| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Short Communication |
Department of Laboratory Medicine, Division of Medical Microbiology, Lund University, University Hospital MAS, SE-20502 Malmö, Sweden
Correspondence
Ola Forslund
Ola.forslund{at}med.lu.se
 |
ABSTRACT |
|---|
 TOP ABSTRACT MAIN TEXTREFERENCES |
|---|
A supplementary table showing GenBank accession numbers for all sequences used in this study is available with the online version of this paper.
|
MAIN TEXT |
|---|
|
TOPABSTRACTMAIN TEXTREFERENCES |
|---|
). It is also clear that cutaneous human papillomaviruses (HPV) are commonly present on healthy human skin (Antonsson et al., 2000, 2003a, b; Astori et al., 1998; Boxman et al., 1997; Forslund et al., 2003b, 2004; Harwood et al., 2004; Wieland et al., 2000). Based on phylogenetic relatedness of the L1 gene, the cutaneous HPV types are classified in different genera, of which Betapapillomavirus contains 25 fully characterized HPV types [previously designated epidermodysplasia verruciformis (EV) types], Gammapapillomavirus contains seven characterized HPV types, Mupapillomavirus includes two HPV types (HPV1 and 63) and Nupapillomavirus harbours only one HPV type (HPV41) (de Villiers et al., 2004). The genus Betapapillomavirus has been divided further into five distinct species with related HPV types (Beta-1: HPV5, 8, 12, 14, 19, 20, 21, 24, 25, 36, 47, 93; Beta-2: HPV9, 15, 17, 22, 23, 37, 38, 80; Beta-3: HPV49, 75, 76; Beta-4: HPV92; and Beta-5: HPV96), and Gammapapillomavirus into five species (Gamma-1: HPV4, 65, 95; Gamma-2: HPV48; Gamma-3: HPV50; Gamma-4: HPV60; Gamma-5: HPV88) (de Villiers et al., 2004). In addition, species Alpha-2, -4 and -8 contain 13 HPV types that cause cutaneous lesions (HPV2, 3, 7, 10, 27, 28, 29, 40, 43, 57, 78, 91, 94) (de Villiers et al., 2004).
Although no cutaneous high-risk HPV types, similar to the genital HPVs, have been defined (Lörincz et al., 1992), HPV5 and HPV8 are associated with squamous cell carcinoma among individuals with the rare hereditary disease EV (Orth, 1986). Furthermore, among immunosuppressed renal-transplant recipients, the betapapillomaviruses have frequently been detected in both pre-malignant and malignant skin lesions (Antonsson et al., 2000; Berkhout et al., 1995, 2000; de Jong-Tieben et al., 2000; de Villiers et al., 1997; Forslund et al., 2003b; Hopfl et al., 1997; Shamanin et al., 1994b). Also, among immunocompetent patients, the betapapillomaviruses have been commonly detected in both skin tumours (Antonsson et al., 2000; Boxman et al., 2000; Forslund et al., 2003a, b; Harwood et al., 2000, 2004; Iftner et al., 2003; Meyer et al., 2000, 2001; Pfister et al., 2003; Shamanin et al., 1996; Wieland et al., 2000) and healthy skin (Antonsson et al., 2000; Astori et al., 1998; Harwood et al., 2004; Iftner et al., 2003; Meyer et al., 2001).
The development of PCR testing with general primers for amplification of a broad range of HPV types has had a major impact on the molecular epidemiology of HPV, including detection of novel putative cutaneous HPV types identified by sequencing of subgenomic amplicons. Several putative HPV types have been detected by PCRs with general primers that target the L1 open reading frame (Fig. 1) (Berkhout et al., 1995, 2000; Forslund et al., 1999, 2003a; Harwood et al., 1999; Shamanin et al., 1994a, b, 1996). However, although the number of cutaneous putative HPV types has increased considerably, knowledge about their phylogeny is insufficient.
|
) and reported previously in 10 studies (Alotaibi et al., 2006; Antonsson & Hansson, 2002; Antonsson et al., 2000, 2003a, b; Forslund et al., 1999, 2003b, 2004; Hazard et al., 2007b; Nordin et al., 2007).
