Epidermodysplasia Verruciformis Defines a Subset of Cutaneous Human Papillomaviruses

In a very interesting and provocative article, Antonsson et al. reported a high prevalence of known or as-yet-uncharacterized human papillomavirus (HPV) genotypes on the healthy skin of immunosuppressed and immunocompetent individuals, as detected by a PCR approach (1). This demonstrates unambiguously the ubiquity and great multiplicity of cutaneous HPVs, in agreement with previous reports (2–5).

Most HPV genotypes or type candidates detected by Antonsson et al. belong to a group of phylogenetically related viruses that were originally found in skin lesions of patients suffering from epidermodysplasia verruciformis (EV), a rare genodermatosis (7). The authors claim that it seems warranted to stop designating these viruses as EV-associated HPVs because of their high prevalence in healthy individuals (1, 2) and the high rate of PCR detection in skin cancers of renal transplant recipients (3). We cannot agree with this proposal because EV HPVs display very specific biologic properties that are under the control of specific cellular genes (7). Due to a recessive mutation in a gene (EV1) mapped to chromosomal region 17q25 (8), EV patients show an abnormal susceptibility to this specific group of HPVs only, including the oncogenic HPV type 5 (HPV5) (7). Infection results in pathognomonic pityriasis versicolor-like lesions, red plaques, and flat wart-like lesions. A specific cytopathic effect is linked to the high level of viral replication in differentiating keratinocytes. Invasive squamous cell carcinomas of the skin which develop in about half of the patients contain high copy numbers of HPV5 genomes and abundant transcripts of the E6 and E7 open reading frames (7). Phenocopies of EV are exceptionally observed in immunosuppressed patients (7).

The ubiquity of EV HPVs—a feature shared by all HPV genotypes—and their impressive genomic diversity led to the authors' conclusions regarding their commensalic nature (1). Our recent data strongly suggest, however, that commensalism is not the only alternative to EV (4–6). Whereas the prevalence of antibodies to HPV5 L1 capsid protein is low (2 to 5%) in the general population and in renal transplant recipients (4), HPV5 antibodies are elicited upon epidermal repair processes in patients with burns or cutaneous autoimmune bullous diseases (5). Extensive keratinocyte proliferation thus favors the expression of EV HPVs which, in turn, could enhance epidermal regeneration and be beneficial to their host. Conversely, the prevalence of HPV5 antibodies (25%) and the high PCR detection rate (85%) of HPV5 DNA, among other EV HPVs, in patients with psoriasis (4) suggest that persistent expression of EV HPV genomes might participate in the autoimmune processes of this disease (6). Psoriasis is a chronic hyperproliferative, inflammatory cutaneous disorder with a complex genetic background. The EV1 locus colocalizes with a major susceptibility locus for familial psoriasis (8). It is tempting to speculate that distinct defects affecting the same (still unknown) gene may be involved in the two skin conditions, leading to a somewhat less efficient host restriction in psoriasis (8).

We thus strongly believe that the term EV HPVs is relevant. The identification of the EV1 gene is within reach (8), and this should open new avenues for understanding the role of EV HPVs in the biology and pathology of the skin.