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Journal of Virology, December 2000, p. 11636-11641, Vol. 74, No. 24
Department of Medical
Microbiology1 and Department of
Nephrology and Transplantation,2 Malmö
University Hospital, Lund University, Malmö, Sweden
Received 10 July 2000/Accepted 26 September 2000
Human papillomaviruses (HPV) are epitheliotropic viruses, with some
types suggested to be associated with skin cancer. In this study, swab
samples collected from five different sites on the skin of renal
transplant recipients, dialysis patients, and age- and sex-matched
healthy controls were analyzed for HPV DNA by a newly designed PCR
test. Most individuals were found to have asymptomatic HPV infections;
more specifically, 94% of the renal transplant patients, 82% of the
dialysis patients, and 80% of the healthy controls were positive for
HPV DNA. The multiplicity of the HPVs detected was astounding: 20 previously described and 30 putatively new types were identified by
cloning and sequencing of 33 samples from 13 individuals. These results
demonstrate that normal human skin harbors an array of
papillomaviruses, most of them previously unknown.
To date, 85 different genotypes of
the human papillomaviruses (HPV) have been fully characterized. In
addition to being the causative agents of common skin warts, there is
evidence that certain types of HPV play a role in the pathogenesis of
skin cancer associated with the rare hereditary disease
epidermodysplasia verruciformis (EV) (22, 27), and they are
therefore designated EV-associated HPV.
Renal transplant recipients given immunosuppressive therapy for long
periods of time have an increased incidence of cutaneous neoplasia
(2, 10, 29). Also, more than 90% of kidney recipients develop skin warts and 40% develop skin cancer within 15 years of
transplantation, a 50- to 100-fold increase compared to the general
population (7), and EV-associated HPV types have been found
in skin tumors from such patients (5, 12, 16, 21, 28).
Interestingly, EV HPV types have also been detected in hairs plucked
from normal skin of 94% of renal transplant recipients (8)
and 67% of healthy controls (9), and in another study (1), 35% of biopsy specimens of normal skin obtained during cosmetic surgery were positive for HPV DNA.
In a recent report (20), we presented a PCR test that holds
promise as a potent tool for exploring HPV both in skin tumors and in
normal skin. In the present investigation, we used the test to study
the presence of HPV at various sites on normal skin of both renal
patients who were or were not on immunosuppression and matched healthy
controls, and there is a serendipitous aspect to the results.
Subjects.
We studied 52 of about 130 renal transplant
recipients being followed up at the outpatient clinic of nephrology of
Malmö University Hospital, Malmö, Sweden. The median time
since transplantation was 5 years and 2 months, and the range was 2 months to 26 years. Also included in the study were 28 of the 67 patients being treated at the Dialysis Unit; the median length of
dialysis treatment was 2 years and 5 months (range, 1 month to 14 years). All of the transplant and dialysis patients were randomly
selected, and a sex- and age-matched healthy control was recruited for
each of the patients. The age range of the individuals in the three groups was 21 to 80 years, with a median of 54 years. History of skin
cancer as well as other forms of cancer was assessed by a questionnaire.
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
The Ubiquity and Impressive Genomic Diversity of
Human Skin Papillomaviruses Suggest a Commensalic Nature of
These Viruses
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Samples.
Samples from the renal transplant recipients,
dialysis patients, and healthy controls were collected with prewetted
(0.9% NaCl solution) cotton-tipped swabs (Bio Hospital, Kopparberg, Sweden) that were drawn back and forth five times over the skin within
an area of 5 by 10 cm and then suspended in 1 ml of 0.9% NaCl
solution. These samples were taken at five different sites: the
forehead, the volar aspects of the left and right forearms, and the
anterior aspects of the left and right thighs. For the longitudinal
study, samples were collected from the same five sites, as well as the
abdomen. Furthermore, for an environmental survey, samples were taken
(with cotton-tipped swabs, as described above) from the floor and
laboratory bench of the PCR setup room, and in a room used for
preparation of cloned material. Samples were also collected from the
floors of the kitchen, bedroom, living room, and bathroom of the
apartment of one of the volunteers in the longitudinal study. All
samples from renal transplant recipients, dialysis patients, and
healthy controls were kept at 4°C for a maximum of 72 h before
being analyzed and were then frozen at 
20°C until tested. For the
longitudinal study, the samples were kept frozen until tested.
