nationale de medecine, 2010
The outcomes of infection by human papillomaviruses (HPV), both oncogenic and non oncogenic, show... more The outcomes of infection by human papillomaviruses (HPV), both oncogenic and non oncogenic, show major interindividual variability The underlying genetic factors and mechanisms are poorly known, but their complexity is illustrated by epidermodysplasia verruciformis (EV), a rare autosomal recessive genodermatosis associated with a high risk of non melanoma skin cancer. This model disease is characterized by abnormal susceptibility to widespread betapapillomaviruses, including HPV-5, a virus associated with EV cancers. Most cases of EV are caused by a mutation that inactivates either of two related genes, EVER1 and EVER2. This inactivation likely compensates for the absence of a viral gene (E5 or E8) essential for HPV pathogenicity. Proteins E5 and E8 interfere with the interaction between EVER proteins and ZnT1, a zinc transporter EV is thus likely to represent a primary defect of intrinsic (constitutive) immunity or innate immunity to betapapillomaviruses, involving modulation of z...
Recent studies indicate that human papillomaviruses (HPVs) from the genera Betapapillomavirus and... more Recent studies indicate that human papillomaviruses (HPVs) from the genera Betapapillomavirus and Gammapapillomavirus are abundant in the human oral cavity. We report the cloning and characterization of a 7304 bp HPV120 genome from the oral cavity that is related most closely to HPV23 (L1 ORF, 83.7 % similarity), clustering it in the genus Betapapillomavirus (b-PV). HPV120 contains five early and two late genes, but no E5 ORF. HPV120 was detected from heterogeneous human biological niches, including the oral cavity, eyebrow hairs, anal canal and penile, vulvar and perianal warts. Characterization of the clinical spectrum of HPV120 infections indicates a broader spectrum of epithelial tropism than appreciated previously for HPV types from the genus b-PV.
Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood d... more Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood disease that presents with recurrent growth of papillomas in the upper airway. Two common human papillomaviruses (HPVs), HPV-6 and -11, are implicated in most cases, but it is still not understood why only a small proportion of children develop JRRP following exposure to these common viruses. We report 2 siblings with a syndromic form of JRRP associated with mild dermatologic abnormalities. Whole-exome sequencing of the patients revealed a private homozygous mutation in NLRP1, encoding Nucleotide-Binding Domain Leucine-Rich Repeat Family Pyrin Domain-Containing 1. We find the NLRP1 mutant allele to be gain of function (GOF) for inflammasome activation, as demonstrated by the induction of inflammasome complex oligomerization and IL-1β secretion in an overexpression system. Moreover, patient-derived keratinocytes secrete elevated levels of IL-1β at baseline. Finally, both patients displayed...
Epidermodysplasia verruciformis (EV) is an autosomal recessive skin disorder with a phenotype con... more Epidermodysplasia verruciformis (EV) is an autosomal recessive skin disorder with a phenotype conditional on human beta-papillomavirus (beta-HPV) infection. Such infections are common and asymptomatic in the general population, but in individuals with EV, they lead to the development of plane wart-like and red or brownish papules or pityriasis versicolor-like skin lesions, from childhood onwards. Most patients develop non-melanoma skin cancer (NMSC), mostly on areas of UV-exposed skin, from the twenties or thirties onwards. At least half of the cases of typical EV are caused by biallelic loss-of-function mutations of TMC6/EVER1 or TMC8/EVER2. The cellular and molecular basis of disease in TMC/EVER-deficient patients is unknown, but a defect of keratinocyte-intrinsic immunity to beta-HPV is suspected. Indeed, these patients are not susceptible to other infectious diseases and have apparently normal leukocyte development. In contrast, patients with an atypical form of EV due to inborn errors of T-cell immunity invariably develop clinical symptoms of EV in the context of other infectious diseases. The features of the typical and atypical forms of EV thus suggest that the control of beta-HPV infections requires both EVER1/EVER2-dependent keratinocyte-intrinsic immunity and T cell-dependent adaptive immunity.
