Current and emerging viruses continue to pose a significant threat to the health, wealth and well-being of the European Community and the world at large. There are few areas of greater need for a concerted research effort than hepatitis C virus (HCV) and the human immunodeficiency virus type 1 (HIV-1). Based in the Queen’s Medical Centre, the Virus Research Group (VRG) perform research at the clinical interface. This ensures their findings are able to inform health policy and practice as well as provide the platform to identify, then progress, lead therapeutics from bench to bedside. They carry out basic and clinical research that has resulted in patented and licensed lead antiviral therapies, as well as findings that have informed current Department of Health and Health Protection Agency policies for clinical management. The work of the VRG is divided into the following themes:
Blood-borne virus glycoprotein research
Viruses such as HIV and HCV rely on interactions between their surface glycoproteins and cell receptors to gain entry into a cell. The Virology group directs an international translational hepatitis C virus (HCV) research program whose main focus is on gaining a better understanding of this process. In particular we are interested in defining functional and antigenic determinants and in using this knowledge to inform the development of peptide, antibody and small molecule entry inhibitors and vaccine candidates. Major achievements include: (1.) the identification and characterisation, of potent and broadly neutralising murine and human monoclonal antibodies; (2.) identification of glycoprotein domains and residues critical for receptor binding, entry and infectivity; (3.) the discovery that selective transmission of CCR5-tropic HIV can not be explained by selective expression of CCR5 in the female and male genital tract, and (4.) that the genital tract harbours HIV strains that exhibit unusual phenotypic properties not represented by strains circulating in the periphery.
Clinical virology research
The Trent hepatitis C cohort provides a unique opportunity to study the natural history of disease progression, including correlation of fibrosis markers with histology (over 1500 liver biopsies with serum stored) and as predictors of development of cirrhosis and long term clinical complications of liver disease. Research using this unique dataset has already resulted in a number of key findings that include (1.) the discovery that polymorphisms in the apoE gene and differential MBL levels are associated with HCV disease severity; (2.) quantification of transition rates of liver disease progression in untreated patients defined by liver histology; (3.) application of those rates in mathematical models to predict future disease burdens (de Angelis, Cambridge); (4.) description and quantification of the biphasic standardised mortality rates arising from injecting drug use and liver disease within the HCV-infected population; (5.) delineation of the natural history of HCV-induced severe fibrosis; and, (6.) analysis of the failure of newly-diagnosed patients to enter appropriate care pathways. In addition, the Trent hepatitis C study cohort is currently undergoing meticulous genotyping and phenotyping studies with the aim of providing a unique resource for the further understanding of the pathogenesis and natural history of HCV infection and identification of new therapeutic interventions.
The VRG is working with the Department of Tissue Engineering in Nottingham to develop novel three dimensional models of human liver for the study of viral pathogenesis. These models support the maintenance of hepatocyte specific functions and permit the interrogation of inflammatory signalling between parenchymal and non-parenchymal liver cells. Models are being used to study the molecular pathogenesis of HCV infection and to develop nanotechnology-based systems for the delivery of antiviral therapy.