Papillomavirus

Epitheliotropic, naked double-stranded DNA viruses. Human papillomaviruses belong to the human pathogenic genus papillomavirus, which includes the species human papillomavirus. Papillomaviruses have a size of 55 nm. They infect the squamous epithelia of skin and mucosa. Target cells are the basal cells of the epithelia. The receptors on the basal cells are not yet known (integrins, heparan sulfate substituted proteoglycans?).

Currently, > 170 different HPV subtypes are known. Some cause benign epithelial tumors in humans and animals (e.g., verrucae planae juveniles, verrucae vulgares, verrucae plantares, condylomata acuminata). Others are associated with genital or extragenital carcinomas(cervical carcinoma, periungual carcinomas).

HPV are assigned to 5 supergroups (A-E) based on their sequence relatedness (see Fig.). Here, HPV infecting the mucosa form group A, while HPV infecting the skin belong to groups B and E.

A distinction is made between manifest, subclinical and latent infection (virus persistence in basal keratinocytes).

The circular genome comprises 7,500-8,000 base pairs. The genome is packaged in an icosahedral capsid. The capsid is composed of the two structural proteins L1 and L2, with L1 being the major capsid. All protein-coding sequences are located on one DNA strand.

The site of origin of the replication of the viral genome in the infected host cell is the 400-1,000 base pair LCR region (LCR = long control region). Downstream follow the translation reading frames E1-E7 (E = early), which encode proteins required for viral DNA replication, transcription and cell transformation. This is followed by 2 reading frames required for structural proteins L1 and L2 (L = late). The viral genomes are transcribed into numerous, distinct mRNA molecules starting from multiple promoters. The promoter activity is controlled by several viral and cellular factors.

Papova group viruses (HPV). HPV 16, 18, 31, 45 are considered to be at high risk of carcinoma (detected in 5% invasively growing cervical carcinomas), HPV 33, 35, 39 at intermediate risk (detected in 1-5% invasively growing cervical carcinomas) and HPV 6, 11, 42, 43, 44 at lower risk (only rarely detected in invasively growing cervical carcinomas).

HPV infection of basal cells occurs via minor lesions of the epithelium, stimulates cell proliferation, and leads to lateral as well as vertical expansion. Heparin sulfate proteoglycans (HSPGs) from the cellular surface as well as certain integrins appear to be the primary receptor for initial binding. The common binding is mediated by the last 15 amino acids from the outermost carboxyl terminus of the L1 protein. Virions enter the cell by endocytosis through the clathrin-dependent pathway. Decapsidation of the particle occurs at the endosome, releasing the capsid genome and proteins into endocytic vesicles.

Early functions of the virus delay physiological differentiation of keratinocytes. The E5 and E6/E7 genes are required for these cell transformations. The oncogenic proteins encoded there form complexes with cellular proteins involved in cell cycle control and apoptosis. E6 interacts with the tumor suppressor genes p53 and bak to inhibit apoptosis. E7 induces (uncontrolled) synthesis of cellular (host) DNA. Only extensively differentiated epithelial cells are permissive for HPV replication, show cytophagic effects ( koilocyte) and viral particles in the nucleus.

Infections caused by HPV can be identified by the clinical and histological picture. The Anti-HPV 16 L1 DRH1 test system provides a serological validation procedure for HPV-induced squamous cell carcinoma (Hilfrich R 2018)

Initial therapeutic approaches (phase II or phase III trials) for prophylactic treatment with an HPV 16 and HPV 16/-18 vaccine (vaccination with HPV-16/18 L1 viruslike particle) were successful in women. Meanwhile, a multicenter study using a quadrivalent HPV vaccine in young women aged 16-26 years showed a significant decrease in HPV 6, 11, 16 and 18 induced infections. Precancerous dysplasia or genital warts were not observed. Approval in the EU for the vaccine Gardasil (MSD) was given at the end of 2006. Approval for a bivalent HPV-16/18 vaccine (GlaxoSmithKline) was granted in 2008. Currently, some statutory health insurers in Germany cover the costs of treatment for young women aged 9-15 years.

General hygiene measures (e.g. surface disinfection in public baths).

Early sexual activity and many partners increase the risk of HPV infection of the cervix in women. Immunocompressed, e.g. transplant recipients and HIV-infected persons, develop more persistent HPV-induced tumours, which degenerate more rapidly into malignant tumours. HPV 13 and 32 induce focal epithelial hyperplasia more frequently in certain ethnic groups (Native Americans; Inuit). HPV infection in men increases the risk of miscarriage.

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2. Bzhalava D et al. (2015) International standardization and classification of human papillomavirus types. Virology 476:341-344.
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4. Ockenfels HM (2016) Therapeutic management of cutaneous and genital warts. J Dtsch Dermatol Ges 14:892-899.
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