Human papillomavirus
Infection with the human papillomavirus (HPV) is the most common sexually transmitted infection (STI) in the world. HPV is a wily pathogen that causes a spectrum of clinical diseases, all of which involve cutaneous or mucosal squamous surfaces. From the evolutionary standpoint, HPVs are very successful infectious agents because they induce chronic infections that have no systemic sequelae and rarely kill the host. Instead they periodically shed large amounts of infectious virus for transmission to naïve individuals.
The broad spectrum of genital HPV infection includes: (i) latent infection; (ii) clinically apparent lesions (condylomata accuminata, warts); and (iii) HPV-associated neoplasia. Latent infections are identified by the presence of HPV DNA in tissue samples acquired for epidemiologic study. In the absence of tissue collection, latent infections would go unrecognized because neither microscopic nor visible lesions are present. Overt genital warts, also known as condyloma acuminata, are flesh-colored, pink or pigmented papules with a frond-like surface. Sessile warts, or flat condyloma-like lesions, are less common, accounting for only 20% of visible genital warts. Most genital warts in men are on the penis. In women, they are found most often at the vaginal introitus and on the labia. Most genital warts are asymptomatic. When symptoms do occur, they are often secondary to local friction-induced irritation from clothing or intercourse. HPV-associated neoplasias include intraepithelial lesions of the cervix (CIN) and vulva (VIN) and invasive carcinomas at both sites. Cervical cancer is discussed in detail in Chapter 44.
Because most genital warts are sexually transmitted, their presence indicates risk for other STIs. Treatment of genital warts involves cryotherapy or topical application of agents that cause cytolysis.
Epidemiology of HPV
The primary risk factor for HPV infection is sexual activity. It is estimated that 75% of sexually active women will acquire latent HPV infection. Fortunately, most HPV infections are transient; up to 90% of infections in women will resolve spontaneously within 2 years of acquisition. Unfortunately, persistent infection is more common with HPV genotypes that have neoplastic potential.
Although rare, it is possible to acquire HPV through nonsexual transmission. Neonates can become infected during delivery.
Biology of human papillomaviruses
HPV is a member of the Papovaviridae family of DNA viruses. Other well-known members of this family are the polyomaviruses (polio virus and SV40). Of the 130 different HPV genotypes identified to date, about 40 are associated with genital lesions. Types 6 and 11 are most commonly identified in genital warts, and types 16 and 18 are most closely associated with neoplasia (high-risk subtypes). HPV subtypes 1–5 are associated with common skin warts and plantar warts.
The success of HPV as an infectious agent is directly linked to a virus replication cycle that effectively evades immunologic detection by the host. The virus infects primitive keratinocytes in the basal layers of squamous epithelia followed by a round of viral DNA replication that appears independent of the host cell cycle (Fig. 47.1). Once the infected keratinocyte enters the proliferative compartment of the epithelium, viral gene expression is minimal. The oncogenes E6 and E7 are highly repressed by the viral genes E1 and E2 until the infected keratinocyte exits the cell cycle and enters the uppermost differentiating compartment (Table 47.1). Thus, high levels of viral protein synthesis and assembly only occur in the upper layers of the squamous epithelium. In this infectious cycle, the virus hitches a ride in the keratinocyte at the beginning of its journey and replicates in cells that will terminally differentiate and die by natural causes. Thus, there is no viral-induced cytolysis, necrosis or inflammation. Because there is no blood-borne phase of the HPV life cycle and only minimal amounts of replicating virus are exposed to immune defense, the virus is essentially invisible to the host. It is only when host integration occurs with E1 and E2 disruption, that E6 and E7 are overexpressed. E6 and E7 are capable of interfering with important tumor suppressor proteins in the host cell. Their overexpression is associated with neoplastic transformation, explaining the oncogenic potential of HPV.
Table 47.1 Important human papillomavirus (HPV) genes
| E1* | Necessary for viral DNA replication |
| May have a role as a repressor of immortalization | |
| E2* | Necessary for viral DNA replication along with E1 |
| E6† | Interacts with p53; transforming signal |
| E7† | Interacts with Rb-1; strong transforming signal |
| L1 | Major capsid protein |
| L2 | Minor capsid protein |
* Mutations in E1 and/or E2 result in integration of viral DNA into host DNA.
† Disruption of growth regulation necessary to propagate virus.
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