Article

Human papillomavirus DNA in cutaneous primary and metastasized squamous cell carcinomas from patients with Epidermodysplasia verruci formis

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Abstract

DNA extracted from squamous cell carcinomas from patients with the chronic wart disease syndrome, epidermodysplasia verruciformis, was analyzed for the presence of human papillomavirus (HPV)-specific DNA sequences by Southern blot hybridization analysis. Employing an HPV probe obtained by molecular cloning of viral DNA purified from benign warts from these patients, we have unequivocally identified HPV-specific nucleotide sequences in squamous cell carcinomas from these patients. Restriction endonuclease mapping indicated that the DNA present in the carcinomas was of the same type (type 5) as that found in the benign tumors from these patients and was present as unintegrated, free viral DNA. Moreover, we have demonstrated the presence of HPV-5 DNA in a subcutaneous metastatic tumor from one of these patients. This latter observation essentially eliminates the possibility that the HPV-5 DNA present in the malignant tumors in these patients resulted from cross-contamination from an adjacent benign warty lesion. In addition to wild-type HPV-5 DNA, both the primary and metastatic carcinomas analyzed also contained an HPV-5 DNA species lacking approximately 20% of the HPV-5 DNA genome. These subgenomic forms of HPV-5 DNA could not be detected in benign papillomas from these patients.

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... which are grouped into different genera such as alpha-, beta-, gamma-, mu-, and nu-PV. Persistent infections with a high-risk (HR) HPV (HPV16,18,31,33,35,39,45,51,52,58,and 59), which belong to the alpha-PV, can lead to the development of cancer of the anus, cervix uteri, larynx, oropharynx, oral cavity, penis, vulva, and vagina, resulting in 530,000 new cases per year worldwide (2). Therefore, prophylactic vaccines have been introduced to prevent infections with the most prevalent HR-HPV (3). ...
... HR-HPV genomes are present as either extrachromosomal elements or integrated into the host chromosomes and are expressed in all precancer and cancer cells, but only viral early but not late genes are transcribed in the majority of cancers (14). cSCC of EV patients maintain high levels of extrachromosomal beta-HPV DNA and only rarely integrated virus sequences and express late viral proteins, suggesting that productive viral replication takes place (6,(15)(16)(17)(18)(19)(20)(21)(22). In contrast, beta-HPV copy number decreases from precursor lesions to cSCC to less than one viral genome per tumor cell in OTR, indicating that the majority of tumor cells does not express viral gene products (23). ...
... On the other hand, it is also possible that the mechanisms driving integration of HR-HPV genomes into host chromosomes while maintaining expression of the E6 and E7 oncogenes is fundamentally different between HR-HPV and beta-HPV. Interestingly, beta-HPV genomes in cSCC from EV patients are present at high copy numbers in an extrachromosomal state, which may indicate that also in these cases high-level viral gene expression is required to maintain the tumor phenotype (6,15,(18)(19)(20)(21)(22). A UV-irradiation-induced increase in HPV8 gene expression in a transgenic mouse model results in enhanced skin tumorigenesis in vivo, providing further evidence that deregulated gene expression can contribute to beta-HPV oncogenicity in vivo (62). ...
Article
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Significance High-risk (HR) human papillomaviruses (HPV) from the genus alpha cause anogenital and oropharyngeal cancers, whereas the contribution of HPV from the genus beta to the development of cutaneous squamous cell cancer is still under debate. HR-HPV genomes display potent immortalizing activity in human keratinocytes, the natural target cell for HPV. This paper shows that immortalization of keratinocytes by the beta-HPV49 genome requires the inactivation of the viral E8^E2 repressor protein and the presence of the E6 and E7 oncoproteins but also of the E1 and E2 replication proteins. This reveals important differences in the carcinogenic properties of HR-HPV and beta-HPV but also warrants further investigations on the distribution and mutation frequencies of beta-HPV in human cancers.
... to the development of cancer, most notably epidermodysplasia verruciformis [3,4] and Human papillomavirus es (HPV) are a hetero-squamous cell carcinoma of the cervix [5]. genous group of DNA viruses with over 60 HPV has also been linked to head and neck types now identified. ...
... Squamous cell carcinoma, which comprises 80-85% of esophageal cancers, is generally thought to arise through a complex, multistep process involving the synergistic actions of various factors. Conditions associated with squamous cell cancer include: [1] diets contaminated with certain fungi and diets which are rich in nitrosamines and nitrites, [2] chronic nutritional deficiences, [3] esophagitis and stasis, and [4] chronic alcohol and tobacco abuse [15]. In contrast, adenocarcinoma, comprising 5-10% of esophageal cancers, often appears to arise in the background of Barrett's mucosa, which goes through a sequence of changes from normal appearing gastric or intestinal mucosa, to dysplasia, then carcinoma in situ, and finally to invasive carcinoma [16]. ...
... In other anatomical sites, HPV infection has been associated with the development of cancer. HPV infection with virotypes 5 and 8 is associated with the development of epidermodysplasia verruciformis, 30% of which progress to malignancy [3,4]. Virotypes 6 and 11 are commonly associated with benign lesions (condyloma accuminata, papillomas of the aerodigestive mucosa, and "flat" condylomas of the cervix and vagina). ...
Article
Our recent experience demonstrating an association between Human Papillomavirus (HPV) and colon neoplasms prompted us to search esophageal tissues for a similar association. Using an immunohistochemical technique, we examined 36 paraffin embedded sections of esophageal tissue, including normals, squamous carcinomas, and adenocarcinomas for the presence of viral capsid protein. In situ DNA hybridization employing pooled probe DNA sequences to HPV types 6, 11, 16, 18, 31, 33, and 35 was performed on the same tissues to demonstrate presence of viral genome. Viral capsid protein was detected uniformly in over two-thirds of specimens regardless of the type. Viral genome was detected in one third of the squamous carcinomas, but none of the normals or adenocarcinomas. All samples demonstrating genome tested positive for protein. We conclude that: [1] HPV is present in all esophageal tissues as evidenced by immunohistochemical detection of HPV capsid protein; [2] the HPV virotype associated with squamous cell carcinoma is one of those represented in the pooled probes; and [3] the HPV associated with adenocarcinoma is one of the other 60 known virotypes or is present in such low concentration as to be undetectable by in situ hybridization.
... Colposcopy is a diagnostic procedure that can visually detect dysplastic changes and guide biopsies to obtain a histologic diagnosis [38]. The most common site of persistent HPV infection and cervical cancer development is the transformation zone between the columnar epithelium of the endocervix and squamous epithelium of the ectocervix [39,40]. ...
... In the 1990s, an office-based excisional procedure known as loop electrosurgical excision procedure (LEEP) became available and was widely adopted [41][42][43]. Unnecessary cervical excisions must be avoided in young women because these procedures increase the risk of preterm birth and mid-trimester pregnancy loss [40,44]. ...
... Potential treatment modalities for invasive cancer include surgery (i.e., cone biopsy, trachelectomy, or hysterectomy); lymph node evaluation/dissection; radiotherapy (brachytherapy or systemic therapy) [40]. ...
Article
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Advances in virology and skin cancer over recent decades have produced achievements that have been recognized not only in the field of dermatology, but also in other areas of medicine. They have modified the therapeutic and preventive solutions that can be offered to some patients and represent a significant step forward in our knowledge of the biology of skin cancer. In this paper, we review the viral agents responsible for different types of skin cancer, especially for solid skin tumors. We focus on human papillomavirus and squamous cell cancers, Merkel cell polyomavirus and Merkel cell carcinoma, and human herpesvirus 8 and Kaposi’s sarcoma.
