Virus-host interactions in hepatitis C virus infection
Lead Research Organisation:
MRC Virology Unit
Abstract
At least 250,000 people in the UK are thought to be infected with hepatitis C virus (HCV), which can cause severe liver damage in up to 20 per cent of patients. HCV is much easier to contract than HIV, with prisoners and drug users particularly vulnerable to infection. While there has been considerable progress in the scientific understanding of the disease in recent years, it is extremely difficult to effectively track the spread of HCV and to understand the biological roots of the illness. The lack of surveillance of the disease in the UK has also made it harder for doctors to determine why some patients can develop symptoms as soon as they are infected, while others only go onto develop cirrhosis of the liver after many years. Treatments that can cure patients of infection are available but they are not always successful. By collecting and then analysing clinical samples taken from patients, along with use of laboratory-based methods for studying the virus, the projects in this programme will help us to understand why some people develop disease more rapidly than others and also why certain patients fail to respond to treatment.
Technical Summary
Chronic hepatitis C virus (HCV) infection causes liver disease, with those developing end-stage liver disease and hepatocellular carcinoma expected to double over the next decade. Whereas HCV infection can be cured in a proportion of patients, the determinants for treatment response are incompletely described. Characterising the complexity of virus/host interactions is essential for a complete understanding of the mechanisms underlying disease progression and treatment response. The programme combines clinical studies on the natural course of HCV infection with fundamental research that enables examination of the virus using in vitro models. Major elements of the programme are:
Patient Cohorts for Clinical and Fundamental Research – I am principal grant holder for HCV Research UK, a consortium funded by the Medical Research Foundation to recruit 10,000 infected patients from centres across the UK. Funding has established a clinical database and biorepository for research studies into natural infection. We have also created a local cohort, HCV Outcomes, for specific research projects.
Gene Expression Changes in HCV Genotype 1 and 3 Infection - There are 6 HCV genotypes (gts), two of which, gts1 and 3, are the most prevalent in the UK. The pattern of pathogenesis for these genotypes is not identical and they have different responses to pegylated interferon-alpha and ribavirin. Our transcriptomic and microarray studies have found alterations in gene expression between gt1 and gt3 in liver biopsies and PBMCs. This could identify genetic signatures related to disease progression and treatment response. Samples have also been analysed for markers of senescence since T-cell exhaustion occurs during chronic HCV infection. Such an approach aims to link HCV and enhanced biological ageing in infected patients.
The Effect of Infection on the T-cell Receptor Repertoire – T-cells are crucial for combating HCV. We are developing the technology to explore the T-cell receptor repertoire by high-throughput sequence methods to analyse T-cell populations that temporally change in different population groups (e.g. chronic vs cleared infection) and that recognise specific HCV antigens. These studies will be important for developing possible T-cell based vaccines.
Development of Systems to Examine HCV Infection - Model systems for studying HCV isolates have been restricted to HCV gts1 and 2 (strain JFH-1). Given the high prevalence of gt3 in the UK, we are creating gt3/gt2 chimeric constructs with the JFH-1 strain. This enables studies on gt3 isolates to examine i) the properties of quasispecies in natural infection, ii) sequences involved in evading intrinsic immune responses and iii) resistance to antiviral therapies.
Host Factors and Processes that Regulate Productive Infection - Host factors and processes are intimately involved in maintaining and regulating HCV infection in vivo. We are conducting studies that examine ISG15, an interferon-regulated factor and the effect of HCV infection on the cell ubiquitinome. For ISG15, our studies examine the mechanism through which ISG15 reduces HCV RNA replication and whether its activity requires ISGylation of cellular or viral substrates. Both cell biology and proteomic approaches are being applied to determine whether HCV infection alters disrtibution of ubiquitinylated proteins and the cell ubiquitinome. Presently, the group has shown that infection induces novel polyubiquitin foci that are being characterised.
Patient Cohorts for Clinical and Fundamental Research – I am principal grant holder for HCV Research UK, a consortium funded by the Medical Research Foundation to recruit 10,000 infected patients from centres across the UK. Funding has established a clinical database and biorepository for research studies into natural infection. We have also created a local cohort, HCV Outcomes, for specific research projects.
Gene Expression Changes in HCV Genotype 1 and 3 Infection - There are 6 HCV genotypes (gts), two of which, gts1 and 3, are the most prevalent in the UK. The pattern of pathogenesis for these genotypes is not identical and they have different responses to pegylated interferon-alpha and ribavirin. Our transcriptomic and microarray studies have found alterations in gene expression between gt1 and gt3 in liver biopsies and PBMCs. This could identify genetic signatures related to disease progression and treatment response. Samples have also been analysed for markers of senescence since T-cell exhaustion occurs during chronic HCV infection. Such an approach aims to link HCV and enhanced biological ageing in infected patients.
The Effect of Infection on the T-cell Receptor Repertoire – T-cells are crucial for combating HCV. We are developing the technology to explore the T-cell receptor repertoire by high-throughput sequence methods to analyse T-cell populations that temporally change in different population groups (e.g. chronic vs cleared infection) and that recognise specific HCV antigens. These studies will be important for developing possible T-cell based vaccines.
Development of Systems to Examine HCV Infection - Model systems for studying HCV isolates have been restricted to HCV gts1 and 2 (strain JFH-1). Given the high prevalence of gt3 in the UK, we are creating gt3/gt2 chimeric constructs with the JFH-1 strain. This enables studies on gt3 isolates to examine i) the properties of quasispecies in natural infection, ii) sequences involved in evading intrinsic immune responses and iii) resistance to antiviral therapies.
Host Factors and Processes that Regulate Productive Infection - Host factors and processes are intimately involved in maintaining and regulating HCV infection in vivo. We are conducting studies that examine ISG15, an interferon-regulated factor and the effect of HCV infection on the cell ubiquitinome. For ISG15, our studies examine the mechanism through which ISG15 reduces HCV RNA replication and whether its activity requires ISGylation of cellular or viral substrates. Both cell biology and proteomic approaches are being applied to determine whether HCV infection alters disrtibution of ubiquitinylated proteins and the cell ubiquitinome. Presently, the group has shown that infection induces novel polyubiquitin foci that are being characterised.
Organisations
- MRC Virology Unit, United Kingdom (Lead Research Organisation)
- University of Southampton, United Kingdom (Collaboration)
- Aarhus University, Denmark (Collaboration)
- Howard Hughes Medical Institute (Collaboration)
- AstraZeneca plc (Collaboration)
- National Institute of Health and Medical Research (INSERM) (Collaboration)
- Newcastle University, United Kingdom (Collaboration)
- University Hospital Regensburg (Collaboration)
- Pasteur Institute, Paris (Collaboration)
- University of Texas at San Antonio, United States (Collaboration)
- University of Cambridge, United Kingdom (Collaboration)
- University of Heidelberg, Germany (Collaboration)
People |
ORCID iD |
John McLauchlan (Principal Investigator) |
Publications