PCR. All specimens were tested without previous DNA extraction. The final volume of 25 µl of PCR solution contained 5 µl of the sample, 0.75 µM each primer (FAP59 and FAP64) (20), 0.2 mM each deoxynucleoside triphosphate (Boehringer GmbH, Mannheim, Germany), 0.2% bovine serum albumin, 0.625 U of AmpliTaq Gold DNA polymerase, GeneAmp 10× PCR buffer II, and 3.5 mM MgCl2 (Perkin-Elmer, Foster City, Calif.). Forty-five cycles of amplification were performed after denaturation for 10 min at 94°C. Each cycle consisted of 94°C for 90 s, 50°C for 90 s, and 72°C for 90 s. In each batch of tests, proteinase K-treated human embryonal lung fibroblasts (HEL) and H2O without DNA were included as negative controls. HPV 11 and HPV 20 (both clinical samples) served as positive controls. Moreover, 62 samples that were PCR negative for HPV DNA were analyzed for the presence of the human L1 sequence (13). Human cells contain more than 105 copies of the L1 sequence; thus, this sequence can be used to detect small amounts of human DNA and as an indirect marker to ensure that a sample does not contain any PCR-inhibiting substances. PCR products (5-µl aliquots) were analyzed by electrophoresis in a 2% agarose gel (SeaKem; FMC Bioproducts, Rockland, Maine) containing ethidium bromide (0.02 µg/ml).
Cloning and sequence analysis. PCR-amplified sample DNA was cloned into the pCR-script SK(+) cloning vector (Stratagene, La Jolla, Calif.). A minimum of 4 and a maximum of 13 clones from each sample were sequenced (Big Dye Terminator cycle sequencing; Perkin-Elmer) and analyzed on a Perkin-Elmer 373A automated sequencer with both forward and reverse primers. The forward and reverse complementary sequences were aligned with MacMolly computer software (version 3.8). The relatively conserved DNA sequence of the L1 open reading frame was used for comparison of the new HPV isolates with previously established HPV types available through the BLAST server (National Center for Biotechnology Information [NCBI]) (http://www.ncbi.nlm.nih.gov/blast/blast.cgi).
An isolate is defined as a new HPV type if the sequence of its L1 gene displays less than 90% homology with the L1 genes of all types that are already known; as a subtype if it shows between 90 and 98% homology with a known HPV type; and as a type variant if it displays greater than 98% homology (Papillomavirus Nomenclature Committee, 1995) (15, 32). This nomenclature was followed to define new HPV type candidates derived from the skin samples.Sequence alignment and phylogenetic analysis. Phylogenetic analysis was based on multiple alignment with Clustal X (version 1.8) (24, 31) edited with Genedoc (version 2.4.000) (25). Phylip (version 3.5) (18, 19) was used for neighbor-joining and maximum likelihood analysis. These programs were obtained from the website of the University of Washington Department of Genetics (http://evolution.genetics.washington.edu/phylip/software.html).
The taxonomic system with the papillomavirus supergroups
to 
was
created by zur Hausen (34) and also proposed by E. M. de Villiers at the taxonomy workshop of the 18th International Papillomavirus Conference in Barcelona, 2000. This system was applied
to investigate relatedness between the HPV type candidates and
previously established HPV types. Thus far, supergroup is the
largest of the five clades, and it includes mucosal and genital HPV
types. Supergroup 
comprises ungulate papillomaviruses, and supergroup comprises a mix of animal papillomaviruses and cutaneous HPV. Most of the cutaneous HPV are found in supergroups 
and 
.