... The range of infections, precancers, and malignancies associated with HPV continues to grow. The International Agency for Research on Cancer (IARC) has classified mucosal types 16,18,31,33,35,39,45,51,52,56,58, and 59 as carcinogenic types (Class 1), mainly causing cervical cancer; type 68 as probably carcinogenic (Class 2A); and types 26,30,34,53,66,67,69,70,73,82,85, and 97 as possibly carcinogenic (Class 2B). HPV6 and HPV11 were not classifiable as to its carcinogenicity to humans, and the remaining mucosal HPV types were not taken into consideration by IARC (Class 3) [15]. ...
... This process is facilitated by integration of the viral episome into the cellular DNA, disturbing the E2 ORF, thereby causing a lack of control of E6 and E7 expression [32]. In general, Beta-PV are found episomal, also in actinic keratoses and SCC, although (integrated) HPV has been occasionally isolated from an SCC metastatic lesion in an OTR [43,58]. ...
Chapter
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Keratinocyte carcinomas are by far the most common malignancies seen in organ transplant recipients (OTR). Life-long immunosuppressive therapy is the most important risk factor for developing squamous cell carcinoma (SCC) in OTR. In the years after transplantation, OTR develop numerous warts and wart-like lesions followed by the development of SCC, which resembles the clinical picture of epidermodysplasia verruciformis patients in which human papillomavirus (HPV) infection was linked with skin cancer for the first time. HPV can be divided into genera and cause several distinct benign and (pre-) malignant diseases.There is evidence linking beta HPV infection with the development of SCC in OTR. However, the role of beta HPV in cutaneous SCC carcinogenesis is still enigmatic. Beta HPV is not integrated in the human cellular DNA and is not necessary for the maintenance of the malignant phenotype of cutaneous SCC. Whether different beta HPV types have different effects on cellular mechanisms and a combination of these HPV types may further increase the risk of cutaneous SCC is unknown. The carcinogenic effect, if present, is subtle and probably exerted early in carcinogenesis.
... A transformação maligna ocorre em torno de 30 a 50% dos casos e está associada aos HPVEVs oncogênicos, fatores genéticos do hospedeiro e à ação de co-carcinógenos extrínsecos, principalmente UVB e radioterapia. 1,5,8,12,28,31,32 Os doentes podem apresentar, precocemente, elastose solar e numerosas lesões de queratose actínica-símile nas áreas de maior fotoexposição. 8,28,33 Essas lesões immunosuppressor therapy) which can justify a generalized infection by HPV and cutaneous cancer (syndrome similar to EV). 12,13,14,27 In three siblings (23%), variable degrees of mental retardation were observed, showing a rate higher than the 10% referred to in the literature. ...
... The malignant transformation occurs in about 30 to 50% of cases and is associated with oncogenic HPVEVs, genetic factors of the host cell, and actions of the extrinsic co-carcinogens, mainly UVB and radiotherapy. 1,5,8,12,28,31,32 Patients can prematurely show solar elastosis and numerous actinic keratosis-like lesions in the areas of greatest photoexhibition. 8,28,33 These lesions demonstrate clinical characteristics equal to those observed population in general, but with more malignization power. ...
Article
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FUNDAMENTOS: A epidermodisplasia verruciforme (EV) é genodermatose rara, caracterizada por infecção disseminada por tipos específicos de vírus papiloma humano (HPV), desenvolvimento de tumores cutâneos malignos e distúrbios imunológicos. OBJETIVOS: Correlacionar aspectos clínicos em 13 doentes com EV, na tentativa de contribuir para melhor conhecimento da enfermidade. MÉTODOS:Avaliação clínica de 13 doentes com EV durante o período de três anos. O diagnóstico clínico foi confirmado pelo exame histopatológico e imuno-histoquímico. RESULTADOS: A EV teve início na infância com lesões de verruga plana-símile e/ou máculas eritematosa na face e região cervical. A consangüinidade foi observada na maioria dos doentes (12/13). Clinicamente, o polimorfismo das lesões foi intenso, caracterizado por lesões de verruga plana-símile, pitiríase versicolor-símile, máculas eritematosas e lesões de queratose seborréica-símile. A transformação maligna das lesões foi observada em oito doentes (62%). O crescimento tumoral provocou perda tecidual importante em 50% dos casos, e em 25% foi registrado óbito pelas metástases. CONCLUSÃO: A EV apresenta alta incidência familiar e provável transmissão autossômica recessiva. O intenso polimorfismo clínico das lesões não afeta o couro cabeludo e mucosas. A apresentação clínica "maligna" foi a mais freqüente (62%), seguida pela "benigna" (23%) e "mista" (15%). Os tumores cutâneos malignos são freqüentes, múltiplos, destrutivos, geram metástases e provocam morte.
... Epidermodysplasia verruciformis (EV, OMIM#226400) is a rare, lifelong, hereditary disorder with an extremely increased susceptibility to HPV infection affecting the skin. EV was described by Lewandowsky and Lutz in 1922 [90] and was probably the first description of a PID as well as the first evidence for the involvement of HPV infection in the development of skin cancer [91,112,114]. ...
Chapter
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The innate immunity is the first line of defense against pathogens, exerting fast and effectiveresponses via preformed receptors. Toll-like receptors (TLRs) recognize specific molecular patterns found in a broad rangeof microbial pathogens such as bacteria and viruses, triggering inflammatory and antiviral responses, which result in the eradication of invading pathogens. Primary immunodeficiency diseases with primary defects in TLR signaling include Interleukin-1 receptor-associated kinase-4 (IRAK-4) deficiency, UNC-93B deficiency and TLR3 deficiency. These defects predispose patients to a narrow range of infections; pneumococcal infections in IRAK-4 deficiency, and herpes simplex encephalitis in UNC-93B and TLR3 deficiencies. Anhidrotic ectodermal dysplasia with immunodeficiency is caused by defects in the nuclear factor NF-κB signaling. In these disorders, TLR signaling is also impaired. Poor inflammatory response despite severe infection and absence of fever are characteristic of TLR defects. Mendelian susceptibility to mycobacterial diseases are characterized by recurrent and severe infections caused by weakly virulent organisms, such as environmental mycobacteria and Bacille Calmette-Guérin, and is associated with impaired IL-12/Interferon-γ dependent innate immunity. WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome is a primary immunodeficiency disease caused by mutation of the CXCR4 chemokine receptor gene. Both innate and adaptive immunity are impaired in this disorder. Epidermodysplasia verruciformis is a rare autosomal recessive disorder associated with a high risk of skin carcinoma that results from an abnormal susceptibility to infection by specific human papillomaviruses (HPVs).
... The most common types of HPV detected in the lesions of EV patients are 5, 8,17 and 20, although there are large numbers of rare HPVs found only in EV patients (Orth, 1987;Ostrow et al., 1982;Kremsdorf et al., 1984) and these are listed in Table 1.1. Progression of macular plaques to malignancy is frequent, but only in association with HPV types 5, 8 and 17 and in the areas of skin which are exposed to sunlight. ...
