Gulshan Sethi Human papilloma viruses (HPVs) are small non‐enveloped double‐stranded DNA viruses that infect the basal epithelial cells of skin and mucous membranes. There are over 100 different subtypes that are responsible for a wide variety of benign and malignant lesions. Types 6 and 11 (‘low‐risk’ types) are the causative agents of anogenital warts (condylomata acuminata) and have little or no potential for malignant transformation, whereas types 16, 18, 31, 33, 45, and 51 (‘high‐risk’ types) have significant potential to cause malignant change and are implicated in the aetiology of cervical and anal cancers. HPV16 and 18 are responsible for the majority of high‐grade squamous intraepithelial lesions (HSILs; see Chapter 40). HPV16 is the most prevalent of the high‐risk types and is seen in at least half of all cases of invasive cervical carcinomas worldwide and many vulval cancers. The new classification of intraepithelial lesions includes genital warts as low‐grade squamous intraepithelial lesions (LSIL) [1]. HPV infection is the commonest viral sexually acquired disease worldwide. It is estimated that 80–85% of unvaccinated individuals will be infected with one or more HPV types during their lifetime [2]. The prevalence of HPV infection varies from country to country. In a study of women aged 15–74 without cytological abnormalities, from 11 countries, a prevalence range from 1.4% in Spain to 25.6% in Nigeria was demonstrated [3]. In the United Kingdom, between 2018 and 2019, there was an 11% decrease in the number of diagnoses of first‐episode genital warts from 57 311 to 51 274 [4]. This sustained decrease is largely due to the substantial reduction in incidence in younger women, the majority of whom would have received the quadrivalent HPV vaccine when aged 12 or 13 years. There is also a decline in heterosexual young men developing genital warts, probably attributable to substantial herd protection [4]. Factors associated with an increased risk of acquiring genital warts include the number of sexual partners, presence of other sexually transmitted infections, smoking, and use of the oral contraceptive pill, although some of this evidence is conflicting [5–9]. HPVs have an icosahedral capsid enclosing a circular viral genome. The genome has eight open reading frames (ORFs) which code for six early proteins (E1, E2, E4, E5, E6, and E7) and two late proteins (L1 and L2). These all have different roles in pathophysiology (Table 16.1). L1 alone or with L2 can self‐assemble into virus‐like particles (VLPs) when expressed in eukaryotic or prokaryotic expression systems. Although these VLPs lack the virus genome DNA, their morphological and immunological characteristics are very similar to those of naturally occurring HPV and have been the basis for the development of HPV vaccines [17]. Human HPVs do not possess the E3 ORF [18]. Table 16.1 HPV protein functions. Transmission occurs via direct skin‐to‐skin contact during sexual activity. Studies show that although condoms are beneficial for reducing transmission and duration of symptoms, they do not completely eliminate the risk of infection. This is likely to be because HPV may be transmitted from infected skin not covered by the condom [9, 19]. HPV is thought to gain access to the basal epithelial cells via abrasions in the skin. Once the virus enters the nucleus, its genome becomes episomal and early promoter activity begins. Here, low levels of viral DNA synthesis occur, and the expression of the viral proteins E6 and E7, important in malignant transformation, is kept in check by the E2 protein, which acts as a suppressor of transcription. Infection is initially latent, but as differentiation proceeds towards the surface, late promoter activity is stimulated, leading to the production of late gene products L1 and L2. This results in viral capsid formation and the production of complete viral particles. Clinical lesions are thought to represent the clonal expansion of a population of keratinocytes derived from a single HPV‐infected basal cell [18]. HPV infection is generally transient, with most infections being cleared within 12–18 months [20]. This suggests that the immune system is important in eradicating disease. The role of humoral immunity in HPV infection is not clear. An antibody response may be detected approximately 8 months after infection and persists for up to 40 months. Women who develop antibodies are more likely to develop persistent infection than women who do not develop antibodies, suggesting that antibodies are not protective and serve only as markers of progression [21]. In immunosuppressed individuals, multiple resistant warts are common, and difficult to treat. These individuals are at increased risk of developing anogenital cancers with the high‐risk types of HPV. The incubation period of HPV ranges from several weeks up to 18 months, but the majority of infected individuals have subclinical disease which will go unnoticed [19]. Genital HPV low‐risk types present as genital warts but may also cause lesions at extragenital sites, including the face, oropharynx, conjunctivae, and nasal cavity. Figure 16.1 Vulval and perianal papular warts.
16
Human Papillomavirus Infections
Epidemiology
Pathophysiology
Virology
Protein
Function
E1
Important for viral replication
E2
Important for viral replication and suppresses the expression of E6 and E7, which are important in malignant transformation [10,11]
E4
Codes for proteins that disrupt cytokeratin networks, resulting in the formation of koilocytes, the vacuolated squamous epithelial cells characteristic of HPV infection [12]
E5
Involved in cellular transformation and may interact with epidermal growth factor to induce cellular proliferation [13]
E6
Involved in cellular transformation via interactions with the p53 tumour suppressor gene, causing downregulation of p53 activity [14] as well as accelerated degradation of p53 [15]
E7
Involved in cellular transformation via interactions with the p53 tumour suppressor gene, causing downregulation of p53 activity [14] as well as accelerated degradation of p53 [15] and also interacts with retinoblastoma (Rb) gene proteins, increasing degradation of these proteins as well as binding to other cellular proteins, causing loss of cell cycle control [16]
L1
Encodes for the viral capsid proteins
L2
Encodes for the viral capsid proteins and is important in interactions between the virus and host cell
Transmission
Immunology
Clinical features
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