Papillomaviruses have evolved over many millions of years to propagate themselves at specific epithelial niches in a range of different host species. This has led to the great diversity of papillomaviruses that now exist, and to the appearance of distinct strategies for epithelial persistence. Many papillomaviruses minimise the risk of immune clearance by causing chronic asymptomatic infections, accompanied by long-term virion-production with only limited viral gene expression. Such lesions are typical of those caused by Beta HPV types in the general population, with viral activity being suppressed by host immunity. A second strategy requires the evolution of sophisticated immune evasion mechanisms, and allows some HPV types to cause prominent and persistent papillomas, even in immune competent individuals. Some Alphapapillomavirus types have evolved this strategy, including those that cause genital warts in young adults or common warts in children. These strategies reflect broad differences in virus protein function as well as differences in patterns of viral gene expression, with genotype-specific associations underlying the recent introduction of DNA testing, and also the introduction of vaccines to protect against cervical cancer. Interestingly, it appears that cellular environment and the site of infection affect viral pathogenicity by modulating viral gene expression. With the high-risk HPV gene products, changes in E6 and E7 expression are thought to account for the development of neoplasias at the endocervix, the anal and cervical transformation zones, and the tonsilar crypts and other oropharyngeal sites. A detailed analysis of site-specific patterns of gene expression and gene function is now prompted.

Animal papillomaviruses are widely used as models to study papillomavirus infection in humans despite differences in genome organization and tissue tropism. Here, we have investigated the extent to which animal models of papillomavirus infection resemble human disease by comparing the life cycles of 10 different papillomavirus types. Three phases in the life cycles of all viruses were apparent using antibodies that distinguish between early events, the onset of viral genome amplification, and the expression of capsid proteins. The initiation of these phases follows a highly ordered pattern that appears important for the production of virus particles. The viruses examined included canine oral papillomavirus, rabbit oral papillomavirus (ROPV), cottontail rabbit papillomavirus (CRPV), bovine papillomavirus type 1, and human papillomavirus types 1, 2, 11, and 16. Each papillomavirus type showed a distinctive gene expression pattern that could be explained in part by differences in tissue tropism, transmission route, and persistence. As the timing of life cycle events affects the accessibility of viral antigens to the immune system, the ideal model system should resemble human mucosal infection if vaccine design is to be effective. Of the model systems examined here, only ROPV had a tissue tropism and a life cycle organization that resembled those of the human mucosal types. ROPV appears most appropriate for studies of the life cycles of mucosal papillomavirus types and for the development of prophylactic vaccines. The persistence of abortive infections caused by CRPV offers advantages for the development of therapeutic vaccines.

We have previously demonstrated, by the combined application of two degenerate polymerase chain reaction primer sets, the presence of human papillomavirus (HPV) DNA in 91% of cutaneous squamous cell cancers from renal allograft recipients, with multiple types being present in one-third of these tumors. Five HPV types--HPV 20, HPV 23, HPV 38, DL40, and DL267--accounted for 73% of positive results. These HPV types are all related to the epidermodysplasia verruciformis group, and HPV 38 was originally isolated from a melanoma. The aims of this study were to determine: (i) whether HPV DNA could readily be demonstrated in skin tumors, as well as in perilesional skin, of immunocompetent patients using two polymerase chain reaction primer sets; (ii) the prevalence of infections in normal skin; and (iii) the prevalence of HPV 38 or HPV 38 related viruses in melanoma. The HPV types detected in lesions from renal allograft recipient were present not only in the perilesional skin and tumors of immunocompetent patients, but also in 35% of normal skin biopsies. HPV DNA was present in 13% of the melanoma samples, but none harbored HPV 38 DNA. We identified four putatively new HPV types. Infections with different types of human papillomavirus are widespread and often occur in clinically normal skin. In vitro studies are required to determine the specific molecular mechanisms by which these HPV types may be involved in the etiology of nonmelanoma skin cancer.

