Characteristics of the lesions and risk of malignant conversion associated with the type of human papillomavirus involved in epidermodysplasia verruciformis.
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Biomedical subjects
Publications and source records attributed to O Croissant.
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Molecular hybridization technique and immunofluorescence studies with use of specific immune sera against the purified virions isolated from various types of warts and wart-like lesions of epidermodysplasia verruciformis (EV) made it possible to detect four different types of human papilloma viruses (HPV). The recognition of the viruses is important because of the different morphology of the lesions induced and their various oncogenic potentials. HPV1 is mainly responsible for plantar warts, HPV2 for common (hand) warts, HPV3 has been found both in flat warts and in the variety of EV in which skin lesions are of flat wart type, the course is relatively more benign, and usually malignant transformation is not to be expected. HPV4 was up to now found exclusively in the cases of EV with prevalent red and red-brownish plaques and hyper- and depigmentations similar to those of pityriasis versicolor. In all cases of this variety of EV malignancies occured invariably. In patients with EV, as also in--to a lesser extent--longstanding flat and/or common warts cell mediated immunity was in general lowered, but humoral specific anti-HPV antibodies were usually present. HPV type seems to be of a decisive significance for potential oncogenesis, because in a vast majority of cases EV due to HPV3 no malignancies occured in spite of anergy, whereas malignant transformation has been found in all cases due to HPV4, even in a patient with still preserved, although lowered, CMI.
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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.
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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.
Immunofluorescence and cell mediated immunity studies have been performed in 14 cases of epidermodysplasia verruciformis (EV), 3 of those abortive or regressing in members of the families of the patients with EV. Two different types of human papillomavirus (HPV)--HPV3 and HPV4--have been found in cases of EV. HPV3 was detected also in flat warts without features of EV. There was no cross-reactivity between these two viruses, neither with HPV1 responsible for plantar warts nor with HPV2 inducing common warts. There was a relationship between the type of HPV and the clinical picture of EV as well as the malignant transformation, namely HPV4 has been found to be more oncogenic. Cell mediated immunity (CMI) seems to be an important factor because it was depressed in a vast majority of active cases and preserved in regressing and abortive cases (in the members of the families of EV patients). However, low CMI has been found in EV cases infected with HPV3 and in persistent flat warts also due to HPV3, which did not undergo malignant transformation. In contrast, in a case of EV due to HPV4 a malignant transformation occured in spite of still preserved, although lowered CMI. Various human papillomaviruses seem to differ in their oncogenic potential. HPV1 responsible for plantar warts, and HPV2 for common warts have no evident oncogenic potential, HPV3 inducing both EV and flat warts has a low oncogenicity, whereas HPV4 inducing some cases of EV seems more oncogenic.
Four low-molecular-weight polypeptides migrating like H2a, H2b, H3, and H4 calf liver histones were detected by sodium dodecyl sulfate-acrylamide gel electrophoresis of highly purified preparations of bovine papillomavirus (BPV) and human papillomavirus (HPV). Complexes of these polypeptides and viral DNA were isolated by agarose-gel filtration of the alkaline disruption products of both viruses. When observed under the electron microscope, these complexes appeared as circular structures composed of nucleosomes with a diameter of about 8.0 nm interconnected by a naked DNA filament. The maximal frequency of nucleosomes per molecule was 30 for both viruses, corresponding to a condensation ratio of the viral DNA of 2.5.
The DNA of human papillomavirus (HPV) obtained from a pool of plantar warts is cleaved by bacillus amyloliquefaciens (BamI) and Haemophilus parainfluenzae (HpaII) restriction endonucleases at one and four specific sites, respectively. These sites were localized on the previously established cleavage map of HPV DNA, using the Hind, HindIII, HpaI, and EcoRI endonuclease restriction sites as reference. The four HpaII sites were mapped, clockwise, at 1.4, 41.1, 44.3, and 52.8% of the genome length from the unique BamI cleavage site taken as point zero. The HpaII site mapped at 1.4% of the genome length was absent in 40 to 50% of the molecules, thus showing a genetic heterogeneity of HPV DNA.
