Chapter 185

### Definition

Human papillomaviruses (HPVs) selectively infect the epithelium of skin and mucous membranes. These infections may be asymptomatic, produce warts, or be associated with a variety of both benign and malignant neoplasias.

### Etiologic Agent

Papillomaviruses constitute the Papillomavirus genus of the family Papillomaviridae. They are nonenveloped, measure 50–55 nm in diameter, have icosahedral capsids composed of 72 capsomeres, and contain a double-strand circular DNA genome of ∼7900 base pairs. The genomic organization of all papillomaviruses is similar and consists of an early (E) region, a late (L) region, and a noncoding upstream regulatory region (URR). Oncogenic HPV types can immortalize human keratinocytes, and this activity has been mapped to products of early genes E6 and E7. E6 protein facilitates the degradation of the p53 tumor-suppressor protein, and E7 protein binds the retinoblastoma gene product and related proteins. The E1 and E2 proteins modulate viral DNA replication and regulate gene expression. The L1 gene codes for the major capsid protein, which makes up 80% of the virion mass. L2 codes for a minor capsid protein. Type-specific conformational antigenic determinants are located on the virion surface. Papillomavirus types are distinguished from one another by the degree of nucleic acid sequence homology. Distinct types share <90% of their DNA sequences in L1. More than 100 HPV types are recognized, and individual types are associated with specific clinical manifestations. For example, HPV-1 causes plantar warts, HPV-6 causes anogenital warts, and HPV-16 infection can produce cervical dysplasia and invasive cervical cancer. HPVs are species-specific and have not been propagated in routine tissue culture or in common experimental animals. However, some HPV types have been propagated in organotypic culture systems, and some have been produced in human tissues implanted in immunodeficient mice.

### Epidemiology

There are few good studies of the incidence or prevalence of human warts in well-defined populations. Common warts (verruca vulgaris) are found in as many as 25% of some groups and are most prevalent among young children. Plantar warts (verruca plantaris) are also widely prevalent; they occur most often among adolescents and young adults. Anogenital warts (condyloma acuminatum) represent one of the most common sexually transmitted diseases in the United States. HPV infection of the uterine cervix produces the squamous cell abnormalities most frequently detected on Papanicolaou smears.

Most anogenital HPV infections are transmitted through direct contact with infectious lesions. However, lesion characteristics that are associated with transmission, including appearance, have not been defined, and individuals without obvious disease may transmit infection. Close personal contact is also assumed to play a role in the transmission of most cutaneous warts; the importance of fomites in this setting is not clear. Minor trauma at the site of inoculation may facilitate transmission. Recurrent respiratory papillomatosis in young children is an uncommon disease that is acquired from the infected maternal genital tract. In adults, orogenital sexual contact may transmit the disease.

A large body of epidemiologic and biologic data has established that some HPV infections cause cervical cancer. For example, >95% of cervical cancers contain HPV DNA of oncogenic (high-risk) types, such as 16, 18, 31, 33, and 45. HPV DNA is also present in the precursor lesions of cervical cancer (cervical intraepithelial neoplasias). Such lesions containing DNA of oncogenic types are more likely to progress than those associated with low-risk HPV types, such as 6 and 11. ...

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