Thesis
The overall aim of the project was to establish whether human papillomaviruses (HPV) are associated with cervical intraepithelial neoplasia (CIN) and cervical carcinoma and examine the use of HPV 16 as an indicator of cervical disease. For this purpose, a Southern blot hybridization system was developed to detect HPV DNA in cervical scrape samples. However, following the description of the polymerase chain reaction for detection of nucleic acid a PCR system for detection of HPV DNA was developed. The ability of Southern blot hybridization and PCR to detect HPV DNA in cervical scrape samples was compared to determine the most suitable method for use as a diagnostic test for HPV. The PCR method was 100,000 times more sensitive than Southern blot and was more accurate in identifying women with cervical disease. The PCR system was used to analyse cervical scrape samples from two study groups for the presence of HPV 16 DNA. The first group (Study A) consisted of 200 women from a General Practice population who were expected to have normal cervical cytology.HPV 16 was present in 17% of women with no cervical abnormalities. In those women from Study A who had cervical disease (n = 22) the prevalence of HPV 16 increased with greater severity of disease from 15.4% in those with CIN 1, 40% in those with CIN 2, to 75% of those with CIN 3. The presence of HPV 16 DNA was significantly associated with CIN 2 and 3 (p = 0.009) and was therefore useful as an indicator of severe cervical disease in this population. The ability of PCR for HPV 16 to identify women with disease was compared with that of standard cytological analysis. There was no significant difference between the two methods, although a combination of screening by cytology and PCR resulted in the identification of a higher proportion of women with disease and PCR was associated with a higher false positive rate. The second group (Study B) consisted of 200 women who had been referred to the Royal Free Hospital colposcopy clinic with a smear report suggesting mild dyskaryosis. Within this group there were 54 women who were cytologically normal, 59 women who had CIN 1 or WVI and 66 women with severe cervical disease (CIN 2 or 3). The results of Study B concurred with Study A in demonstrating an increasing prevalence of HPV 16 with greater severity of disease from 53% in women with CIN 1, 64% of women with CIN 2 to 74% of patients with CIN 3. However, the prevalence of HPV 16 in the normal women in Study B was 63%, and this high value precludes the use of HPV 16 as an indicator of severe cervical disease in this population. Duplicate analysis of each cervical scrape sample from Study A and Study B allowed the reproducibility of the HPV 16 PCR system to be determined. The false positive rate was 0.1% and the false negative rate was 0.77%. The long control region (LCR) of HPV 16 was cloned from a woman without cervical disease (CO) and a woman with CIN 3 (C3). The DNA sequence of each isolate was determined and compared with the prototype HPV 16 sequence. Nucleotide variations were evident in both isolates, but LCRC3 shared less homology with the prototype sequence than LCRCO. A single nucleotide mutation occurred within the glucocorticoid responsive element of LCRC3, which disrupts the palindrome of the protein binding domain. The level of expression from the HPV 16 LCR was determined using a chloramphenicol acetyltransferase assay and found to be 5-fold lower than that of the SV40 early promoter.
... This cancer rate is even higher among two clusters of patients: organ transplant patients who are on immunosuppressive therapy and EV patients. Patients with EV develop lifelong warty lesions, 25% of which convert to SCC in sun -exposed areas (Orth et al., 1978(Orth et al., , 1979Ostrow et al., 1982 ;Orth, 2006 ). Genus beta HPVs are ubiquitously found in skin and hair follicle samples (Orth, 2006 ) and typically lead to benign lesions. ...
Chapter
Epidermodysplasia verruciformis (EV) is a rare lifelong skin disease, which begins during infancy or childhood. It is induced by numerous specific types of human papillomaviruses (HPVs), sometimes including the HPVs associated with flat warts in the general population. EV is characterized by refractory, disseminated skin lesions resembling flat warts, or presenting as macules of various colors. Cutaneous carcinomas in situ or invasive carcinomas usually of Bowen’s type, appear in a high proportion of the patients, generally at an early age. HPV DNA sequences, usually HPV type 5, are regularly detected in EV carcinomas. EV is a multifactorial disease which involves genetic, immunological, and extrinsic factors, in addition to specific HPVs. This has been suggested by the parental consanguinity and the sibling involvement observed in some cases, the impaired cell-mediated immunity reported in most patients, and the usual localization of skin cancers in light-exposed areas. Reviews on EV have been published by Maschkilleisson (1931), Sullivan and Ellis (1939), Midana (1949), Jablonska and Milewski (1957), Bilancia (1961), Jablonska et al. (1966, 1972), Oehlschlaegel et al. (1966), Relias et al. (1967), Tsoitis et al. (1973), Rueda and Rodriguez (1976), Kaufmann et al. (1978), Lutzner (1978), Orth et al. (1980), Jablonska and Orth (1985), and Orth (1986).
Chapter
Papillomaviruses are clearly proven to be the etiologic agents of anogenital lesions, with the potential to progress to squamous cell carcinomas. Viral particles, DNA, and/or capsid antigens can be demonstrated in benign precursors and the proliferations can be transmitted from person to person by cell-free extracts. The complete nucleotide sequences of Human Papillomaviruses (HPVs)—namely, HPV 6, HPV 11, and HPV 16—revealed the familiar genome organization of papillomaviruses and homologous sequences to those open reading frames that were shown to code for transforming functions in the case of BPV1. Malignant conversion of papillomavirus-induced tumors is well established for a number of animal systems and for the human disease epidennodysplasia verruciformis. HPV DNA persists in genital carcinomas either integrated into the host genome or extrachromosomally and is transcribed at least in some tumors. The worldwide prevalence of HPV 16 is noteworthy and may possibly indicate an increased cancerogenic potential of this virus. A tentative calculation indicates that the cancer risk after HPV infection equals or exceeds the risk attended with the infections by other human tumor viruses such as HTLVI, Epstein-Barr virus, or hepatitis B virus. Tumor progression is certainly subjected to additional factors such as chemical or physical carcinogens, hormones, and systemic or local immune deficiencies. The molecular biology of HPV infection has to be further examined to learn more about the viral role in keratinocyte transformation, which will be essential to define relevant diagnostic probes and possible candidates for therapeutic intervention.
Chapter
During the past two decades, remarkable strides have been made in the field of renal transplantation. From a fascinating experiment in human biology, renal transplantation has evolved into a practical therapeutic modality widely applied to the treatment of chronic renal failure. For the first time in history, not only does renal transplantation offer the best chance for rehabilitation of the uremic patient but, in addition, at many centers, it offers at least as good a chance for patient survival as the other widely available treatment modality, chronic hemodialysis. For example, at the Massachusetts General Hospital over the past 3 years, the 1-year patient survival for recipients of kidneys from living related and cadaveric donors has been greater than 95%, with a 1-year graft survival of more than 85%. For patients surviving with a functioning graft at 1 year, the subsequent mortality rate is less than 5% per year. By comparison, the reported patient loss on hemodialysis is 5–10% each year.
Chapter
The papillomaviruses are grouped together with the polyomaviruses to form the papovavirus family (1). Each of these genera are physically distinguishable by capsid size (55 nanometers versus 40 nanometers) and by the size of their double-stranded DNA genomes (8000 bp versus 5000 bp). The biology of the polyomaviruses which includes SV40 and the human polyomaviruses BK and JC have been well-characterized because they are generally easily replicated in tissue culture. Because of the lack of a tissue culture system to propagate the papillomaviruses, they remained relatively refractory to study until the late 1970s when recombinant DNA technology permitted the cloning of the genomes of individual papillomaviruses which then permitted a systematic study of this group of viruses.
