... 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:
  • Epitranscriptomic control of virus replication
  • Virus production of specialised ribosomes
  • Virus-mediated mechanisms inducing cancer metastasis
  • Quantitative proteomic approaches to study virus infection
  • Antiviral structural-based rational drug design 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 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 ▲
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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. Schumann S, Jackson BR, Yule I, Whitehead SK, Revill C, Foster R, Whitehouse A . Targeting the ATP-dependent formation of herpesvirus ribonucleoprotein particle assembly as an antiviral approach Nature Microbiology 2 -, 2017

  2. Hughes DJ, Tiede C, Penswick N, Tang AAS, Trinh CH, Mandal U, Zajac KZ, Gaule T, Howell G, Edwards TA, Duan J, Feyfant E, McPherson MJ, Tomlinson DC, Whitehouse A Generation of specific inhibitors of SUMO-1- and SUMO-2/3-mediated protein-protein interactions using Affimer (Adhiron) technology Science Signaling 10 -, 2017

  3. Bussey KA, Lau U, Schumann S, Gallo A, Osbelt L, Stempel M, Arnold C, Wissing J, Gad HH, Hartmann R, Brune W, Jänsch L, Whitehouse A, Brinkmann MM The interferon-stimulated gene product oligoadenylate synthetase-like protein enhances replication of Kaposi’s sarcoma-associated herpesvirus (KSHV) and interacts with the KSHV ORF20 protein PLoS Pathogens 14 -, 2018

  4. Nwogu N, Boyne JR, Dobson SJ, Poterlowicz K, Blair GE, Macdonald A, Mankouri J, Whitehouse A Cellular sheddases are induced by Merkel cell polyomavirus small tumour antigen to mediate cell dissociation and invasiveness. PLoS pathogens 14 e1007276-, 2018