To define a novel papillomavirus type, the complete L1 sequence should be <90 % identical to the L1 of characterized types (de Villiers et al., 2004). Although the FA sequence generated by the primers FAP59 and FAP64 only constitutes about 30 % of the L1, it could be considered for identification of putative HPV types (Fig. 1
). In order to investigate whether the FA sequence is valid for taxonomic purposes, the FA sequence and the L1 sequence of HPV5 were aligned pairwise with corresponding sequences of 24 characterized HPV types within the genus Betapapillomavirus, and those of HPV4 with eight HPV types across the genus Gammapapillomavirus, by using BioEdit, allowing ends to slide (Hall, 1999). Furthermore, comparative analysis was performed on phylogenetic trees based on the FA sequence and the entire L1 for 34 HPV types within the beta- and gammapapillomaviruses (see below for description of method).
In the present study, the analysis included FA sequences up to FA164 (putative subtypes and variants were omitted) within the genera Betapapillomavirus and Gammapapillomavirus with <90 % sequence identity to any known HPV type or to each other. No HPV sequences from the genera Alphapapillomavirus, Mupapillomavirus or Nupapillomavirus were included, as only one FA sequence (FAIMVS3; GenBank accession no. AF489705) has hitherto been grouped within the alphapapillomaviruses. FA sequences were obtained from GenBank; accession numbers are available in Supplementary Table S1 in JGV Online. Due to partially overlapping amplicons, FA53 was presented in the tree as vs73-1, FA114 as vs102-4, FA118 as vs42-1, FA119 as vs75-3 and FA127 as vs20-4 (Shamanin et al., 1994b). Corresponding sequences of characterized HPV types were included from HPV4, HPV5, HPV8, HPV9, HPV12, HPV14, HPV15, HPV17, HPV19, HPV20, HPV21, HPV22, HPV23, HPV24, HPV25, HPV36, HPV37, HPV38, HPV47, HPV48, HPV49, HPV50, HPV60, HPV65, HPV75, HPV76, HPV80, HPV88, HPV92, HPV93, HPV95, HPV96, HPV101, HPV103 and RTRX7. Members of the genus Gammapapillomavirus have been shown to have a phylogenetic position adjacent to some animal papillomaviruses (de Villiers et al., 2004), and their FA sequences were therefore included as an outgroup: hamster oral papillomavirus (HaOPV; GenBank accession no. E15110
[GenBank]
), Phocoena spinipinnis papillomavirus (PsPV; AJ238373
[GenBank]
), bovine papillomavirus 3 (BPV3; NC_004197
[GenBank]
), BPV4 (X05817
[GenBank]
) and BPV6 (AJ620208
[GenBank]
).
The average size of the subgenomic fragments was 438 nt (range, 424–449 nt) without primer sequences. For all sequences, one N was added to the first nucleotide to make up a triplet and sequences were aligned by CLUSTAL_W using BioEdit (Hall, 1999). Then, sequences were edited manually to repair disrupted codons of amino acids. Aligned sequences were converted to the format of MEGA version 2.1 (Kumar et al., 2001). A neighbour-joining tree was generated by the Tamura three-parameter (Tamura-3) algorithm, using pairwise deletions of gaps, and bootstrap values were estimated on 1000 replicates. The aligned sequences were also used to calculate a pairwise sequence identity matrix using BioEdit.
In order to investigate the taxonomic validity of the FA sequence, it was compared with the L1 sequence of HPV by pairwise comparisons with corresponding sequences of 24 characterized HPV types within the genus Betapapillomavirus. The mean difference of nucleotide identity was 1.4 % (range, 0–4 %) across the genus Betapapillomavirus between the FA sequence and the L1 sequence of HPV5. The corresponding analysis of HPV4 with eight HPV types across the genus Gammapapillomavirus showed a mean difference of 1.1 % (range, 0–2 %). This is in agreement with that of Hazard et al. (2007a), reporting a mean difference of 1.1 % between the FA sequence and the L1 sequence. Comparative analysis of trees based on the FA sequence and the L1 for 34 HPV types within the genera Betapapillomavirus and Gammapapillomavirus demonstrated largely congruent tree topologies (Fig. 2a, b). The bootstrap values were generally high for both the FA sequences and the entire L1 sequences, although they were slightly lower for the FA sequences. Thus, the comparable results suggest that the FA sequence is representative for phylogenetic analysis.