The region of the L1 gene used for the phylogenetic analysis extends
from nucleotide 6044 to 6480, relative to the HPV 20 sequence. The
following papillomaviruses were included in the analysis: from
supergroup , HPV 5, 8, 9, 12, 14, 15, 17, 19 to 25, 36 to 38, 49, 75, 76, and 80, RTRX7, and Colobus monkey papillomavirus type 2 (CgPV
2); from supergroup , HPV 4, 48, 50, 60, and 65; from supergroup
, bovine papillomavirus types 1 and 2 (BPV 1 and 2), ovine
papillomavirus types 1 and 2 (OvPV 1 and 2), European elk
papillomavirus (EEPV), and deer papillomavirus (DPV); from supergroup
, HPV 1, 41, and 63, cottontail rabbit papillomavirus (CRPV), and
canine oral papillomavirus (COPV); from supergroup , HPV 13, 44, and
55, and pygmy chimpanzee papillomavirus type 1 (PCPV 1). Also included
in the analysis were the HPV type candidates FA1 to FA42. The sequences
from previously characterized HPV types were obtained from GenBank
(http://www.ncbi.nlm.nih.gov/).
Statistical analysis. The general chi-square test was used to compare the prevalence of HPV DNA on the forehead, arms, and thighs. Analysis of age-related HPV DNA prevalence was done by the chi-square test for linear trends, and comparison of difference in HPV DNA prevalence between the renal transplant recipients and the healthy control group was accomplished with the chi-square test with Yates' correction.
Nucleotide sequence accession numbers. HPV type candidate sequences FA14 to FA43 have been submitted to GenBank with the following accession numbers: FA14, AF217656; FA15, AF217657; FA16.1, AF217658; FA16.2, AF217659; FA17, AF217660; FA18, AF217661; FA19, AF217662; FA20, AF217663; FA21, AF217664; FA22, AF217665; FA23.1, AF217666; FA23.2, AF217667; FA24, AF217668; FA25, FA217670; FA26, AF217671; FA27, AF217672; FA28, AF217673; FA29, AF217674; FA30, AF217675; FA31, AF217676; FA32, AF217677; FA33, AF217678; FA34, AF217679; FA35, AF217680; FA36, AF217681; FA37, AF217682; FA38, AF217683; FA39, AF217684; FA40, AF217685; FA41, AF217686; FA42, AF217687; and FA43, AF252606.
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RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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HPV DNA was detected in at least one of the samples from 94% (49 of 52) of the renal transplant recipients, 82% (23 of 28) of the
dialysis patients, and 80% (64 of 80) of the healthy controls (Table
1). A history of skin cancer (basal or
squamous cell carcinoma) was common in the renal transplant recipient
group (11.5% [6 of 52]), whereas no cases of skin cancer had been
noted in the dialysis patients or the healthy controls. Five of the six
renal transplant recipients with a history of skin cancer were positive
for HPV DNA.
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There was a significant difference between the renal transplant recipients and the dialysis and healthy control groups with regard to the prevalence of HPV DNA (P < 0.05). Also, HPV DNA was significantly more prevalent in the forehead samples than in samples from arms and thighs (P < 0.001).
HPV type determination.
PCR products of the samples from one
male and one female from each of the three groups of subjects (i.e.,
the transplant patients, the dialysis patients, and the healthy
controls) were selected for cloning. Five of these individuals had HPV
DNA-positive samples from the forehead, arms, and thighs, whereas one
of the healthy controls had one HPV DNA-positive sample only, from the
forehead. Five clones from each sample were DNA sequenced and analyzed
(Table 2).
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Longitudinal study.
Considering all three volunteers over the
7-month study period, skin swab specimens collected from the foreheads
showed a higher prevalence of HPV DNA than specimens from the other
sampling sites (arms and thighs). At least one sample was positive for HPV DNA on 19 of the 20 (95%) different sampling occasions for the
38-year-old male, on 14 of the 20 (70%) occasions for the female, and
on 15 of 17 (88%) occasions for the 55-year-old male. The total
prevalence of positive samples was 23 of 120 (19%) for the female, 59 of 120 (49%) for the younger male, and 27 of 102 (26%) for the older
male. Detailed results for the younger male are given in Table
6.
