The Graham Group
My group investigates the links between human papillomavirus (HPV) infectious lifecyle & epithelial differentiation and how HPV-associated tumour progression is achieved.
The human papillomavirus life cycle
Human papillomaviruses cause a range of diseases from common warts on the hands to a number of cancers, including cervical cancer, the third most common cancer in women worldwide. There is a clear clinical need to develop tests to identify cervical disease that will progress to cancer from cervical disease that will not. Although a prophylactic vaccine to protect against HPVs that cause cancer is now available for teenage girls it is of no help to the millions of women who are already infected and may develop cancer in future. So, new therapies against the virus are still urgently required.
HPVs infect the epithelium and there is a very tight linkage between epithelial cell metabolism and virus replication. Over the last decade the HPV group have made significant inroads into understanding how HR-HPV interacts with the infected epithelium. Changes in viral and cellular expression have been mapped in depth using next generation sequencing. These studies have revealed that HR-HPV infection causes massive changes in epithelial gene expression. Such gene expression changes, either at the level of RNA or protein, have potential as targets for developing novel biomarkers of disease.
Moreover, an in depth understanding of the regulatory relationship of epithelial cells in the viral life cycle may lead to development of novel therapies to inhibit virus replication and reduce spread of the virus. Over the last ten years we have identified several key cellular RNA processing factors, in particular SR splicing factors (SRSFs) that are required for completion of the virus replication process. Small molecule inhibitors are available against a number of these proteins that might be potential new drugs to interfere with HR-HPV replication.
Biomarker development for use in liquid based cytology samples
Cervical disease is currently diagnosed using liquid based cytology (LBC), a type of smear test. We are developing RNA and protein biomarkers to detect persistent viral infection in patient LBC samples. Together with Professor Heather Cubie and Dr Kate Cuschieri at the Scottish HPV Reference Laboratory in Edinburgh we have analysed expression of viral early and late messenger RNAs in patient samples.
HPV mRNA can be quantified in these samples as a direct measure of virus activity. Virus activity profiles may prove useful in future for risk stratification of cervical disease. In collaboration with Dr John Doorbar, University of Cambridge we have developed a technique to stain cervical epithelial cells in LBC samples with known biomarkers that can detect persistent HPV infection. Biomarkers are also being used to detect persistent HPV infection in HPV-associated non-cervical anogenital and HPV-associated oropharyngeal samples.
- Professor Heather Cubie and Dr Kate Cuschieri, Scottish HPV Reference Laboratory, Royal Infirmary of Edinburgh
- Dr David Millan, Pathology, South Glasgow Hospitals
- Dr Katie Wakeham & members of the Scottish HPV Investigators’ Network (SHINe)
- Dr John Doorbar, University of Cambridge
- Dr Joe Conner, Virttu Biologics