A human papillomavirus (HPV) was isolated from the lesions of a patient (ML) bearing numerous hand common warts. This virus was compared with the well-characterized HPV found in typical plantar warts (plantar HPV). ML and plantar HPV DNAs have similar molecular weights (5.26 x 10(6) and 5.23 x 10(6), respectively) but were shown to be different by restriction enzyme analysis. When the cleavage products of both DNAs by endonuclease EcoRI, BamI, HpaI, or Hind were analyzed by electron microscopy, one, two, one, and four fragments were detected for ML HPV DNA instead of the two, one, two, and six fragments, respectively, detected for plantar HPV DNA. In contrast to plantar HPV DNA, a high proportion of ML HPV DNA molecules were resistant to these restriction enzymes. Most, if not all, of the molecules were either resistant to BamI and sensitive to EcoRI or sensitive to BamI and resistant to EcoRI. After denaturation and renaturation of the cleavage products of ML HPV DNA by a mixture of the two enzymes, the circular "heteroduplexes" formed showed one to three heterology loops corresponding to about 4 to 8% of the genome length. No sequence homology was detected between ML and plantar HPV DNAs by cRNA-DNA filter hybridization, by measuring the reassociation kinetics of an iodinated plantar HPV DNA in the presence of a 25-fold excess of ML HPV DNA, or by the heteroduplex technique. The two viruses had distinct electrophoretic polypeptide patterns and showed no antigenic cross-reaction by immunodiffusion or immunofluorescence techniques. Preliminary cRNA-DNA hybridization experiments, using viral DNAs from single or pooled plantar or hand warts, suggest that hand common warts are associated with viruses similar or related to ML HPV. The existence of at least two distinct types of HPVs that cause skin warts was demonstrated; they were provisionally called HPV type 1 and HPV type 2, with plantar HPV and ML HPV as prototypical viruses, respectively.
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Human papillomavirus (HPV) DNA form I (supercoiled) was prepared from plantar warts. HPV DNA was cleaved with restriction enzymes obtained from the following sources: escherichia coli (EcoRI), Hemophilus influenzae strain Rd (both unfractionated Hind and aeparated HindII and HindIII enzymes) and Hemophilus parainfluenzae (HpaI). The cleavage products were analyzed by polyacrylamide gradient slab gel electrophoresis and electron microscopy. HPV DNA was cleaved into two fragments by EcoRI (87% and 13% of the genome) and into six fragments, ranging in size from 33.5 to 1.2% of the genome, by Hind endonucleases. The six Hind fragments result from the cleavage of three sequences recognized by HindII, two of which are also cleaved by HpaI, and of three sequence recognized by HindIII. The order of these fragments was determined by comparing their size with that of the fragments obtained with HindII, HindIII, HpaI, and the mixture of HindIII + Hpal. The two EcoRI cleavage sites were located on two adjacent Hind fragments and one of these sites has been taken for the zero point to construct a physical map. The treatment of superhelical HPV DNA with bacteriophage T4 gene 32 protein yields circular structures with a denaturation loop. The cleavage of these complexes with EcoRI and HindIII has shown two easily denatured regions which were located on the cleavage map.
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Nucleoprotein complexes containing viral DNA and cellular histones were extracted from nuclei of permissive cells infected with polyoma virus or simian virus 40 (SV40) and examined by electron microscopy. Polyoma and SV40 nucleoprotein complexes are almost identical. They appear as relaxed circular molecules consisting of 20 to 21 globular particles interconnected by thin filaments. Their contour length in 0.02 M salt is 2.7 times shorter than that of viral DNA form I obtained after dissociation of the proteins in 1 M NaCl. The nucleosomes have an average diameter of 12.5 nm. Each nucleosome contains 175 to 205 DNA base pairs condensed fivefold in length. The nucleosomes are regularly spaced on the circular molecule. The internucleosomal filaments are made of naked DNA, and each filament contains about 55 base pairs. The partial sensitivity of the nucleoprotein complex to cleavage by EcoR1 endonuclease suggests that the nucleosomes are not formed at specific sites on the viral genome. Faster sedimenting nucleoprotein complexes containing replicative intermediates were studied. Isopycnic centrifugation in metrizamide gradients in the absence of aldehyde fixation showed that these molecules conserved the same DNA-to-protein ratio as the form I DNA-containing complexes.
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