Article
The association between beta human papillomavirus (HPV) types and cutaneous squamous cell carcinomas (cSCCs) is controversial. Several studies have found such an association, especially at early stages of carcinogenesis, but the presence of beta HPV types in aggressive cSCCs has only been reported in three patients previously. We aimed to search for beta HPV DNA in primary cSCCs and their corresponding lymph node metastases in a series of patients. The presence of DNA from 25 beta HPV types was determined using a multiplex PCR protocol in 35 primary cSCCs from 35 patients and their corresponding lymph node metastases. DNA from beta HPV types was detected in 9 % of primary cSCCs and in 13 % of metastases. No primary cutaneous SCC or lymphatic metastases were found to share the same HPV DNA. These data suggest that beta HPV types do not play an etiopathogenic role in advanced stages of squamous cell carcinogenesis.
Until recently, the significance of HPV in the etiology of various benign, premalignant, and malignant lesions has been grossly underestimated. Because of new knowledge available through molecular biology techniques, we now know that the human morbidity due to papillomaviruses goes far beyond the common hand and plantar warts. Indeed, papillomaviruses represent a major sexually transmitted disease with probable oncogenic capabilities. They are, in fact, involved in some rare malignat-prone wart syndromes and perhaps in some other human cancers as well. With the current state of molecular biology, the biology of the viruses, their use as a role model for human oncogenesis and, perhaps, therapeutic strategies, are open to immediate study.
Article
We performed ultrastructural studies of apoptosis (previously referred to as "malignant, dyskeratosis") in a case of genital Bowen's carcinoma in which human papillomavirus (HPV) type 33 genome was identified and in two cases of cutaneous Bowen's disease with no detectable viral DNA; herein we present the sequential stages in the development of apoptotic bodies. The apoptotic process in the HPV-containing genital Bowen's disease was similar to that in the cutaneous lesions with no detectable HPV. The presence of a large number of apoptotic bodies in Bowen's disease may be responsible for the slow progression and noninvasive growth of this carcinoma in situ.
Article
Human papillomaviral (HPV) infection is now widely advanced as an important etiologic factor in cervical cancer. This study was undertaken to clarify morphologic relationships within the biologic spectrum linking subclinical papillomaviral infection (SPI) to cervical intraepithelial (CIN). Two pathologists analyzed 72 colposcopic biopsies, using a semi-objective rating scheme that scored 24 different histologic criteria. Each individual criterion was checked for reproducibility, and validated against an objective measure of papillomaviral infection (immunoperoxidase staining) or premalignant change (microspec-trophotometry). The individual criteria were then combined into histologic indices of benign warty change, presumed viral atypia, abnormal cell phenotype, and disturbed tissue maturation. Histologic expression of papillomaviral infection decreased with increasing degrees of premalignant change. Plotting the index of abnormal cell phenotype against that of disturbed tissue maturation produced a linear plot in which cases clustered into four diagnostic groups. The histologic indices of papillomaviral infection displayed significant curvilinear correlations with genotypic distortion, benign warty change being maximal in the CIN 1 range and presumed viral atypia in the CIN 2 range. Disturbance of nuclear DNA content also increased with worsening diagnosis; diploidy being most common in SPI (67%), polyploidy in CIN 1 (59%), and aneuploidy in CIN 2 (65%) and CIN 3 (82%). Conversely, capsid antigen production decreased from 36% in SPI to 9% in CIN 3. Three aneuploid epithelia were immunoperoxidase positive. These inverse relationships between late viral expression and nuclear distortion fit experimental models of viral oncogenesis. The gradual transition and morphologic overlap between diagnostic groups support the postulate that SPI and CIN are a single disease spectrum, in which differences are those of degree rather than of kind.
Thesis
In den letzen Jahren gab es durch epidemiologische und molekularbiologische Studien vermehrt Hinweise, dass kutane humane Papillomviren (HPV) ursächlich an der Entstehung nicht-melanozytärer Hauttumore (engl. NMSC) beteiligt sind. Ziel der vorliegenden Arbeit war die Identifizierung molekularer Mechanismen der viralen Proteine E6 und E7 kutaner HPV-Typen. Die E6 oder E7 Gene der verschiedenen HPV-Typen 1, 4, 5, 8, 20, 38 und RTRX7 wurden untersucht. Natürliche Wirtszellen dieser Viren, humane primäre Keratinozyten (HPK) der Haut, wurden mit rekombinanten, für E6 oder E7 kodierenden Retroviren infiziert. Die Analysen erfolgten in Monolayer-Kultur (undifferenzierte Keratinozyten) oder in organotypischen Hautmodellen (Induktion der Keratinozytendifferenzierung). Die Expression von E6 oder E7 führte in Monolayer-HPK zu einer Verlängerung der Lebensspanne und zu einer deutlich erhöhten Verdoppelungsrate. Eine Telomeraseaktivierung, die charakteristisch für immortale Zellen ist, wurde nur in HPV 8 E6 positiven HPK nachgewiesen. In organotypischen Hautmodellen induzierte das E7 Protein von HPV 1, 4 und 38 starke Veränderungen in der Differenzierung sowie eine Zunahme der Proliferation. Weiterhin wurde eine Aufhebung der normalen Zellzykluskontrolle in suprabasalen HPV 5 E7 oder HPV 8 E7 beobachtet. Hinweise auf ein starkes invasives Potential von E7-infizierten HPK wurden für HPV 8 E7 bestätigt und für HPV 4 E7, HPV 38 E7 und RTRX7 E7 erweitert. Molekulare Mechanismen der viralen Gene E6 und E7 kutaner HPV unterscheiden sich von mukosalen Typen. Das Mehrstufenmodell der Karzinogenese beinhaltet eine Reihe fundamentaler Zelltransformationen, die für eine Tumorgenese nötig sind. In dieser Arbeit beschriebene Mechanismen der Modulation der Zelldifferenzierung und Zellproliferation durch die kutanen HPV-Typen 4, 5, 8 und 38 können unter Umständen zur Induktion und Progression früher Stadien von Plattenepithelkarzinomen (SCC) beitragen.
Article
In females with immunodeficient states there is an increase in the frequency of genital papillomaviral infection, intraepithelial neoplasia, and invasive cancer. The target structures are those of the lower genital tract rather than the uterine body and ovaries. Human papillomaviral (HPV) infections are the likely first manifestation of the neoplastic spectrum, and possible progression to premalignant and invasive cancer is widely suspected. After a variable latent period, HPV infection is common in immuno-suppressed women, and incidence increases with duration of immune impairment. Even in this population, regression of HPV lesions and intraepithelial neoplasia can occur. While the overall number of women with immunodeficiency is not large, an understanding of this problem can shed light on many other clinical problems.
Article
Since 1842 (Rigoni-Stern), numerous epidemiological studies point to an infectious event in the etiology of human cervical cancer (reviewed by: Rotkin, 1973; Kessler, 1977; zur Hausen, 1977). Venereal transmission of a carcinogenic factor with a long latency period has been postulated in many of these studies. Sexual promiscuity, early onset of sexual activity, and poor hygienic conditions appear to be the prime risk factors for cervical cancer.