|
). The right part of the tree harbours HPVs of the genus Betapapillomavirus, with 36 putative HPV types (including RTRX7) and 25 characterized HPV types, comprising a total of 61 HPV types/putative types (Fig. 2c). The left part of the tree displays HPVs of the genus Gammapapillomavirus, with 97 putative HPV types and nine characterized HPV types, thus with a total of 106 HPV types/putative types (Fig. 2c). The bootstrap values were generally high for the nodes of the betapapillomaviruses (Fig. 2d), whereas for the gammapapillomaviruses, several of the nodes had bootstrap values of <70 %, indicating less powerful discrimination within this genus (Fig. 2e). Comparative analysis of trees generated by the Tamura-3 distance model/neighbour-joining tree and by the maximum-likelihood algorithm by PhyML (Guindon & Gascuel, 2003) revealed very similar and congruent topologies (data not shown), further supporting the adequacy of the presented tree (Fig. 2c).
HPV types within a species share between 71 and 89 % nucleotide identity of the complete L1 sequence (de Villiers et al., 2004). Among the 36 putative HPV types clustered in the tree within the species Beta-1, -2, -3 or -5, nucleotide identities to the HPV type representing each species were generally >71 % (Table 1). Among the 97 putative HPV types within the genus Gammapapillomavirus, only FA41 and FA104 were grouped within species 1, and FA27 and FA58 were within species 2 (Table 1). The other 93 putative HPV types demonstrated mean sequence identities of <71 % to the HPV types representing each species (Table 1). Thus, the vast majority of the putative HPV types within the genus Gammapapillomavirus were segregated outside the defined species. Accumulation of complete L1 gene sequence information from these putative HPV types would probably allow additional species in the genus Gammapapillomavirus to be defined.
|
). Comparative analysis of the FA sequences of HPV101 and HPV103 demonstrated 63 and 61 % nucleotide identity to HPV4 (species 1), respectively (Table 1). They probably belong to a separate species within the genus Gammapapillomavirus because, within a genus, an HPV type of a species shares 60–70 % nucleotide identity to an HPV type in another species (de Villiers et al., 2004). However, the FA sequences of these HPV types also showed nucleotide identities of 60 and 61 % to HaOPV (Table 1), which may indicate that these HPV types overlap between the genera Gammapapillomavirus and Pipapillomavirus (HaOPV), as has been proposed previously (Chen et al., 2006).
The included animal papillomaviruses formed a branch separated from the gamma- and betapapillomaviruses (Fig. 2c). In addition, pairwise nucleotide comparisons demonstrated that the animal papillomaviruses within the genera Omicronpapillomavirus and Xipapillomavirus had <60 % sequence identities to the gamma- and betapapillomaviruses, although those of the genera Xipapillomavirus showed identities of about 60 % to species Beta-1 (Table 1).
It was also noted that the majority of the putative HPV types had been initially isolated from healthy skin (83 %, 105/127) compared with lesions (17 %, 22/127). This observation strengthens the earlier suggestion of a commensal nature of the cutaneous HPVs (Antonsson et al., 2000).
The mucosal HPV types, such as HPV16 and others within the genus Alphapapillomavirus, comprise about 60 HPV types/putative types (de Villiers et al., 2004). Thus, it appears that HPV types/putative types of the genera Betapapillomavirus and Gammapapillomavirus with cutaneous tropism substantially outnumber those with mucosal tropism. Albeit, additional HPV types within the genus Alphapapillomavirus might be discovered in future. The evolutionary basis for the larger genetic diversity within the genera Betapapillomavirus and Gammapapillomavirus is unknown. Speculatively, UV light-induced damage may contribute to a higher mutation rate of the sun-exposed papillomaviruses of the skin. Moreover, genetic variation of cutaneous papillomaviruses also appears to be common on skin of other mammals (Antonsson & Hansson, 2002).
