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

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.

Human Papillomaviruses cause around 6% of all human cancers, as well as a wide diversity of problematic skin lesions. Although the basic functions of many papillomavirus proteins have been elucidated, the effect of viral gene expression on epithelial homeostasis has not been examined, with the mechanics of lesion-formation and lesion-persistence being only poorly understood at the molecular and cellular levels. The particular focus of the study will be on the organisation and patterns of viral gene expression at of one of the most important epithelial sites where the high risk HPV types cause cancer - the cervical transformation zone, and will compare expression at other vulnerable sites within the body, including oropharyngeal and anal sites. These variations in gene expression have dramatic consequences on clinical pathogenesis and disease outcome, with deregulated viral gene expression driving neoplastic progression and eventually cancer. We will also examine the interaction between viral gene expression and cellular microenvironment following initial infection, as well as during lesion regression and subclinical persistence. These studies will support development of disease stratification approaches that employ biomarker combinations to provide a clearer rationale for markers that are currently in use (e.g. methylation, E4 (4) etc), and will define potential biomarkers to target cell type, microenvironment and viral gene expression, which are urgently required as a complement to HPV DNA testing. As epithelial site-specific regulation patterns become clearer, we also anticipate opportunities to evaluate new antiviral therapies.

Our work is focused toward understanding the mechanisms that human papillomaviruses (HPV) use to live in the skin, and how they cause disease at particular epithelial sites. Academics, clinicians, and members of the general public who are at risk of HPV infection, will benefit from this research. Individuals living in developing countries will benefit specifically, as HPV-driven cervical cancer represents the second most common cancer amongst young women aged 15 to 44 years in Africa, with approximately 119,284 new cervical cancer cases being diagnosed annually across the continent (estimates for 2018)(HPV information centre (https://hpvcentre.net/)). With the introduction of HPV prophylactic vaccines alongside with screening in some high income countries, HPV-associated malingnancies are expected over the next 50 years to become more and more a disease of the poor. The primary impact of our work will come from our specific understanding of how HPV infection at specific sites can directly lead to high grade neoplasia. We will also examine viral gene expression in the context of the cellular immune response. To our knowledge this examination has never been done before and will guide future molecular work as well as clarifying the interpretation of current studies of the cellular immune response and control of HPV infection. As with our past work, which has attracted development support from GSK in the area of vaccine development, from Sanofi Pasteur in the area of lesion regression and latency, and currently from Johnson & Johnson in the area of virus transmission, we anticipate that the proposed studies will also lead to new initiatives in antiviral discovery. Indeed, a number of initial research contacts have already been made to facilitate this, and as there is currently no cure for any papillomavirus-associated diseases, this is a very important objective of our research on HPV. The ultimate benefit of our past and future work, will be to individuals with problematic papillomavirus infections, such as de novo high grade neoplasia, and other increasingly important HPV-driven diseases (e.g. oropharyngeal cancers), as a result of the development of improved treatment options. Our recent diagnostic studies, and the licence arrangements that have come from them will facilitate more accurate screening and better patient care. Cost and time savings are expected within the healthcare system as a result of extended screening intervals, less referral to colposcopy - and following the introduction of HPV testing as a primary screen, the implementation of efficient and cost effective approaches to triage. In due course, these studies will result in lower patient morbidity and mortality.


Animal use is not anticipated, but is discussed briefly in the text as a possible alternative to the ex vivo analysis if longer infection time courses are required. Provision is made in our current animal licence for such studies if required. These will be on a small scale.