Article
In epidermodysplasia verruciformis (EV), the infection with specific human papillomaviruses (HPV) might be under control of the local immunosurveillance mechanisms related to cytokines produced by epidermal cells. We have investigated by in situ hybridization the expression of mRNA coding for TGF-1 and TNF in the skin of patients with EV (n = 4) as compared to the skin lesions of patients with other premalignant (actinic keratosis; n = 5) or malignant (squamous cell carcinoma; n = 4) skin lesions, and to the skin of healthy individuals (n = 5). The expression of TGF-1 and TNF mRNA was higher in the epidermis of EV patients as compared to the control skin from healthy individuals. The increased expression of mRNA for both cytokines was confirmed by northern blot analysis of RNA isolated from the skin lesions of the patient with EV. No specific signals for TGF-1 and TNF were detected in actinic keratosis, and in cases of squamous cell carcinomas only single neoplastic cells were positive for TGF-1. It is conceivable that in EV TGF-1 and TNF can be involved in the regulation of the growth and differentiation of HPV-infected keratinocytes and in the persistence of HPV-induced skin lesions.
Article
Aberrant immune responses may play a role in the susceptibility of patients with epidermodysplasia verruciformis to human papilloma virus (HPV). We examined the stimulatory capacity of antigen-presenting cells from HPV-infected skin and peripheral blood T-cell responses of patients with epidermodysplasia verruciformis. The percentage of Langerhans cells in relation to total epidermal cells in suspension was slightly reduced in HPV-infected lesions, relative to apparently clinically uninfected epidermis. In addition, the morphologic appearance of Langerhans cells was altered in lesional epidermal sheets. Despite these abnormalities, Langerhans cells were functionally intact in their capacity to present alloantigens to T cells and, in fact, the epidermis of HPV-infected lesions demonstrated enhanced antigen- presenting activity in three of four patients tested. The antigen-presenting activity was entirely abrogated by removal of Langerhans cells and was not associated with increased activity of cytokines with stimulatory activity for the thymocyte co-stimulation assay. Although epidermodysplasia verruciformis T cells were unresponsive to autologous HPV-infected epidermis, they responded well to mitogens, allogeneic mononuclear leukocytes, and allogeneic epidermal cells. Epidermodysplasia verruciformis T cells were inhibited in their capacity to respond to allogeneic epidermal cells when they were simultaneously exposed to autologous epidermal cells from HPV-infected lesional epidermis, but not to normal-appearing epidermis. Thus, although Langerhans cell activity is intact in epidermodysplasia verruciformis, these individuals fail to respond to autologous papillomas, which may, at least in part, be explained by an interaction between papillomal epidermal cells and autologous T cells that results in an inhibited response.
Article
By hybridization under stringent conditions, one out of two anal carcinomas and one out of 36 laryngeal carcinomas were shown to harbor HPV 16 DNA in high copy number. Further analysis of both tumor DNAs indicated a rearrangement of the viral DNA in the tumor cells. HPV 16 DNA in the anal carcinoma could chiefly be found episomally in two different forms: (1) a minority as 7.9-kb oligomeric episomes with no apparent modifications; (2) as 10.7-kb rearranged oligomeric episomes with a duplication of the part of the viral genome encoding the open reading frames (ORF) E7, E1 and parts of E6 and E2. In the laryngeal carcinoma, integrated and episomal HPV 16 DNA molecules of 7.9 kb were present, together with rearranged molecules of approximately 18 kb with multiple duplications of the ORF E4 and parts of the ORFs E2, E5, L1 and L2. Possible consequences for transcription of the modified viral genomes are discussed.
Chapter
The term precancerous as introduced by Dubreuilh in 1896 is admittedly outdated after 100 years of service. Nonetheless we have retained it, for many physicians and patients clinically consider lesions such as actinic keratoses precancerous, i.e. they have the potential to turn into skin cancers. Histologically, these lesions are carcinoma in situ; preinvasive lesions might be a better term. Another fertile ground for cancer is some types of chronic inflammation with associated epithelial hyperplasia, such as burn scars, acne inversa and tuberculous sinus tracts. One can speak of carcinoma in situ as an obligate precancerous lesion. If the patient lives long enough, at least some of the lesions can be expected to progress to invasive carcinoma. The hyperplastic inflammatory lesions are considered facultative precancerous lesions for they only rarely develop into malignancies.
Chapter
The presence of a virus infection can be documented either by isolation of the virus by culture or by detection of a virus-specific component. These viral components include structural proteins (which are usually identified on the basis of their antigenicity), virus-induced enzymes, and viral nucleic acids.
Article
Background Epidermodysplasia verruciformis is a rare genetic disorder characterized by development of lesions associated with HPV#5 or HPV#8 in early childhood; malignant transformation occurs in approximately half of individuals during adulthood. Objective Our goal was to study the presence and spectrum of EV-HPV types in Brazilian EV patients, a population that had never been studied in this regard. Patients and Methods Forty-one biopsies from different lesions (benign and skin tumors) and one biopsy from clinically normal skin from each of 20 Brazilian patients with EV were studied for HPV typing using nested PCR. Results EV-HPV DNA was detected in all 41 skin lesions of the patients and was also identified in specimens considered as normal skin from 8 patients (40%). In this study HPV-EV 25 was the most prevalent (70%), and HPV 14d (67%) was highly associated with malignant lesions. Conclusion EV-HPV 25 was the most prevalent in our study. The noteworthy association of EV-HPV type 14d with skin cancers suggests its possible oncogenic role in malignant transformation in this population.
Chapter
The infectious aetiology of human warts was established in 1907 by Ciuffo1, who successfully induced warts in volunteers after injection of cell-free extracts from common warts (verrucae vulgares). Warts occur in man as well as in a wide variety of animals, including Bolivian side-neck turtles2, African gray parrots3 and Indian elephants4, among many other species. It appears that at least the majority of these papillomatous proliferations is caused by papillomaviruses. These viruses are regarded as a sub-group of the genus papovaviruses5, although they have very little in common with the polyomavirus sub-group. On the basis of structural features, the genomic organisation and biological characteristics, it would be justified to regard the papillomavirus group as an independent genus.
Article
Virological studies have been made on 12 cases of EV patients in particular reference to clinical features. High frequency of parental consanguinity and familial occurrence indicate that EV occurrence is closly related with genetic factor. The abnormality of cell mediated immunity has been frequently observed, so genetic defects may be related to abnormality of cell mediated immunity. Three types of eruption have been observed, that is, red plaque, pityriasis versicolor-like wart and flat wart. Red plaque was observed among young patients only, whereas PV-like wart among elder patients (average age 41). From these lesions, human papillomavirus (HPV) -5, 12, 14, 17, 20, 21 and 38 have been isolated, but HPV 8, which have been frequently detected in foreign countries, have not been isolated. Skin cancer has been observed in six cases (50%) and all of their benign letions were PVlike. At least one of HPV-5, 17 or 20 have been isolated from those benign letions and HPV-17 or 20 have been detected in cancer tissue. These results suggest uhat three types of HPV may be closely related with malignant transformation of EV patients. © 1987, Meeting of Osaka Dermatological Association. All rights reserved.
Chapter
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The innate immunity is the first line of defense against pathogens, exerting fast and effective responses via preformed receptors. Moreover, this sensitive system puts together signals to induce adaptive host responses. This field has evolved a lot during the recent decades after the discovery of pattern recognition receptors that recognize pathogen specific molecular patterns. The increased understanding of the molecular and cellular components of the innate immune system authorized the dissection of novel human PIDs. The development and testing of a human genetic theory of infectious diseases has resulted in the discovery of single-gene inborn errors of (innate) immunity underlying severe infections in otherwise healthy children.