In summary, the present survey demonstrates a large genetic diversity within the genera Betapapillomavirus and Gammapapillomavirus and suggests that the majority of the putative HPV types within the genus Gammapapillomavirus appear to be segregated outside the defined species.
|
ACKNOWLEDGEMENTS |
|---|
|
REFERENCES |
|---|
|
TOPABSTRACTMAIN TEXTREFERENCES |
|---|
Antonsson, A. & Hansson, B. G. (2002). Healthy skin of many animal species harbors papillomaviruses which are closely related to their human counterparts. J Virol 76, 12537–12542.
Antonsson, A., Forslund, O., Ekberg, H., Sterner, G. & Hansson, B. G. (2000). The ubiquity and impressive genomic diversity of human skin papillomaviruses suggest a commensalic nature of these viruses. J Virol 74, 11636–11641.
Antonsson, A., Erfurt, C., Hazard, H., Holmgren, V., Simon, M., Kataoka, A., Hossin, S., Håkangård, C. & Hansson, B. G. (2003a). Prevalence and type spectrum of human papillomaviruses in healthy skin samples collected in three continents. J Gen Virol 84, 1881–1886.
Antonsson, A., Karanfilovska, S., Lindqvist, P. G. & Hansson, B. G. (2003b). General acquisition of human papillomavirus infections of skin occurs in early infancy. J Clin Microbiol 41, 2509–2514.
Astori, G., Lavergne, D., Benton, C., Hockmayr, B., Egawa, K., Garbe, C. & de Villiers, E. M. (1998). Human papillomaviruses are commonly found in normal skin of immunocompetent hosts. J Invest Dermatol 110, 752–755.[CrossRef][Medline]
Berkhout, R. J., Tieben, L. M., Smits, H. L., Bavinck, J. N., Vermeer, B. J. & ter Schegget, J. (1995). Nested PCR approach for detection and typing of epidermodysplasia verruciformis-associated human papillomavirus types in cutaneous cancers from renal transplant recipients. J Clin Microbiol 33, 690–695.[Abstract]
Berkhout, R. J., Bouwes Bavinck, J. N. & ter Schegget, J. (2000). Persistence of human papillomavirus DNA in benign and (pre)malignant skin lesions from renal transplant recipients. J Clin Microbiol 38, 2087–2096.
Boxman, I. L., Berkhout, R. J., Mulder, L. H., Wolkers, M. C., Bouwes Bavinck, J. N., Vermeer, B. J. & ter Schegget, J. (1997). Detection of human papillomavirus DNA in plucked hairs from renal transplant recipients and healthy volunteers. J Invest Dermatol 108, 712–715.[CrossRef][Medline]
Boxman, I. L., Russell, A., Mulder, L. H., Bavinck, J. N., Schegget, J. T. & Green, A. (2000). Case-control study in a subtropical Australian population to assess the relation between non-melanoma skin cancer and epidermodysplasia verruciformis human papillomavirus DNA in plucked eyebrow hairs. The Nambour Skin Cancer Prevention Study Group. Int J Cancer 86, 118–121.[CrossRef][Medline]
Chen, Z., Schiffman, M., Herrero, R., Desalle, R. & Burk, R. D. (2006). Human papillomavirus (HPV) types 101 and 103 isolated from cervicovaginal cells lack an E6 open reading frame (ORF) and are related to gamma-papillomaviruses. Virology 360, 447–453.[Medline]
de Jong-Tieben, L. M., Berkhout, R. J., ter Schegget, J., Vermeer, B. J., de Fijter, J. W., Bruijn, J. A., Westendorp, R. G. & Bouwes Bavinck, J. N. (2000). The prevalence of human papillomavirus DNA in benign keratotic skin lesions of renal transplant recipients with and without a history of skin cancer is equally high: a clinical study to assess risk factors for keratotic skin lesions and skin cancer. Transplantation 69, 44–49.[CrossRef][Medline]
de Villiers, E. M., Lavergne, D., McLaren, K. & Benton, E. C. (1997). Prevailing papillomavirus types in non-melanoma carcinomas of the skin in renal allograft recipients. Int J Cancer 73, 356–361.[CrossRef][Medline]
de Villiers, E.-M., Fauquet, C., Broker, T. R., Bernard, H.-U. & zur Hausen, H. (2004). Classification of papillomaviruses. Virology 324, 17–27.[CrossRef][Medline]
Forslund, O., Antonsson, A., Nordin, P., Stenquist, B. & Hansson, B. G. (1999). A broad range of human papillomavirus types detected with a general PCR method suitable for analysis of cutaneous tumours and normal skin. J Gen Virol 80, 2437–2443.
