18 Chapter 1 HPV infections 50, 51. HPV E4 expression is mainly observed in CIN1 and productive CIN2 lesions, with only a small proportion of CIN3 lesions exhibiting E4 expression 52, 53. Immunohistochemical analysis of E4 expression in cervical disease may facilitate the detection and monitoring of low-grade lesions 52, 54. A minority of hrHPV infections (~10-20%) are able to evade immune surveillance, persist during many years and may lead to the development of high-grade cervical premalignant lesions, classified as CIN2 and CIN3 and also cervical cancer. These clinical manifestations are associated with so-called transforming infections, in which the normal viral life cycle is aborted and the viral early genes E6 and E7 are expressed in proliferating cells 25, 55. HPVinduced transformation is initiated with this deregulated expression of the viral E6 and E7 genes, and is characterised by the absence of viral progeny. In the context of dividing cells, viral proteins E6 and E7 serve as oncoproteins by interaction with tumour suppressor gene products p53 and Retinoblastoma protein (pRB), respectively 56. The interaction of E6 with p53 leads to the degradation of p53 through the ubiquitin-dependent proteolysis pathway. Consequently, p53-mediated apoptosis and cell cycle arrest are inhibited, resulting in cell cycle progression despite the presence of DNA damage. E6 also activates telomerase, contributing to the immortalisation of host-cells 57, 58. The E7 oncoprotein targets and degrade pRB, thereby facilitating entry into the S-phase of the cell cycle, leading to uncontrolled proliferation 59, 60. The combined disruption of cell cycle control Virus release Virus assembly / Virus release Genome amplification Genome maintenance / Cell proliferation Genome maintenance Infectious virion PE PAE PL PAE PL PAL Transformation zone E6, E7 E1, E2, E4, E5 viral DNA E4 L2 L1 Figure 1.4 The life cycle of high-risk human papillomavirus. HPVs infect epithelial cells and depend on epithelial differentiation for completion of their life cycle different types of viral proteins are expressed at different phases of the viral life cycle of the human papillomavirus. Adapted from Doorbar et al., Vaccines, 2012 49. Abbreviations: PE, Early promoter; PAE, Position of the early polyadenylation site; PL, Late promoter; PAL, Position of the late polyadenylation site
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