Viral persistence and human cancer
A significant subset of viruses produce what are known as persistent infections. This means that after primary infection the host can carry the virus for life, generally with no obvious symptoms and in a state of equilibrium with the immune system. Such long-term, intimate relationships between virus and host can – on rare occasions (often associated with impairment of the immune system) – result in cancer. For example in humans Epstein-Barr virus (EBV) is associated with several B cell lymphomas and carcinomas, Hepatitis B and C viruses are linked to hepatocellular carcinoma and Karposi’s Sarcoma (KS)-associated virus (KSHV) is involved in the pathogenesis of KS and two B cell lymphomas.
We are interested in the circumstances that lead to the development of virus-associated cancers and specifically the contribution EBV makes to the pathogenesis of various B cell lymphomas. We are trying to understand how this relates to normal persistence of the virus in a latent form and whether the virus can provide specific targets for therapeutic intervention.
Specific Research Themes:
Current Research Topics:
What roles do a family of EBV nuclear proteins (EBNA3A, EBNA3B and EBNA3C) play in re-programming B cells to make them and their progeny more likely to become cancerous?
How do EBNAs 3A, 3B and 3C interact with components of the polycomb group protein (PcG) system and other chromatin modifying complexes to epigenetically regulate host and viral gene expression?
How do these proteins help overcome the ‘oncogenic stress’ and DNA damage responses induced by infection of B cells with EBV?
What roles do the EBNA3 proteins play in EBV persistence, immune responses and lymphomagenesis in vivo?
Funding and Collaborators:
The Wellcome Trust (through a Senior Investigator Award), Leukaemia & Lymphoma Research Fund (LLRF) and Singapore Government (A*) fund our research. For the in vivo pathogenesis and immune response studies, we have an ongoing collaboration with Professor Christian Münz and colleagues (University of Zurich).
et al., 2016, EBNA3C Directs Recruitment of RBPJ (CBF1) to Chromatin during the Process of Gene Repression in EBV Infected B Cells, Plos Pathogens, Vol:12, ISSN:1553-7366
et al., 2015, Genome Diversity of Epstein-Barr Virus from Multiple Tumor Types and Normal Infection, Journal of Virology, Vol:89, ISSN:0022-538X, Pages:5222-5237
et al., 2015, Epstein-Barr virus proteins EBNA3A and EBNA3C together induce expression of the oncogenic microRNA cluster miR-221/miR-222 and ablate expression of its target p57KIP2., Plos Pathogens, Vol:11, ISSN:1553-7366
Allday MJ, Bazot Q, White RE, 2015, The EBNA3 Family: Two Oncoproteins and a Tumour Suppressor that Are Central to the Biology of EBV in B Cells, Epstein Barr Virus, Vol 2: One Herpes Virus: Many Diseases, Vol:391, ISSN:0070-217X, Pages:61-117
Allday MJ, 2013, EBV finds a polycomb-mediated, epigenetic solution to the problem of oncogenic stress responses triggered by infection., Front Genet, Vol:4