Forslund, O., Ly, H. & Higgins, G. (2003a). Improved detection of cutaneous human papillomavirus DNA by single tube nested ‘hanging droplet’ PCR. J Virol Methods 110, 129–136.[CrossRef][Medline]
Forslund, O., Ly, H., Reid, C. & Higgins, G. (2003b). A broad spectrum of human papillomavirus types is present in the skin of Australian patients with non-melanoma skin cancers and solar keratosis. Br J Dermatol 149, 64–73.[CrossRef][Medline]
Forslund, O., Lindelof, B., Hradil, E., Nordin, P., Stenquist, B., Kirnbauer, R., Slupetzky, K. & Dillner, J. (2004). High prevalence of cutaneous human papillomavirus DNA on the top of skin tumors but not in "stripped" biopsies from the same tumors. J Invest Dermatol 123, 388–394.[CrossRef][Medline]
Fredricks, D. N. (2001). Microbial ecology of human skin in health and disease. J Investig Dermatol Symp Proc 6, 167–169.[CrossRef][Medline]
Guindon, S. & Gascuel, O. (2003). A simple, fast, and accurate algorithm to estimate large phylogenies by maximum likelihood. Syst Biol 52, 696–704.[CrossRef][Medline]
Hall, T. A. (1999). BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/. Nucleic Acids Symp Ser 41, 95–98.
Harwood, C. A., Spink, P. J., Surentheran, T., Leigh, I. M., de Villiers, E. M., McGregor, J. M., Proby, C. M. & Breuer, J. (1999). Degenerate and nested PCR: a highly sensitive and specific method for detection of human papillomavirus infection in cutaneous warts. J Clin Microbiol 37, 3545–3555.
Harwood, C. A., Surentheran, T., McGregor, J. M., Spink, P. J., Leigh, I. M., Breuer, J. & Proby, C. M. (2000). Human papillomavirus infection and non-melanoma skin cancer in immunosuppressed and immunocompetent individuals. J Med Virol 61, 289–297.[CrossRef][Medline]
Harwood, C. A., Surentheran, T., Sasieni, P., Proby, C. M., Bordea, C., Leigh, I. M., Wojnarowska, F., Breuer, J. & McGregor, J. M. (2004). Increased risk of skin cancer associated with the presence of epidermodysplasia verruciformis human papillomavirus types in normal skin. Br J Dermatol 150, 949–957.[CrossRef][Medline]
Hazard, K., Andersson, K., Dillner, J. & Forslund, O. (2007a). Human papillomavirus subtypes are not uncommon. Virology 362, 6–9.[CrossRef][Medline]
Hazard, K., Karlsson, A., Andersson, K., Ekberg, H., Dillner, J. & Forslund, O. (2007b). Cutaneous human papillomaviruses persist on healthy skin. J Invest Dermatol 127, 116–119.[CrossRef][Medline]
Hopfl, R., Bens, G., Wieland, U., Petter, A., Zelger, B., Fritsch, P. & Pfister, H. (1997). Human papillomavirus DNA in non-melanoma skin cancers of a renal transplant recipient: detection of a new sequence related to epidermodysplasia verruciformis associated types. J Invest Dermatol 108, 53–56.[CrossRef][Medline]
Iftner, A., Klug, S. J., Garbe, C., Blum, A., Stancu, A., Wilczynski, S. P. & Iftner, T. (2003). The prevalence of human papillomavirus genotypes in nonmelanoma skin cancers of nonimmunosuppressed individuals identifies high-risk genital types as possible risk factors. Cancer Res 63, 7515–7519.
