... understanding life in molecular detail

Prof Adrian Whitehouse

Viruses, Cancer, Antiviral Strategies, O’mic Approaches


Viruses are associated with up to 20% of cancers worldwide, representing approximately 1.2 million cancer cases worldwide annually. We are primarily interested in studying the molecular biology of 2 of the 7 viruses, KSHV and MCPyV that have been identified as human tumour viruses.

We are utilising a range of cutting-edge transcriptomic and quantitative proteomic approaches to globally identify how viral proteins affect the cellular environment. These interactions can then be verified using biochemical and con-focal imaging techniques. This is helping to identify essential virus-host cell interactions which we can target by novel antiviral strategies to inhibit virus replication and transformation.

Current major projects include:
  • Identification of essential virus-host cell interactions
  • Quantitiative proteomic approaches to study virus infections
  • Antiviral structural-based rational drug design approaches
  • Understanding the pluirfunctional nature of the nucleolus
  • Development of herpesvirus-based gene delivery vectors

Viruses are associated with up to 20% of cancers worldwide, representing approximately 1.2 million cancer cases worldwide annually. We are primarily interested in studying the molecular biology of 2 of the 7 viruses that have been identified as human tumour viruses.

(i) Kaposi's sarcoma associated herpesvirus (KSHV)
This is a human gamma-2 herpesviruses which has been associated with a variety of lymphoproliferative disorders including Kaposi's sarcoma (KS), primary effusion lymphoma and multicentric Castleman's disease. Widespread HIV infection has now turned KS into an epidemic disease in Africa. KS is now the most common adult tumour in parts of Africa. Like other herpesviruses, KSHV has two distinct forms of infection, latency and lytic replication. Although latency has been implicated in tumourigenesis, reactivation and lytic replication play an important part in the pathogenesis and spread of KSHV infection. Therefore, we have a major research focus to study the molecular mechanisms which regulate reactivation and lytic gene expression to provide a better understanding of KSHV pathogenesis.

(ii) Merkel cell polyomavirus (MCPyV)
Merkel cell carcinoma (MCC) is a highly aggressive human cancer of the skin that occurs in elderly and immunosuppressed patients. Merkel cell polyomavirus was discovered in 2008 and is present in 80% of human Merkel cell carcinomas. Therefore, MCPyV is likely to have a causative role in MCC. Due to its recent discovery, little is known about the link between MCPyV and MCC. Therefore, we are currently investigating the role of MCPyV encoded proteins in transformation and immortalisation of human cells.

Current Projects

1. Identification of essential virus-host cell interactions which are required for virus replication or transformation.

We are utilising a range of cutting-edge transcriptomic and quantitative proteomic approaches to globally identify how viral proteins affect the cellular environment. These interactions can then be verified using biochemical and con-focal imaging techniques. This is helping to identify essential virus-host cell interactions which we can target by novel antiviral strategies to inhibit virus replication and transformation.
We are particularly interested in virus-host cell interactions which
1. Regulate reactivation in Kaposi's sarcoma associated herpesvirus
2. Regulate virus RNA processing
3. Immune evasion strategies employed by oncogenic viruses
4. Virus-host cell interactions required for the aggressive metastatic potential of some virus-induced cancers

2. Structural-based rational drug design approaches to inhibit oncogenic viruses.

To date, there are limited antiviral strategies for oncogenic viruses. Although vaccines have been developed for a few of these viruses, these are not available for all the 7 oncogenic viruses, incluing KSHV and MCPyV. Therefore novel antiviral straetgies are required to combat these important human pathogens.

Upon identification of essential virus-host cell interactions using transcriptomic and quantitative proteomic approaches, we utilise a structural-based rational drug design approach to molecular model and design small molecules to inhibit these interactions. Virtual high-throughput screening campaigns are conducted from a large libraries of commercially available compounds. Docking routines and ligand-similarity searches are utilised to design compounds which have the potential to inhibit these essential virus-host cel interactions. Once the virtual high-throughput screening campaign has been performed selected compounds are then assessed in virus-based assays for antiviral activity.

Detailed research programme                  Close ▲
AWhi.jpg

Professor of Molecular Virology
BSc (Sheffield) PhD (Oxford)
SGM Fleming Award; ESCMID Young Investigator Award; EACR High Commended Research Award

Postdoctoral Research Fellow : 1994 to 1998
MRC Non-Clinical Research Fellow : 1998 to 2002
Lecturer : 2002 to 2005
Reader : 2005 to 2010

Garstang South 9.59
School of Molecular and Cellular Biology
0113 343 7096
a.whitehouse@leeds.ac.uk
http://www.fbs.leeds.ac.uk/staff/Whitehouse_A/

Selected Publications

  1. Jackson, B.R., Norenberg, M. & Whitehouse, A. (2014). A novel mechanism inducing genomic instability in Kaposi’s sarcoma-associated herpesvirus infected cells. PLoS Pathogens, 10(5): e1004098.

  2. Knight, L.M., Stakaityte, G., Wood, J.J., Griffiths, D.A., Howell, G.J., Abdul-Sada, H., Wheat, R., Blair, G.E., Macdonald, A., Blackbourn, D.J. & Whitehouse, A. (2015). Merkel cell polyomavirus small T antigen mediates microtubule destabilisation to promote cell motility and migration. Journal of Virology, 89, 35-47.

  3. Hughes, D.J., Wood, J.J., Jackson, B.R., Baquero-Perez, B. & Whitehouse, A. (2015). NEDDylation is essential for Kaposi's sarcoma-associated herpesvirus latency and lytic reactivation and represents a novel anti-KSHV target. PLoS Pathogens, 11(3):e1004771.

  4. Baquero-Perez, B. & Whitehouse, A. (2015). Hsp70 isoforms are essential for the formation of KSHV replication and transcription compartments. PLoS Pathogens, 11(11):e1005274.