Chapter
In the past, the search for a virus involved in the induction of human cancer has been frustrating. With the advent of more sophisticated techniques in molecular biology, a number of viruses have gained renewed interest as possible human cancer viruses; one such virus is the human papillomavirus (HPV). Although HPV was one of the first viruses to be visualized by the electron microscope, little information was available on the biology of the virus until recently. In early studies (reviewed by Rowson and Mahy, 1967), there was little indication that HPV may be associated with malignancy. As early as the 1930’s, however, experimental evidence indicated that the cottontail rabbit papillomavirus (CRPV) was oncogenic in its host species (Rous and Beard, 1935). Other animal papillomaviruses were subsequently shown to produce tumors in laboratory animals and some were capable of morphologic transformation of cells in culture (Olson et al., 1969). Unfortunately, neither experimental transmission of HPV to laboratory animals nor a tissue culture system permissive for virus replication or expression of biological activity has been successful. For these reasons, research on HPV has been limited for the most part to physical and chemical characterization of virions obtained from papillomas.
Chapter
The concept of multistage carcinogenesis was largely formulated by investigators observing the interactive effects of viruses and chemicals. Rous and his coworkers (Rous and Kidd 1938; Rous and Friedewald 1944) found that virally induced skin papillomas that had regressed could be made to reappear by chemical irritants and concluded that the induced growth of these latent or dormant tumor cells occurred by a different mechanism (tumor promotion) than tumor induction (tumor initiation). Berenblum and Shubik (1947) more precisely divided carcinogenesis into initiation and promotion stages, and today the development of cancer is considered to be a multistep process involving several genetic and epigenetic steps (Boutwell 1974; Cairns 1975). Viruses are able to act at various stages of carcinogenesis, and interactive effects between environmental chemical carcinogens and viruses may be of substantial importance in human carcinogenesis (Fig. 1). Viral infections are widespread in humans, and viruses are factors in several types of human cancer, e.g., Burkitt’s lymphoma, nasopharyngeal cancer, liver cancer, T-cell leukemia, skin cancer, and cervical cancer (for review, see Phillips 1983). The purpose of our review is to summarize the current status of laboratory and epidemiological studies designed to investigate interactive effects of viruses and chemicals in carcinogenesis (Table 1).
Chapter
Papillomaviruses are capable of inducing benign and occasionally malignant tumors in keratinizing epithelia of a wide variety of animal hosts. The basal or germinal cells are thought to be the target of infection. In skin warts these cells show an increased mitotic index (Rashad 1969). No one has demonstrated papillomavirus DNA in basal cells as yet, probably because the number of copies of viral DNA present is below the level of detection by in situ hybridisation. During transit from the basal layer to the surface, the keratinocyte undergoes a complex series of irreversible changes collectively termed keratinization. Only keratinocytes at a certain stage of differentiation provide the necessary cellular machinery which can support productive viral replication. This probably represents the main stumbling block in establishing an in vitro cell culture system for the propagation of these viruses. Viral DNA synthesis has been demonstrated in keratinizing cells (Orth et al. 1971) as early as the first suprabasal layer (Grußendorf and zur Hausen 1979), and viral capsid antigens have been detected in the spinous, granular, and cornified layers (Noyes and Mellors 1957; Orth et al. 1977).
Article
Several primary immunodeficiencies (PIDs) have recently been described that confer an elevated risk of fungal infections and noninfectious cutaneous manifestations. In addition, immunologic advances have provided new insights into our understanding of the pathophysiology of fungal infections in established PIDs. We reviewed PIDs that present with an eczematous dermatitis in part I. In part II of this continuing medical education article we discuss updates on PIDs associated with fungal infections, their biologic basis in PIDs, and noninfectious cutaneous manifestations. Published by Elsevier Inc.
Chapter
Papillomaviruses are well known as etiologic agents of skin warts, condylomata acuminata and laryngeal papillomas. Only during the past few years however it was possible to demonstrate the amazing plurality of this virus group using techniques of molecular biology. At present the genus comprises 40 types, which are responsible for different disease patterns. New virus types were identified and characterized in a series of tumors of previously uncertain etiology, as for example in dysplasias of the cervix uteri, bowenoid papules, in focal epithelial hyperplasias and leukoplakias of the oral mucosa, in keratoacanthomas, solar keratosis, as well as in conjunctival papillomas. There is also first evidence for clinically inapparent papillomavirus infections. Tumors which may progress to carcinomas deserve special interest. The nucleic acid of certain papillomavirus types was detected in more than 90% of cervical carcinomas and of skin cancers from patients with epidermodysplasia verruciformis. This may point to a cancerogenic potential of such representatives. In this case a diagnostic virus classification would be very important for early detection of carcinomas.
Article
Human papillomaviruses (HPVs) cause substantial morbidity and mortality worldwide. HPVs are the etiologic agent responsible for common warts, plantar warts, and genital warts, and they are associated with the majority of anogenital malignancies. In recent years, advances in our understanding of the basic biology of HPV infection have led to the development of immunoassays to detect HPV antibodies and potentially to the development of vaccines against the viruses. Phase I and II: human vaccine trials are under way or in the planning stage.
Article
Cancer of the cervix has the epidemiologic characteristics of a sexually transmitted disease (Rotkin 1973). During the past decade the human papillomaviruses (HPV) have emerged as the most probable venereal agent in the pathogenesis of this disease.
Chapter
The three major forms of skin cancer (melanoma, squamous cell carcinoma, and basal cell carcinoma) are all epidemic in the Caucasian population of North America, and each has therefore been the subject of numerous investigations. This chapter reviews the descriptive and analytic epidemiology of melanoma and nonmelanoma skin cancer. The data reviewed are based primarily on populations in the United States and Canada; the (largely parallel) results that characterize the Scandinavian and Australasian literature are reviewed in Chapters 9 and 10.
Chapter
Papillomaviruses induce epithelial proliferation in man and in a number of animal species (for review see 1, 2). Replication of the virus particles occurs within those tumors, but is restricted to the upper layers of the epidermis (3, 4) indicating that only cells at a certain level of differentiation can support the virus multiplication. This might be the reason for the lack of an in vitro system to propagate the virus particles (for review see 5). Thus, investigation of papillomaviruses depends upon their isolation from biopsy material which contain — as a property of the virus type-different quantities of virus particles. Even those human papillomaviruses which are of special interest because their association with malignant tumors is suggested by epidemiological or histological studies (for review see 6) are poorly replicated in the respective lesions. Therefore the availability of molecularly cloned viral DNA is a prerequisite to investigate the physical organization as well as the biological behaviour of these viruses in more detail.
Chapter
Papillomaviruses are classified as the genus Papillomavirus of the Papovaviridae family by virtue of their capsid structure and biochemical composition (Matthews, 1982). The icosahedral particles contain only DNA and protein, and show a buoyant density in CsCl of 1.34 g/cm3. The single DNA molecule in each virion is double-stranded and circular. Polyomalike viruses form the second Papovaviridae genus, which is distinguished from papillomaviruses by a smaller capsid (55 nm versus 45 nm) and a shorter DNA (7.25 kbp to 8.4 kbp versus 5.25 kbp).