The first evidence for the oncogenic potential of human papillomaviruses (HPVs) was obtained thro... more The first evidence for the oncogenic potential of human papillomaviruses (HPVs) was obtained through the study of epidermodysplasia verruciformis (EV). This rare skin disease is characterized by disseminated, refractor, pityriasis versicolor-like lesions as well as flat wart-like lesions, and by the development of skin carcinomas in about 30% of the patients. EV is a multifactorial disease involving genetic, immunological and extrinsic (actinic) factors, in addition to infection with specific HPV types. A number of HPVs (at least 15 types) have been characterized in benign EV lesions. HPV DNA sequences are regularly detected in EV carcinomas but, in contrast to benign lesions, the types associated with cancers are usually restricted to HPV-5 and, less frequently, HPV-8, an HPV-5-related type. HPV-5 genomes are usually found as free monomeric or oligomeric DNA molecules in EV carcinomas, and frequently contain deletions. This is in contrast with HPV DNA sequences in genital cancers, ...
... J. invest. Derm. (in the press). 23. Orth, G. et al. J. invest. Derm. 76, 97−102 (1981). | Ar... more ... J. invest. Derm. (in the press). 23. Orth, G. et al. J. invest. Derm. 76, 97−102 (1981). | Article |PubMed | ISI | ChemPort |. 24. Davis, RW, Simon, M. & Davidson, N. Meth. Enzym. 21D, 413−428 (1971). | Article | ChemPort |. 25. Croissant, O., Testaniere, V. & Orth, G. Cr Acad. ...
Patients with epidermodysplasia verruciformis (EV) and biallelic null mutations of (encoding EVER... more Patients with epidermodysplasia verruciformis (EV) and biallelic null mutations of (encoding EVER1) or (EVER2) are selectively prone to disseminated skin lesions due to keratinocyte-tropic human β-papillomaviruses (β-HPVs), which lack E5 and E8. We describe EV patients homozygous for null mutations of the gene encoding calcium- and integrin-binding protein-1 (CIB1). CIB1 is strongly expressed in the skin and cultured keratinocytes of controls but not in those of patients. CIB1 forms a complex with EVER1 and EVER2, and CIB1 proteins are not expressed in EVER1- or EVER2-deficient cells. The known functions of EVER1 and EVER2 in human keratinocytes are not dependent on CIB1, and CIB1 deficiency does not impair keratinocyte adhesion or migration. In keratinocytes, the CIB1 protein interacts with the HPV E5 and E8 proteins encoded by α-HPV16 and γ-HPV4, respectively, suggesting that this protein acts as a restriction factor against HPVs. Collectively, these findings suggest that the disr...
Myrm.ecia warts induced by human papillomavirus type 1 (HPV1) are characterized by abundant eosin... more Myrm.ecia warts induced by human papillomavirus type 1 (HPV1) are characterized by abundant eosinophilic inclusions associated with HPVl E4 gene products. The 111ajor BPVl E4 proteins are a 17-kilodalton (kDa) EI-E4 fusion protein and a 16-kDa species lacking the five El aminoacids and a few E4 residues. To study the contribution of E4 proteins to the formation of myrmecia inclusions, we used a previously designed transient expression system in the rabbit VX2-R keratinocyte line. We find that the EI-E4 and an E4 protein without the El residues (E4-3200) form eosinophilic inclusions. Ultrastructural and immunoelectron microscopic studies show that the electron-dense, keratohyalin-like myrrn ecia inclusions are recognized by anti-E4 antibodies. They are associated with tonofilament bundles at their periphery in the cytoplasm or free of filaments in the nucleus. The EI-E4 inclusions formed in vitro are also homogeneously electron S ixty-six types of human papillomavirus (HPV) have been identified so far [1,2). Most of these small epitheliotropic DNA viruses induce benign cutaneous or genital tumors of keratinocytes. Certain HPV types are associated with premalignant lesions that may progress to malignancy under the influence of cofactors still little known [3,4). HPVs replicate exclusively in terminally differentiating ker~ti nocytes of the lesions they induce. Vegetative