Two new types of intracytoplasmic inclusion bodies (ICBs) associated with distinct clinical features, and the presence of DNA of distinct types of human papillomaviruses (HPVs) are reported. One hundred and seven cutaneous warts containing ICBs were grouped into three categories according to distinct clinicopathological features: 67 were wart lesions with well-known granular (Gr)-ICB, 13 were punctate keratotic lesions with filamentous (Fl)-ICB and 31 were pigmented warts with homogeneous (Hg)-ICB. Molecular biological studies were performed in order to assess a specific association of each group of warts with distinct types of HPV. HPV-1 DNA sequences were detected in all the lesions with a Gr-ICB. Punctate keratotic lesions with Fl-ICB were associated with HPV-63, which was newly cloned from such a lesion. One of the samples also contained HPV-1 DNA. Pigmented warts with Hg-ICBs contained one of the related HPVs, i.e. HPV-4, HPV-60 or a novel type of HPV, HPV-65. Based on these associations, a classification of inclusion warts is proposed.

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Human papillomavirus types 2 (HPV-2), HPV-27, and HPV-57, are three closely related viruses within the phylogenetic supergroup formed by the remotely related genital papillomaviruses. In contrast to this phylogenetic association, these three viruses are most often found in common warts at nongenital sites, but also occasionally in genital warts and mucosal lesions of the nasopharyngeal cavity. We studied the genomic diversity of HPV sequences in skin warts presumably caused by these viruses. These biopsies were sampled from 75 patients living in Germany, Japan, or Singapore. Among 27 warts with HPV-2, we found seven new genomic variants and among 32 with HPV-57, eight new variants. In both cases, we did not detect the original prototype genomes. In contrast, 13 of 16 warts with HPV-27 contained the prototype genome, and only one new variant was found in three patients. We did not find variants clearly intermediate between any two types, although HPV-2 and HPV-27 are among the most closely related of the extent HPV types. We also did not detect novel HPV types, although the samples were examined with polymerase chain reaction protocols that would have detected remotely related HPVs. So we propose that the phylogenetic group formed by HPV-2, HPV-27, and HPV-57 has no or only very are additional members. One of the HPV-57 variants found, HPV-57-G44, was most likely identical to the subtype HPV-57b, previously proposed to be associated with nasal neoplasia, but found here frequently in common skin warts. Our publication establishes a foundation for pathological and phylogenetic comparisons of HPV types in skin warts.

Summary Although epidermoid cysts of the palms and soles have long been assumed to develop following implantation of an epidermal fragment as a result of a penetrating injury, the pathogenic mechanism is still controversial, and the discovery of a more common aetiological agent is awaited. Clinical, histological, immunohistochemical and molecular biological studies were performed on 119 epidermoid cysts of palmoplatitur location, in order to examine the rote of the eccrine ducts, and human papillomavirus (HPV), in the pathogenesis of this disorder. Characteristic histological features were found, including intracytoplasmic eosinophilic bodies (ICB: in 14 cases. 12%) in the cyst wall, vacuolar structures (V: in 28 cases, 24%), or parakeratotic nuclei (P: in 85 cases. 71%) within the keratinous mass in the cyst cavity. Ductal structures suggesting eccrine ducts (E: in 63 cases, 53%) were also found in the cyst wall or in the cyst cavity. Hither ductal structures or carcinoembryonic antigen expression (66 cases, 55%) were noted in a total of 73 cases (61%). Papillomavirus common antigens were detected in 36 cases (30%) showing one or more of the three distinct histological features, i.e. ICB, V and P, Subsequently, hybridization experiments to detect HPV DNA were performed in 47 cases, revealing an association between cysts showing ICB or V and the presence of HPV 60 DNA sequences. On the basis of our results, we propose that epidermoid cysts in the palmoplantar regions may develop from eccrine ducts, and that HPV and injury may play a role in their pathogenesis.

Little is known about the target cells of human papillomaviruses (HPVs). The clinical and histological analyses of very early lesions of palmoplantar warts indicate that not only the warts initially developed exclusively in the ridges of the skin, but also that the initial histological changes were restricted to the deep ridges of the epidermis, where epidermal stem cells are thought to exist in the palmoplantar skin. This suggests that HPV infection targets the stem cells.