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Title: Host-virus interactions in human papillomavirus mediated disease
Author: Wall, Sion Richard
ISNI:       0000 0004 2745 8062
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2004
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Human Papillomavirus (HPV) is the cause of a wide spectrum of disease ranging from benign cutaneous warts to malignant anogenital tumours. Two notable features of HPV diseases are that the viruses are highly tissue specific of individual HPV types and the fact that while HPV infections are common only a minority of infected individuals manifest clinical disease, indicating the importance of host virus interactions. In this thesis two HPV mediated diseases have been examined in detail, cervical cancer and Recurrent Respiratory Papillomatosis. Cervical cancer is a major cause of mortality in women in developing nations. In these countries cervical screening programmes are impractical for logistical reasons and there is much interest in the feasibility of developing preventative vaccines. However, before such agents can be developed it must be established that the same HPV types that cause cervical cancer in industrialised nations are associated with cervical cancer in developing nations and that the local clades of HPV have the same amino acid sequence as putative vaccine strains. This thesis presents a study of the prevalence of cervical HPV infection, HPV type distribution and viral genetics carried out in a previously unstudied population of 934 women in rural Gambia. A high cervical HPV prevalence is observed, the most common high risk types were found to be HPV-16 & -35, the former being the most common high risk type worldwide and the latter this study show may be underestimated in African populations. Sequencing of the HPV L1 open reading frames provided data which may have implications for vaccine research. RRP is a rare disease characterised by the presence of papillomata on the larynx and other sites in the upper aerodigestive tract. RRP is usually caused by HPV-6 or -11, two viruses more commonly associated with genital warts. RRP is thought to be contracted from the genital tract. However, genital HPV infection is common yet RRP remains a rare disease, therefore other factors either from the virus or the host must modulate disease pathogenesis. In order to elucidate if RRP is caused by unique HPV clades that might be particularly well adapted to the larynx, the L1 major capsid gene and the oncogenes E6 & E7 have been sequenced. In order to establish the sequence of "normal" genital HPV-11 and to exclude regional differences between UK and US HPV-6 and HPV-11, genital wart tissue from 37 UK donors has also been analysed and compared to papilloma material from 53 RRP patients. Significant sequence differences between RRP and Genital Wart E6 & E7 ORF were observed. In order to examine the possible role of host immunogenetic factors in the pathogenesis of RRP, 50 individuals with RRP were then HLA class typed. A significant association between the HLA class II allele DRB*0301 was found along with a negative association with the HLA DQB1*03 allele. Finally, T-cell proliferation studies using Cytokine Bead Array to detect cytokine production revealed that DQBT03 positive donors produce more IFN-y in response to HPV peptides than DQB1*03 negative individuals.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available