viral DNA replIcation is triggered upon the onset of the differentiation process in the suprabasall~yers and is followed by the.synthes.is of. the L1 and L2 capsid protems and by. the assemb~y o~ vlr~l particles mn~ore superficial layers [5-8). Viral multiplication IS associated With a cytopathic effect recognized by the presence of clear cells in skin warts and koilocytes in genital lesions [9). In HPV1-induced palmo-plantar warts, known also as myrmecia or inclusion warts [10), the cytopathic effect is characterized by the presence of eosinophilic and electron-dense cytoplasmic and nuclear inclusions, usually referred to as keratohyalin [9) or keratohyalin-like granules [7,11, 12). Furthermore, the lack of detection of keratins K1 and K10 [12) , filaggrin, and loricrin (our unpublished observations) indicates that the Manuscript
We identified sequences from two distantly related papillomaviruses in genital warts from two Bur... more We identified sequences from two distantly related papillomaviruses in genital warts from two Burmeister's porpoises, including a PV antigen-positive specimen, and characterized Phocoena spinipinnis papillomavirus type 1 (PsPV-1). The PsPV-1 genome comprises 7879 nt and presents unusual features. It lacks an E7, an E8 and a bona fide E5 open reading frame (ORF) and has a large E6 ORF. PsPV-1 L1 ORF showed the highest percentage of nucleotide identity (54–55 %) with human papillomavirus type 5, bovine papillomavirus type 3 (BPV-3) and Tursiops truncatus papillomavirus type 2 (TtPV-2). This warrants the classification of PsPV-1 as the prototype of the genus Omikronpapillomavirus. PsPV-1 clustered with TtPV-2 in the E6 and E1E2 phylogenetic trees and with TtPV-2 and BPV-3 in the L2L1 tree. This supports the hypothesis that PV evolution may not be monophyletic across all genes.
Human papillomavirus (HPV) DNA sequences coexisting with HPV16 and HPV45 were cloned from an inva... more Human papillomavirus (HPV) DNA sequences coexisting with HPV16 and HPV45 were cloned from an invasive cervical carcinoma. The cloned HPV was shown to be a novel type, named HPV66, and is related to HPV56 (an HPV detected in cervical cancer). After screening 160 anogenital biopsies, four specimens exhibited histological features of intraepithelial neoplasia and contained HPV66 sequences. Of these, three were found to be associated with another HPV type. More than 20 types of human papillomavirus (HPV) are associated with anogenital infections, causing benign prolif-erations (condylomata acuminata) or premalignant lesions (intraepithelial neoplasia) (8). HPV types associated with intraepithelial neoplasia such as HPV16 and HPV18 have been detected in the majority of anogenital invasive carci-nomas (30). Several studies have shown the presence of uncharacterized HPV types in 10 to 30 % of HPV-positive genital lesions (1, 17, 20, 29). These HPVs need to be HPV PROBE 16.18t33 1f 4»:iYP R...
Bulletin de l'Academie nationale de medecine, 2010
The outcomes of infection by human papillomaviruses (HPV), both oncogenic and non oncogenic, show... more The outcomes of infection by human papillomaviruses (HPV), both oncogenic and non oncogenic, show major interindividual variability The underlying genetic factors and mechanisms are poorly known, but their complexity is illustrated by epidermodysplasia verruciformis (EV), a rare autosomal recessive genodermatosis associated with a high risk of non melanoma skin cancer. This model disease is characterized by abnormal susceptibility to widespread betapapillomaviruses, including HPV-5, a virus associated with EV cancers. Most cases of EV are caused by a mutation that inactivates either of two related genes, EVER1 and EVER2. This inactivation likely compensates for the absence of a viral gene (E5 or E8) essential for HPV pathogenicity. Proteins E5 and E8 interfere with the interaction between EVER proteins and ZnT1, a zinc transporter EV is thus likely to represent a primary defect of intrinsic (constitutive) immunity or innate immunity to betapapillomaviruses, involving modulation of z...
