HUMAN PAPILLOMA VIRUSES

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Human Papilloma virus (HPV) contains a protein capsid and ds DNA, of 8 Kbp long. It transcribes early genes and the products are E6 and E7

Papillomaviruses are a family of closely related agents that infect epithelial cells either of the skin or of inner 'mucosal' surfaces.

Pathogenesis & Pathology. Transmission of viral infections occurs by close contact. Viral particles are released from the surface of papillomatous lesions. It is likely that microlesions allow infection of proliferating basal layer cells at other sites or within different hosts.

Papillomaviruses cause infections at cutaneous and mucosal sites, sometimes leading to the development of different kinds of warts, including skin warts, plantar warts, flat warts, genital condylomas, and laryngeal papillomas.

HPV genital infections are sexually transmitted and represent the most common sexually transmitted disease. An estimated 660 million people worldwide have HPV genital infections. The peak incidence of HPV infections occurs in adolescents and young adult under 25 years of age.

Cervical cancer is the second most frequent cancer in women worldwide (about 500,000 new cases annually) and is a major cause of cancer deaths in developing countries. Over 99% of cervical cancer cases are linked to genital infections with HPVs.

Papillomaviruses illustrate the concept that natural viral strains may differ in oncogenic potential. Based on the relative occurrence of viral DNA in certain cancers, HPV types 16 and 18 are considered to be high cancer risk; less common high-risk types are 30, 31, 33, 35, 39, 45, 51–53, 56, 58, 59, 66, 68, 73, and 82. Types 6, 11, 40, 42–44, 54, 61, 70, 72, and 81 are classified as low risk mucosal HPV types. Many HPV types are considered benign.

Although many different HPV types cause genital infections, HPV-16 or HPV-18 is found most frequently in cervical carcinomas, though some cancers contain DNA from other types, such as HPV type 31. Epidemiologic studies indicate that HPV-16 and HPV-18 are responsible for more than 70% of all cervical cancers.

Anal cancer is associated with high-risk HPV infection. Immunocompromised patients are especially at risk, as are men who have sex with men. Oropharyngeal cancers, a subset of head and neck squamous cell carcinomas, are also linked to HPV infections, especially by type 16.

The role of men as carriers of HPV as well as vectors for transmission of infections is well documented; however, most penile HPV infections in men are subclinical and do not result in HPV-associated disease.

Laryngeal papillomas in children, also called recurrent respiratory papillomatosis, are caused by HPV-6 and HPV-11, the same viruses that cause benign genital condylomas. The infection is acquired during passage through the birth canal of a mother with genital warts. While laryngeal papillomas are rare, the growths may obstruct the larynx and must be removed repeatedly by surgical means. About 3000 cases of this disease are diagnosed annually; up to 3% of children will die.

There is a high prevalence of HPV DNA in normal skin from healthy adults. It appears that these asymptomatic HPV infections are acquired early in infancy. A great multiplicity of HPV types are detected in normal skin. Transmission is thought to occur from those in close contact with the child, with a high concordance (about 60%) between types detected in infants and their mothers.

The behavior of HPV lesions is influenced by immunologic factors. Cell-mediated immunity is important. Nearly all HPV infections are cleared and become undetectable within 2–3 years.

Cervical cancer develops slowly, sometimes taking years to decades. It is thought that multiple factors are involved in progression to malignancy; however, persistent infection with a high-risk HPV is a necessary component to the process.

Immunosuppressed patients experience an increased incidence of warts and cancer of the cervix. All HPV-associated cancers occur more frequently in persons with HIV/AIDS.

Mechanism of transformation. The virus matches its own life cycle to the life cycle of the epithelial cells and replicates to produce new virus particles just as the cells become 'squamous' and reach the surface of the skin or mucosa. This replication causes warts (papillomas).

Most warts are benign lesions which eventually clear up, for instance common skin warts caused by HPV types 1 and 2 or genital warts caused by HPV 6 and 11. However, other genital lesions can be caused by particular 'high risk' virus types such as HPV 16 and 18.

A key step in this progression seems to be the accidental integration of viral DNA sequences into the genome of cells in the 'basal' epithelial layer, the cells in which papillomaviruses normally persist as a latent infection.

When the cells move upwards, replication to new virus particles no longer occurs and the normal progress of infection is interrupted. Integrated copies of viral DNA are usually present in cervical cancer cells, though HPV DNA is generally not integrated (episomal) in noncancerous cells or premalignant lesions. Skin carcinomas appear to harbor HPV genomes in an episomal state. Viral early proteins E6 and E7 are synthesized in cancer tissue. These are HPV transforming proteins, able to complex with tumor suppressor proteins Rb and p53 and other cellular proteins and inactivate them, thus they cause immortalization of cells.

Secondary genetic changes occurring in these latently-infected proliferating cells can then complete the oncogenic process.

Co-factors influencing the chances of progression of HPV infection in cervical cancer include cigarette smoking, higher parity, earlier age at first intercourse and immune suppression. Smoking also appears to interact with HPV in vulval cancer. Infection with certain other sexually transmitted infections may also act as a co-factor with HPV infection: A pooled analysis of case-control studies reported almost a doubling in risk of squamous cell carcinoma (SCC) of the cervix among women with evidence of infection with herpes simplex virus-2 (HSV-2) and with HPV DNA in cells compared with women positive for HPV only. HSV-2 infection has also been associated with an increased risk of anal cancer, vaginal cancer, in situ vulval cancer, and penile cancer. An international multi-centre case-control study reported a 70% risk increase for cervical SCC in HPV-positive women with antibodies to chlamydia trachomatis. In addition to HPV prevalence, these factors influence incidence rates of cervical cancer seen in different countries as does the existence of cervical screening programmes.

Prevention & Control. Vaccines against HPV are expected to be a cost-effective way to reduce anogenital HPV infections, the incidence of cervical cancer, and the HPV-associated health care burden. A quadrivalent HPV vaccine was approved in 2006. It is a noninfectious recombinant vaccine produced in yeast and containing virus-like particles composed of HPV L1 proteins. The vaccine contains particles derived from HPV types 6, 11, 16, and 18. The vaccine is effective at preventing persistent infections by the four HPV types and the development of HPV-related genital precancerous lesions. It is not effective against established HPV disease. Adolescent and young adult females make up the initial target population for vaccination. It is not known how long vaccine-induced immunity lasts.