Article
Epidermodysplasia verruciformis (EV) is a rare inherited disorder characterized by disseminated infection by human papillomavirus (HPV), associated with development of cutaneous malignancies and immunological disturbances. Associated mental retardation has been reported in a few patients. We report a case of 23 year old male with plane wart and Pityriasis versicolor-like lesions since the age of 3 years with associated mental retardation and seizure disorder. The case is reported to highlight the association of mental retardation and seizure with a rare dermatological disorder.
Chapter
Papillomaviruses (PVs) are infectious DNA viruses capable of inducing benign and occasionally malignant growths specifically in keratinizing epithelia. A small number of PVs, such as bovine PV type 1 (BPV-1), are capable of inducing tumors of fibroblasts as well as of epithelial cells. However, only in epithelial cells does papillomavirus undergo vegetative replication. Infection of fibroblasts yields no progeny virus and is therefore a biological dead end.
Article
It is generally believed that, whatever the cause, tumorigenesis usually involves specific genetic alterations in an individual cell which then proliferates to form the tumour mass. Since such alterations may be multiple, and each one as inconspicuous as substituting a single nucleotide base within a genome composed of over 109 base pairs, the task of detecting, let alone circumventing, these events at the molecular level is a daunting one. Considerable research efforts have therefore focused not on the cancer cell itself, but on particular viruses which have been shown to induce these genetic alterations in cells and to cause tumours in animals. Such infectious agents offer two obvious opportunities to the cancer researcher. The first is that if viral infections do indeed cause or predispose individuals to the risk of cancer, then prophylactic measures might prevent these effects. The second is that animal-virus model systems provide considerable scope for experimental manipulation. Most of the viruses discussed in this chapter have genomes about a millionfold less complex than those of the cells they infect. Not only are they simpler to analyse, but the ease with which purified virus particles can be isolated often facilitates the preparation of specific nucleic acid and immunological reagents.
Article
M. D. Anderson Hospital cases diagnosed as adenocarcinoma of minor salivary glands before 1977 were reviewed. Within this heterogeneous group of neoplasms there was identified one clinicopathologic tumor entity, which we have designated “polymorphous low-grade adenocarcinoma.” The 14 tumors in that category were characterized by cytologic uniformity and histologic diversity; growth patterns varied (both within and among cases) from solid to tubular to papillary to cribriform (pseudoadenoid cystic) to fascicular, while the cells were always small to medium-sized, regular, and lacking in nuclear atypia. Mitotic figures were infrequent, and tumor necrosis was seen in only one instance (a recurrent neoplasm). Clear cytoplasm, oxyphilic and mucinous metaplasia, and intratubular calcification were sometimes present, and stromal mucinization and hyalinization were common. The tumors were always unencapsulated, and exhibited extension into surrounding tissues including bone. The 14 patients ranged in age from 27 to 76 years (median, 64 years). Eight were male and six were female; eight were white and six were black. The neoplasm was intraoral in all cases, involving the palate in 11, the buccal mucosa in two, and the posterior mandibular area in one. Local recurrence developed in one case, cervical lymph node metastasis in one, and both recurrence and cervical lymph node metastasis in two. The number of successive recurrences ranged up to three, and the interval to recurrence varied up to nine years (the interval to metastasis up to five years). Although radical surgical procedures were necessary for tumor control in some cases, no distant metastases occurred and all patients were clinically tumor-free at latest follow-up.
Article
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Four of five spontaneous benign equine connective tissue tumors of unknown etiology and a bovine papilloma virus (BPV)-induced equine tumor contained BPV-specific DNA sequences as determined by DNA-DNA hybridization of DNA from tumors with BPV DNA labeled in vitro. Analysis of the kinetics of reassociation indicated that 20-75% of the BPV genome was present in the various tumors. The number of partial BPV genome equivalents ranged from 60 to 500 copies per diploid quantity of cellular DNA. Thermal denaturation profiles of duplexes formed between labeled BPV DNA and DNA from tumor cells indicated two tumors contained viral DNA with base sequences identical to BPV DNA. Three tumors (including DNA from the BPV-induced tumor) contained BPV-related DNA sequences that were less thermally stable. The decrease in thermal denaturation temperature may be due to the presence of (adenine + thymine)-rich regions of the BPV genome in the tumor cells.
Article
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Human papillomaviruses (HPVs) found in lesions of 11 patients suffering from epidermodysplasia verruciformis were compared to HPV type 1 (HPV-1) and HPV type 2 (HPV-2) previously characterized in plantar and common warts, respectively. Complementary RNAs (cRNAs) to HPV-1, HPV-2, and viruses obtained from two patients with epidermodysplasia verruciformis (J.D. HPV and J.K. HPV) were used in cRNA.DNA filter hybridization experiments. No sequence homology was detected between HPV-1 or HPV-2 DNAs and DNAs obtained from the 11 epidermodysplasia verruciformis HPV isolates. Furthermore, with J.D. and J.K. HPV cRNAs, epidermodysplasia verruciformis HPV DNAs fell into two groups showing little, if any, sequence homology. A lower extent of annealing was observed for the DNAs of some isolates showing a genetic heterogeneity within each of the two groups. Almost no antigenic crossreaction was detected by immunodiffusion and indirect immunofluorescence tests, either between epidermodysplasia verruciformis HPVs and HPV-1 or HPV-2 or between J.D. and J.K. HPVs. Viruses belonging to the same group have common antigenic properties, but antigenic differences were observed when two of the viruses sharing only partial DNA sequence homology were compared. Viruses related to J.D. HPV were preferentially associated with flat wart-like lesions of epidermodysplasia verruciformis and were further found in the lesions of five patients bearing multiple flat warts. Viruses related to J.K. HPV were found in morphologically distinct lesions (red spots) present in some patients with epidermodysplasia verruciformis. Thus, we propose to distinguish two other types of HPVs designated provisionally as HPV type 3 (HPV-3) and HPV type 4 (HPV-4), with J.D. and J.K. HPVs as prototypes, respectively. Malignant conversion of some epidermodysplasia verruciformis lesions is more frequently associated with HPV-4 than with HPV-3 infection.
Article
Full-text available
The sequence of 72 base pairs of the rightward operator (O-R) of bacteriophage lambda is presented as determined with simple and rapid methods for direct DNA sequencing. The sequence of an operator mutant is also described. The methods are of general use in sequencing DNA fragments with unique 5' ends up to 50 base pairs in length. Previous experiments have shown that this operator contains multiple sites recognized by the lambda phage repressor. We believe we have identified three of these sites.
Article
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Anogenital warts from 26 patients were examined for the presence of human papillomavirus (HPV). Although no whole, intact virus could be identified, varying amounts of nonintegrated HPV DNA were detected in 18 tissue specimens (70%) by employing both an agarose gel-ethidium bromide staining method and the Southern blot hybridization procedure. When hybridization analysis was performed under stringent conditions, six anogenital warts were observed to contain HPV genomic sequences related to either of the cutaneous viruses HPV type 1 (HPV-1) or HPV-2. In 12 tissue samples lacking sequence homology to either HPV-1 or HPV-2 under stringent conditions, HPV-related sequences were detected when the hybridization was performed under less stringent conditions, indicating that an HPV distinct from both HPV-1 and HPV-2 is also associated with these lesions. This anogenital HPV also appeared to be distinct from the other characterized types of HPV. These data indicate that at least three HPVs are associated with anogenital wart disease.