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Environmental survey. HPV DNA was detected in the samples from the floor of the PCR setup room (HPV type candidate FA37, not found in any of the clinical samples), from the laboratory bench (HPV 23 and FA14), and from the floor of the room used for work with cloned material (sample not sequenced). The samples collected from the floors of the kitchen and bedroom in the apartment of one of the volunteers were HPV DNA positive, whereas the bathroom and living room samples were negative. All four of these samples were PCR positive for human DNA.
Phylogenetic analysis.
The phylogenetic tree in Fig.
1 shows that the previously characterized
HPV types fall into six assemblages: the five supergroups , ,
, , and , with supergroup divided into two subordinate groups. Thirteen of the FA HPV candidates were found to belong to
supergroup and 16 to supergroup , the latter comprising only
five previously fully characterized HPV types. Trees obtained using the
neighbor-joining and maximum-likelihood algorithms were similar.
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Our results disclose what has been indicated in previous
publications (1, 4, 5, 8, 16, 20), namely, that the human
skin harbors a very large spectrum of HPV genotypes, most of them
previously unknown. Moreover, there is reason to believe that a further
substantial number of skin papillomavirus types remain to be detected,
because our limited study of 33 samples from only 13 individuals
revealed 20 previously described HPV types and 30 novel HPV type
candidates. Fifteen of the putative HPV types FA1 to FA42 were found to
belong to supergroup , which thereby increased in size by 62%.
Interestingly, we noted that 26 of the putative HPV types belonged to
the small supergroup ; this represents a more than fivefold
expansion of supergroup , which previously included only five fully
characterized HPV types. However, the possibility that some of the FA
HPV type candidates we detected have also been found by other
researchers (5, 28) cannot be ruled out, because we analyzed
a different segment of the L1 gene than they did.
We used a simple sampling method in which a saline-soaked cotton-tipped swab was gently drawn over a small area of skin, and we observed that more than 75% of the samples from the foreheads of healthy individuals were positive for HPV DNA. Also, cloning and DNA sequencing of single PCR products revealed as many as six different HPV types or type candidates in a single sample. Thus, it seems logical to assume that we would have found even more types of HPV if we had analyzed additional clones from the same PCR products.
Many different HPV types and type candidates were found at all of the analyzed skin sites, although prevalence was greatest on the forehead. Other investigators have used more invasively collected samples, such as plucked hairs (8, 9) and skin biopsy specimens (1, 4, 11, 12), but the analytical methods they applied gave HPV harvests that were lower compared to ours.
We also observed that greater age and immunosuppression were correlated with higher prevalences of HPV in the skin samples, but that might simply reflect a difference in the quantity of HPV DNA present rather than a true difference in the prevalence of HPV infection.
Generally, we found certain types or HPV type candidates on several skin sites within one individual as well as longitudinally on the same person.
Skin cancers in EV and immunocompromised patients occur predominantly on parts of the body exposed to UV radiation, indicating that UV light plays a key role in the development of such disease (14, 17, 23). In our study, HPV was found more frequently on the forehead than on the arms or thighs. If the production of HPV in infected skin is balanced by a local immune response, it is conceivable that the local photoimmunosuppression can occur even at low doses of UVB (3, 33), and it would thus be possible that the higher HPV prevalence we observed on foreheads was due to immunosuppression on sun-exposed sites, in both the immunosuppressed patients and the control population.
The ubiquitousness of skin papillomaviruses revealed in our study puts the supposed role of these agents in the natural history of certain skin cancers to a severe test. Obviously, HPV DNA found in a skin tumor might merely be a passenger that has no relevance to the genesis of the malignancy. Therefore, methods such as in situ hybridization tests and measurement of the expression of certain viral genes and their interaction with host cell functions will probably be needed to provide essential information about the involvement of papillomaviruses in skin cancer.
