Understanding the Epithelial Site-Specific Origin of HPV Neoplasia and its Control

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Human papillomaviruses cause a wide range of problematic lesions, including a significant number of human cancers, as well as genital warts, respiratory papillomas, and recalcitrant skin lesions. The cancer-associated HPV types are often referred to as 'high-risk' types and are responsible for about 6% of all human cancers, with cervical cancer being the most significant of these. Cervical cancer is the most common cancer to affect young women, and causes approximately a quarter of a million deaths per year worldwide. High risk HPVs can also cause oropharyngeal, anal and penile cancer. There are currently no antiviral therapies that can cure either high or low-risk HPV-associated disease, although since 2008, vaccines have been available in the UK that protect against some high and some low-risk HPV types. Cervical cancer is also managed with cervical screening, with 'precancerous lesions' being surgically excised if they are detected. Neither vaccination nor screening are totally effective in preventing disease, and are still not widely implemented worldwide. A significant part of our work addresses 'vulnerable epithelial sites' such as the uterine cervix, where high risk HPV types cause pre-cancers and cancers. We suspect that viral gene expression can be disrupted at these epithelial sites from the outset, with this deregulation having a major influence on cancer risk. Our main priority is to examine how site-specific deregulated human papillomaviruses gene expression can lead to disease. We will compare viral gene expression and the target cell primarily at the cervix and then at the various other vulnerable sites within the body. We will also examine viral gene expression in relation to the immune system components during subclinical infection, compared with active infections, regressing lesions and de novo infections. Our combined approach aims to understand more accurately the biology of disease progression, to underpin future developments in screening and potential treatments.