The Human Papillomavirus (HPV)

Cervical Cancer is the second most common malignancy among women worldwide, with approximately 500,000 new cases diagnosed each year, and about 275,000 deaths per year.
Annually, 11,000 new cervical cancer cases and 4,000 deaths occur in the United states, and 52,000 new cases and 27,000 deaths occur each year in Europe (including new member states from Eastern Europe (Jemal CA Cancer J Clin 2009; Arbyn Ann Oncol 2007).

Human papillomavirus (HPV) is the most common sexually transmitted viral disease in the world and is responsible for 99.7% of cervical carcinomas (Walboomers et al., 1999). Over 100 HPV subtypes have been identified, which are divided into low- and high-risk categories, based on the risk that infection evolves to neoplasia and cancer. (Bosch et al., 2002).

Approximately 291 million women are carriers of HPV at any given time, based on recent estimates ( de San José, et. al., 2007). Of these, 14.7 million live in mature pharmaceutical markets and 78.3 million in emerging pharmaceutical markets.

Of approximately 500,000 women worldwide that are diagnosed with having cervical cancer each year, about 70%, or 350,000 patients, carry the DNA of HPV16 and/or 18 (Munoz 2004; Bosch et al., 2008).

• HPV infection causes epithelial abnormalities

Infectious HPV particles introduced into the genital tract upon sexual intercourse can reach the basal cells of the squamous cell epithelium of the cervix uteri through micro-lesions (von Knebel Doeberitz, M. 1994).

Once infection is initiated in the basal cell layer, the viral DNA genome is maintained as a low copy circular episome. Basal cells are the only dividing cells in the epithelium, which generate other basal cells by lateral division and keratinocytes by upward division (K. Munger et al., 2004)

In differentiating keratinocytes in the lower mid-zone, which derive from HPV-infected basal cells, the episomal virus genome expresses early (E) and late (L) genes and amplifies its genome. Once in the upper mid-zone and superficial zone, only late gene expression of the L1 and L2 capsid forming proteins occurs in terminally differentiated squamous keratinocytes (S.A. Southern and C.S. Herrington, 1994). Subsequently progeny virus is released into the vagina from desquamated cells, which can be further transmitted by intercourse.

The presence of the virus in the squamous epithelium causes morphological abnormalities, including papillomatosis, parakeratosis, and koilocytosis. Such abnormalities correspond histologically to Grade 1 cervical intraepithelial neoplasia (CIN 1).

• HPV infection can cause invasive cancer

In some keratinocytes in the mid-zone, viral replication does not occur. In this situation, the viral episome persists as either an extra-chromosomal element or becomes integrated into the host cell chromosome at a random site (C. Popescu and J.A. DiPaolo 1989). Viral integration into the host cell DNA is believed to be a necessary step in cellular transformation of mucosal HPV. The effect is deregulated cell cycle control and uncontrolled cellular proliferation, dependent on constitutive expression of the viral oncogenes E6 and E7 (von Knebel M. et al., 1994).

Through cell division, more and more cells in the epithelium are transformed and form high grade squamous epithelial lesions that histologically correspond to Grade 2 and Grade 3 cervical intraepithelial neoplasia (CIN 2 & CIN 3). This pre-cancer becomes invasive cancer when the lesion disrupts the basement membrane and spreads through the body. A diagram representing HPV disease progression is given below.

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