Kumar, S., Tamura, K., Jakobsen, I. B. & Nei, M. (2001). MEGA2: molecular evolutionary genetics analysis software. Bioinformatics 17, 1244–1245.
Lörincz, A. T., Reid, R., Jenson, A. B., Greenberg, M. D., Lancaster, W. & Kurman, R. J. (1992). Human papillomavirus infection of the cervix: relative risk associations of 15 common anogenital types. Obstet Gynecol 79, 328–337.[Medline]
Meyer, T., Arndt, R., Christophers, E. & Stockfleth, E. (2000). Frequency and spectrum of HPV types detected in cutaneous squamous-cell carcinomas depend on the HPV detection system: a comparison of four PCR assays. Dermatology 201, 204–211.[CrossRef][Medline]
Meyer, T., Arndt, R., Christophers, E., Nindl, I. & Stockfleth, E. (2001). Importance of human papillomaviruses for the development of skin cancer. Cancer Detect Prev 25, 533–547.[Medline]
Nordin, P., Hansson, B. G., Hansson, C., Blohmé, I., Larkö, O. & Andersson, K. (2007). Human papillomavirus in skin, mouth and uterine cervix in female renal transplant recipients with or without a history of cutaneous squamous cell carcinoma. Acta Derm Venereol 87, 219–222.[Medline]
Orth, G. (1986). Epidermodysplasia verruciformis: a model for understanding the oncogenicity of human papillomaviruses. Ciba Found Symp 120, 157–174.[Medline]
Pfister, H., Fuchs, P. G., Majewski, S., Jablonska, S., Pniewska, I. & Malejczyk, M. (2003). High prevalence of epidermodysplasia verruciformis-associated human papillomavirus DNA in actinic keratoses of the immunocompetent population. Arch Dermatol Res 295, 273–279.[CrossRef][Medline]
Shamanin, V., Delius, H. & de Villiers, E. M. (1994a). Development of a broad spectrum PCR assay for papillomaviruses and its application in screening lung cancer biopsies. J Gen Virol 75, 1149–1156.
Shamanin, V., Glover, M., Rausch, C., Proby, C., Leigh, I. M., zur Hausen, H. & de Villiers, E. M. (1994b). Specific types of human papillomavirus found in benign proliferations and carcinomas of the skin in immunosuppressed patients. Cancer Res 54, 4610–4613.
Shamanin, V., zur Hausen, H., Lavergne, D., Proby, C. M., Leigh, I. M., Neumann, C., Hamm, H., Goos, M., Haustein, U. F. & other authors (1996). Human papillomavirus infections in nonmelanoma skin cancers from renal transplant recipients and nonimmunosuppressed patients. J Natl Cancer Inst 88, 802–811.
Wieland, U., Ritzkowsky, A., Stoltidis, M., Weissenborn, S., Stark, S., Ploner, M., Majewski, S., Jablonska, S., Pfister, H. J. & Fuchs, P. G. (2000). Communication: papillomavirus DNA in basal cell carcinomas of immunocompetent patients: an accidental association? J Invest Dermatol 115, 124–128.[CrossRef][Medline]
Received 7 February 2007;
accepted 6 June 2007.
This article has been cited by other articles:
|
|
 |
|
  M. N. C. de Koning, S. J. Weissenborn, D. Abeni, J. N. Bouwes Bavinck, S. Euvrard, A. C. Green, C. A. Harwood, L. Naldi, R. Neale, I. Nindl, et al. Prevalence and associated factors of betapapillomavirus infections in individuals without cutaneous squamous cell carcinoma J. Gen. Virol., July 1, 2009; 90(7): 1611 - 1621. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Vasiljevic, K. Hazard, J. Dillner, and O. Forslund Four novel human betapapillomaviruses of species 2 preferentially found in actinic keratosis J. Gen. Virol., October 1, 2008; 89(10): 2467 - 2474. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| INT J SYST EVOL MICROBIOL | MICROBIOLOGY | J GEN VIROL |
| J MED MICROBIOL | ALL SGM JOURNALS | |
71.0 %, classifying putative HPV types in a species.