Article
The incidence of viral warts, recurrent herpes simplex and herpes zoster has been assessed in a group of patients with possible secondary immune deficiency states and compared to a control group. Patients with cell-mediated immune deficiency appear to be more prone to warts and zoster infection as compared to patients with humoral immune deficiency. Recurrent herpes simplex infection was not increased in either group.
Article
Cattle in upland areas of Scotland and northern England are substantially more prone to alimentary cancer than those of the immediately neighbouring lowlands, and epidemiological evidence implicates a combination of papilloma virus and bracken in the aetiology of the disease. Here Professor Jarrett outlines the circumstantial case against these agents and discusses its implications.
Article
Recent biochemical and serological studies have shown the existence of at least four distinct types of human papillomaviruses (HPVs) causing benign skin lesions. These viruses show hardly no antigenic relationships; their DNAs differ by their sensitivity to restriction endonucleases, and show little, if any, sequence homology, as detected by molecular hybridization using complementary RNAs transcribed in vitro. Data on the pathogenicity of HPVs are still incomplete but indicate that some types of benign skin lesions (plantar warts, common warts, flat warts) may be preferentially associated with some types of HPV. Most interesting is that epidermodysplasia verruciformis has been found associated with two types of virus, and that malignant conversion of some lesions has been observed in all the patients infected with one of them. This suggests that at least a HPV may have a higher oncogenic potential, as do rabbit (Shope) papillomavirus and bovine alimentary tract papillomavirus. Much remains to be known on human papilloma-viruses and further studies may lead to the characterization of additional types of HPVs, especially in genital condylomata acuminata and laryngeal papillomas whose malignant conversion, although rare, may be observed. Progress in this field has been and remains hampered by the lack of cell culture systems allowing replication of these highly host and tissue specific viruses, and by the widely variable virus content of the different human lesions known to be associated with a papillomavirus. Further studies are warranted by the possible role of these widespread and epitheliotropic viruses in the origin of some carcinomas in man.
Article
In an initial efforts to characterize the virological basis of neoplasia in the Shope papilloma-carcinoma system, the extent to which the viral genome is present in non-virus-producing benign and malignant tumors in domestic rabbits was established. Employing nick-translated radioactive viral DNA purified from productively infected papillomas on cotton tail rabbits as a probe, it was found that (i) papillomas, primary carcinomas, and metastatic carcinomas contain 10 to about 100 copies of the viral genome per diploid cell equivalent of DNA and (ii) viral DNA is present in detectable amounts in essentially all neoplastic cells. These results are consistent with the suggestion that continued presence of the viral genome is necessary for induction and maintenance of malignant as well as benign neoplasms.
Article
The construction and analysis of bacterial plasmids that contain and phenotypically express a mammalian genetic sequence are described. Such plasmids specify a protein that has enzymatic properties, immunological reactivity and molecular size characteristic of the mouse dihydrofolate reductase, and render host cells resistant to the antimetabolic drug trimethoprim.
Article
Five cases of epidermodysplasia verruciformis were studied for viral particles and antigens. In all benign lesions tested, viral particles and antigens were observed by electron microscopy of ultrathin sections and/or tissue extracts and by fluorescent antibody staining with an antiserum against human wart virus. Both viral particles and antigens were observed in the cells of the stratum granulosum and the stratum corneum and not in those of deeper layers. Viral particles and antigens were observed in nuclei. Viral particles resembled morphologically the virus of common human warts. In two, one on the forehead and the other on the inner aspect of the upper thigh, of six lesions showing the histology of early malignancy, viral particles were observed by electron microscopy of ultrathin sections and/or tissue extracts. Four advanced malignant lesions, two primary ulcerated squamous cell carcinomas and two recurrent carcinomas, were similarly studied. In none of them, were viral particles or antigens detected. These results suggest that (1) the virus of epidermodysplasia verruciformis is related with that of common human warts both morphologically and antigenically, (2) at least some of the virus-induced lesions of epidermodysplasia verruciformis become malignant, and (3) when the lesions are completely replaced with malignant cells, neither viral particles nor antigens are recognizable in them.
Article
A case of common variable hypogammaglobulinaemia with associated impairment of cell mediated immunity and severe wart virus infection is described. The defect of cell mediated immunity is thought to have predisposed this patient to the development of persistent wart infection which in turn grossly depressed the body's cellular immunity and thus allowed widespread dissemination of the warts. The rapid restoration of cell mediated immunity which followed the reduction in the antigenic load of wart virus by diathermy treatment was followed by the spontaneous regression of all the patient's warts. This unusual case may provide some insight into the complex relationship between wart virus infection and the immune system of the host.
Article
This paper describes a method of transferring fragments of DNA from agarose gels to cellulose nitrate filters. The fragments can then be hybridized to radioactive RNA and hybrids detected by radioautography or fluorography. The method is illustrated by analyses of restriction fragments complementary to ribosomal RNAs from Escherichia coli and Xenopus laevis, and from several mammals.
Article
Plasmid deoxyribonucleic acid (DNA) ranging from 5 x 10(6) to 65 x 10(6) daltons may be isolated from chromosomal DNA by the preferential precipitation of the higher-molecular-weight chromosomal DNA in the presence of sodium lauryl sulfate and a high concentration of NaCl.
Article
Epidermodysplasia verruciformis of Lewandowsky and Lutz (EV) occurred as an autosomal recessive, sex-limited trait in six girls of one Chinese family. Except for one patient, all developed EV lesions at the age of 7 or 8 years. This patient with delayed onset and milder cutaneous lesions was given away for adoption at the age of 1 month to avoid contact with the affected sisters. Clinical and histological pictures were classical of EV but in addition, the cases showed marked pigmentary changes simulating arsenical dermatosis, xeroderma pigmentosum, and Bowen's disease. Histologically, there was extensive vacuolation of the epidermal cells, involving even the midmalpighian layer. Intranuclear viral particles previously found in this condition were also demonstrated. The relationship between this genodermatosis, presence of intranuclear viral infection in skin lesions, and increased frequency of malignant changes in this disease is discussed.
Article
SUMMARY Epidermodysplasia verruciformis is a skin disease caused by a generalized infection by verruca virus in which the verrucous lesions usually change into tumors, most frequently Bowen's carcinoma. Lesions from a case in which papovavirus was evident were transmitted to a healthy person, the virus being found in cell nuclei in the wart lesions and also in lesions with some signs of atypia. This fulfilled the condition for recognition of the virus, demonstrated by electron microscopy, as being causatively involved in the verrucous lesions in epidermodysplasia verruciformis and also in the initiation of the morbid process. The virus could not be demonstrated in lesions showing distinct signs of cancer.
Article
Papillomavirus DNA from common skin warts of four meathandlers has been characterized and compared to the DNA genomes of known human cutaneous papillomaviruses. Virus was purified from one of the human papilloma samples and was found to exhibit a restriction endonuclease cleavage pattern distinct from those of known human papillomaviruses (HPV). Moreover, viral DNA extracted from papillomas from the other three patients exhibited sequence homology and restriction endonuclease cleavage patterns similar to this novel viral DNA. In addition to this unique HPV, one of the patients also contained a second species of HPV which was related to, yet distinct from, HPV-2, a species of HPV associated with common cutaneous warts in man. Finally, employing the Southern transfer procedure and stringent hybridization conditions, each meathandler HPV DNA studied was found to be unrelated to the major species of bovine papillomavirus, types 1 and 2.
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