Most of the previously recognized skin HPV types and 15 of the HPV type candidates detected in our study belonged to the so-called EV-associated HPVs. However, we found that these HPV types or type candidates are frequently present on the skin of normal, healthy individuals, and it has also been reported that they occur in skin cancer lesions of renal transplant recipients (4, 5, 11, 16, 21). Therefore, it seems warranted to stop calling them EV-associated HPVs. Preferably, they should be classified according to phylogenetic supergroups (34), or, in a broader sense, simply referred to as skin HPV types.
Papillomaviruses have been found in most vertebrates investigated (30), and it is assumed that they have developed together with various animal species over hundreds of millions of years (6, 26). Therefore, it is not surprising that some papillomaviruses have adapted in such a way that they can efficiently spread between individuals and cause chronic infections without inducing any tissue damage, at least under normal conditions. An inescapable and fascinating question is whether papillomavirus infections have brought any evolutionary benefits to the vertebrate hosts.
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ACKNOWLEDGMENTS |
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We thank Rose-Marie Carlsson and Susanne Brännlund, nurses at the Dialysis Unit, University Hospital, Malmö, for collecting the samples from the dialysis patients. Thanks are also due to Kenneth Persson, Department of Medical Microbiology, Lund University, University Hospital, Malmö, for invaluable help with statistical analysis of the data.
This work was supported by the Cancer Foundation of University Hospital, Malmö, and the Alfred Österlund Foundation.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Medical Microbiology, Malmö University Hospital, SE-205 02 Malmö, Sweden. Phone: 46 40 331365. Fax: 46 40 337312. E-mail: annika.antonsson{at}mikrobiol.mas.lu.se.
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Journal of Virology, December 2000, p. 11636-11641, Vol. 74, No. 24
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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Weissenborn, S. J., De Koning, M. N. C., Wieland, U., Quint, W. G. V., Pfister, H. J.
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Gheit, T., Billoud, G., de Koning, M. N. C., Gemignani, F., Forslund, O., Sylla, B. S., Vaccarella, S., Franceschi, S., Landi, S., Quint, W. G. V., Canzian, F., Tommasino, M.
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Vasiljevic, N., Hazard, K., Eliasson, L., Ly, H., Hunziker, A., de Villiers, E.-M., Norrild, B., Dillner, J., Forslund, O.
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de Koning, M. N. C., Struijk, L., Bavinck, J. N. B., Kleter, B., ter Schegget, J., Quint, W. G. V., Feltkamp, M. C. W.
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Tobler, K., Favrot, C., Nespeca, G., Ackermann, M.
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(2005). Worldwide Genomic Diversity of the High-Risk Human Papillomavirus Types 31, 35, 52, and 58, Four Close Relatives of Human Papillomavirus Type 16. J. Virol.
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Calleja-Macias, I. E., Kalantari, M., Allan, B., Williamson, A.-L., Chung, L.-P., Collins, R. J., Zuna, R. E., Dunn, S. T., Ortiz-Lopez, R., Barrera-Saldana, H. A., Cubie, H. A., Cuschieri, K., Villa, L. L., Bernard, H.-U.
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Wolf, P., Seidl, H., Back, B., Binder, B., Hofler, G., Quehenberger, F., Hoffmann, C., Kerl, H., Stark, S., Pfister, H. J., Fuchs, P. G.
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Peh, W. L., Brandsma, J. L., Christensen, N. D., Cladel, N. M., Wu, X., Doorbar, J.
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Feltkamp, M. C. W., Broer, R., di Summa, F. M., Struijk, L., van der Meijden, E., Verlaan, B. P. J., Westendorp, R. G. J., ter Schegget, J., Spaan, W. J. M., Bouwes Bavinck, J. N.
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Miracco, C., Palummo, N., Lavergne, D., Nyongo, A., Tosi, P., de Villiers, E.-M.
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Orth, G., Favre, M., Majewski, S., Jablonska, S., Antonsson, A., Forslund, O., Hansson, B. G., Ekberg, H., Sterner, G.
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