The McLauchlan Group
Our group is interested in the virus-host interactions that promote or restrict virus infection and lead to disease. We investigate these topics in hepatitis C virus (HCV) and Dengue virus (DENV), two viruses that are closely related genetically but which cause very different diseases.
HCV typically establishes a chronic infection that can lead to the development of life-threatening liver disease, including liver cancer. How the virus causes liver disease is not fully understood but is linked to the host response to infection. Therefore, we study the nature of the response in the liver and examine how this may be connected to the development of liver disease. Effective anti-HCV treatments called direct-acting antivirals have recently become available with cure rates of 95% for the most common UK HCV strains. An important question that we address is whether these therapies are also effective against other strains of the virus worldwide.
DENV is endemic in most tropical regions of the world. It is transmitted by mosquitoes and can cause hemorrhagic fever, a rare but fatal condition. The annual outbreaks can overwhelm the healthcare systems in some countries due to an inability to predict who may develop serious complications. Our studies are aimed at determining host and viral factors in blood samples (biomarkers) that predict the different categories of DENV-associated disease with the objective of establishing prognostic tests.
Our research investigates these key topics:
1) How do viruses like HCV and DENV evolve? The scope of our interest spans populations to individuals to single cells.
2) How does this evolution impact drug response and disease? We identify and investigate the emergence or natural occurrence of drug-resistant variants in HCV-infected individuals that also helps to guide retreatment strategies.
3) What is the host response to infection? We focus on the role of specific components in regulating the virus life cycle and response, and the impact of viral infection in the heterogeneous microenvironment.
Determining the mechanisms that underlie the outcome of HCV infection relies on in vivo data derived from well-characterised clinical cohorts. This strategy also needs a suite of technologies and analytical tools. Below is a brief outline of two large consortia with which the group is intimately involved.
HCV Research UK
We are one of the founding members of the HCV Research UK consortium, which was established to promote translational studies into HCV infection in the UK. The consortium was funded by the Medical Research Foundation to create a national cohort of 10,000 HCV-infected patients, supported by an infrastructure consisting of linked databases to hold clinical data and patient specimens in a biorepository. The CVR administers HCV Research UK and houses its biorepository. Following successful NIHR portfolio adoption, the recruitment network for HCV Research UK has grown from 18 to 60 sites. Patient recruitment has reached 10,300 and the initiative has attracted 50 applications to access data and samples for wide-ranging research activities, including provision of 'real world' clinical data for regulatory bodies such as the FDA, EMA and NICE. HCV Research UK has also acted as the central data and specimen repository for the NHS Early Access Programme (EAP), which has provided new all-oral, IFN-free therapies to patients with advanced liver disease before NICE approval. More than 700 EAP patients have been recruited into HCV Research UK, making it one of the largest cohorts receiving new therapies for which collated data and serial samples are available.
In addition, we are key partners in the STOP-HCV consortium, which is led by the University of Oxford. This is a MRC-funded study on stratified medicine which aims to optimise treatment options for infected patients. Samples held in the HCV Research UK biorepository at the CVR underpins much of the scientific strategy for STOP-HCV (for viral and host genomics, biomarkers, immunophenotyping). We also collaborate with members of STOP-HCV on the development of pipelines and bioinformatics for viral sequencing.