Recent studies indicate that human papillomaviruses (HPVs) from the genera Betapapillomavirus and... more Recent studies indicate that human papillomaviruses (HPVs) from the genera Betapapillomavirus and Gammapapillomavirus are abundant in the human oral cavity. We report the cloning and characterization of a 7304 bp HPV120 genome from the oral cavity that is related most closely to HPV23 (L1 ORF, 83.7 % similarity), clustering it in the genus Betapapillomavirus (b-PV). HPV120 contains five early and two late genes, but no E5 ORF. HPV120 was detected from heterogeneous human biological niches, including the oral cavity, eyebrow hairs, anal canal and penile, vulvar and perianal warts. Characterization of the clinical spectrum of HPV120 infections indicates a broader spectrum of epithelial tropism than appreciated previously for HPV types from the genus b-PV.
Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood d... more Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood disease that presents with recurrent growth of papillomas in the upper airway. Two common human papillomaviruses (HPVs), HPV-6 and -11, are implicated in most cases, but it is still not understood why only a small proportion of children develop JRRP following exposure to these common viruses. We report 2 siblings with a syndromic form of JRRP associated with mild dermatologic abnormalities. Whole-exome sequencing of the patients revealed a private homozygous mutation in NLRP1, encoding Nucleotide-Binding Domain Leucine-Rich Repeat Family Pyrin Domain-Containing 1. We find the NLRP1 mutant allele to be gain of function (GOF) for inflammasome activation, as demonstrated by the induction of inflammasome complex oligomerization and IL-1β secretion in an overexpression system. Moreover, patient-derived keratinocytes secrete elevated levels of IL-1β at baseline. Finally, both patients displayed...
Epidermodysplasia verruciformis (EV) is an autosomal recessive skin disorder with a phenotype con... more Epidermodysplasia verruciformis (EV) is an autosomal recessive skin disorder with a phenotype conditional on human beta-papillomavirus (beta-HPV) infection. Such infections are common and asymptomatic in the general population, but in individuals with EV, they lead to the development of plane wart-like and red or brownish papules or pityriasis versicolor-like skin lesions, from childhood onwards. Most patients develop non-melanoma skin cancer (NMSC), mostly on areas of UV-exposed skin, from the twenties or thirties onwards. At least half of the cases of typical EV are caused by biallelic loss-of-function mutations of TMC6/EVER1 or TMC8/EVER2. The cellular and molecular basis of disease in TMC/EVER-deficient patients is unknown, but a defect of keratinocyte-intrinsic immunity to beta-HPV is suspected. Indeed, these patients are not susceptible to other infectious diseases and have apparently normal leukocyte development. In contrast, patients with an atypical form of EV due to inborn errors of T-cell immunity invariably develop clinical symptoms of EV in the context of other infectious diseases. The features of the typical and atypical forms of EV thus suggest that the control of beta-HPV infections requires both EVER1/EVER2-dependent keratinocyte-intrinsic immunity and T cell-dependent adaptive immunity.
The first evidence for the oncogenic potential of human papillomaviruses (HPVs) was obtained thro... more The first evidence for the oncogenic potential of human papillomaviruses (HPVs) was obtained through the study of epidermodysplasia verruciformis (EV). This rare skin disease is characterized by disseminated, refractor, pityriasis versicolor-like lesions as well as flat wart-like lesions, and by the development of skin carcinomas in about 30% of the patients. EV is a multifactorial disease involving genetic, immunological and extrinsic (actinic) factors, in addition to infection with specific HPV types. A number of HPVs (at least 15 types) have been characterized in benign EV lesions. HPV DNA sequences are regularly detected in EV carcinomas but, in contrast to benign lesions, the types associated with cancers are usually restricted to HPV-5 and, less frequently, HPV-8, an HPV-5-related type. HPV-5 genomes are usually found as free monomeric or oligomeric DNA molecules in EV carcinomas, and frequently contain deletions. This is in contrast with HPV DNA sequences in genital cancers, ...
... J. invest. Derm. (in the press). 23. Orth, G. et al. J. invest. Derm. 76, 97−102 (1981). | Ar... more ... J. invest. Derm. (in the press). 23. Orth, G. et al. J. invest. Derm. 76, 97−102 (1981). | Article |PubMed | ISI | ChemPort |. 24. Davis, RW, Simon, M. & Davidson, N. Meth. Enzym. 21D, 413−428 (1971). | Article | ChemPort |. 25. Croissant, O., Testaniere, V. & Orth, G. Cr Acad. ...
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