Middleton, Kate; (2002) Analysis of papillomavirus e1^e4 expression with respect to epithelial proliferation and differentiation in productive and neoplastic papillomavirus lesions. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Papillomaviruses are small DNA viruses which specifically infect epithelial tissue. The majority of papillomavirus types are associated with benign lesions (warts), but a small subset, which includes HPV 16, are associated with lesions that progress to neoplasia. The lifecycle of all papillomaviruses is dependent on epithelial differentiation, with late viral proteins being expressed only in the differentiating epithelial layers. The E1^E4 protein is generally considered to be a late viral protein and is expressed at high levels during the late stage of the virus lifecycle. At present the role of this protein is unclear. The work described in this thesis shows that the HPV lifecycle follows a clearly defined pattern where E1^E4 is first expressed in cells expressing E7, whilst L1 is expressed only in E1^E4 positive cells in the upper epithelial layers. This pattern was conserved in all papillomavirus types studied. An 11-week time course of ROPV infection demonstrated that wart formation occurs as early as 2 weeks post infection (including the expression of ROPV E1^E4), and that the ROPV lifecycle follows the same defined pattern as observed in HPV infections. Regression of ROPV lesions occurs from week 8 onwards The virus lifecycle is disrupted during progression to neoplasia with progressive loss of late viral markers and an increase in markers of the early virus lifecycle and cellular proliferation. The work presented here suggests that knowledge of the relative levels of E7, E1^E4 and L1 at the surface of the epithelium during neoplastic progression may provide a rationale for predicting the grade of cervical neoplasia by facilitating the identification of abnormal cells in cervical smear samples. Work described in this thesis indicates that there is no specific relationship between the late stage of the virus lifecycle and epithelial differentiation. However, certain disrupted patterns of cellular differentiation are conserved in lesions caused by different papillomavirus types. Striking similarities between the in vitro expression patterns of HPV2 E4 and HPV16 E1^E4 have also been observed, with both E1^E4 proteins co-localising to the keratin filament network and causing its collapse.

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