HPV and Cervical Cancer

HPV infection with oncogenic types is the necessary cause of cervical cancer (Bosch et al 2002). Every woman is at risk of infection: between 50 and 80% of all sexually active women will be exposed to HPV in their lifetime (of whom 75% will be exposed to oncogenic HPV (Peto 2004; Cushieri 2004)), and the risk starts from the first sexual encounter (Baseman and Koutsky 2005; Bosch and de Sanjose 2003; Brown et al 2005; Ho et al 1998). In most cases, HPV infection is transient, but in some women the infection may become persistent. It is persistent infection with oncogenic HPV types that may lead to the development of cervical cancer.

The oncogenic transformation of infected cervical cells is largely due to interactions between viral E6 and E7.

These E6 and E7 proteins act on the host cell proteins p53 and pRb (DeFilippis et al 2003; Longworth and Laimins 2004) to disrupt normal host cell activity, which may lead to oncogenic transformation of cervical cells (Münger and Howley 2002).

Early HPV genes

Pathogenesis of oncogenic HPV starts with entry of the virus into the basal cell layer of the epithelium. Whilst the late genes are responsible for the structure of the virus, the early genes control viral replication (Prendiville and Davies 2004b). These HPV early genes are expressed rapidly after infection. It is the integration of these HPV genes into the DNA of the human host cell that ultimately allows oncogenic transformation (Wentzensen et al 2004).

The protein products of the early HPV genes E6 and E7 are responsible for transforming and immortalising cells, which may lead to the development of cervical cancer in women (Halbert et al 1992; Münger and Howley 2002).

This occurs as a result of their interactions with numerous host cell proteins, in particular p53 and pRb (Münger and Howley 2002). In uninfected cells, p53 is responsible for ensuring that cells with damaged DNA do not undergo cell division. However, when cells become infected with oncogenic HPV types, the E6 and E7 viral proteins can interact with p53 and pRb to override these host cell control mechanisms, allowing the replication of cells with DNA damage that would not normally be allowed to divide. Eventually, the uncontrolled replication of cells with damaged DNA may lead to cancer (Halbert et al 1992; Münger and Howley 2002).

HPV disrupts the host cell p53 and pRb pathways

The HPV genome contains up to eight early genes, which are not sufficient to direct replication of the viral genome.

Callout: HPV disrupts normal host cell activity, which may lead to oncogenic transformation of cervical cells (Münger and Howley 2002)

The HPV E6 and E7 gene products are known to interact with a number of host proteins (Motoyama et al 2004), but the most important of these interactions in the development of cervical cancer are with the proteins p53 and pRb (DeFilippis et al 2003; Halbert et al 1992; Longworth and Laimins 2004).

HPV disrupts the host cell p53 pathway

The tumour suppressor protein p53 plays an important role in recognising DNA damage and halting the progression of the cell cycle from G1 phase to S phase in cells with DNA damage.

p53 is important in controlling programmed cell death. The viral E6 protein inhibits the normal function of p53, ultimately preventing cell death, which may contribute to the development of cancerous cells (Burd 2003; DeFilippis et al 2003; Longworth and Laimins 2004; Münger et al 2004; Prendiville and Davies 2004b).

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(Reference: Burd 2003)

HPV disrupts the host cell pRb pathway

The host cell protein pRb is a tumour suppressor protein with an important role in controlling the cell cycle progression from G1 phase to S phase. pRb controls this cell cycle checkpoint. In healthy human cells, this control is exerted by the interaction between pRb and a second human protein, E2F:

• in cells that are resting in G1 phase, pRb is bound to E2F, thus rendering E2F inactive
  
• for the cell cycle to progress to S phase, pRb must be destroyed, releasing E2F in the process
  
• once E2F is released, it is free to activate the transcription of a cascade of genes that allows progression into S phase of the cell cycle.

In infected cells the HPV E7 protein binds to pRb, and causes E2F to be released (Prendiville and Davies 2004b). This results in progression of the cell cycle from G1 phase to S phase. With the E6 protein acting on p53, this leads to uncontrolled cell growth, allowing DNA damage to accumulate over successive cell divisions, which can be the first step in the oncogenic transformation of cervical cells (Burd 2003; DeFilippis et al 2003; Longworth and Laimins 2004; Münger et al 2004).

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(Reference: Burd 2003)