Angus AG
(2010)
Requirement of cellular DDX3 for hepatitis C virus replication is unrelated to its interaction with the viral core protein.
in The Journal of general virology

Ansari MA
(2019)
Interferon lambda 4 impacts the genetic diversity of hepatitis C virus.
in eLife

Benga WJ
(2010)
Apolipoprotein E interacts with hepatitis C virus nonstructural protein 5A and determines assembly of infectious particles.
in Hepatology (Baltimore, Md.)

Boulant S
(2008)
Hepatitis C virus core protein induces lipid droplet redistribution in a microtubule- and dynein-dependent manner.
in Traffic (Copenhagen, Denmark)

Boulant S
(2007)
Disrupting the association of hepatitis C virus core protein with lipid droplets correlates with a loss in production of infectious virus.
in The Journal of general virology

Boulant S
(2006)
Structural determinants that target the hepatitis C virus core protein to lipid droplets.
in The Journal of biological chemistry

Bradshaw D
(2019)
Consensus recommendations for resistance testing in the management of chronic hepatitis C virus infection: Public Health England HCV Resistance Group.
in The Journal of infection

Da Silva Filipe A
(2018)
Reply to: "Reply to: 'Response to DAA therapy in the NHS England Early Access Programme for rare HCV subtypes from low and middle income countries'".
in Journal of hepatology

Felmlee DJ
(2010)
Intravascular transfer contributes to postprandial increase in numbers of very-low-density hepatitis C virus particles.
in Gastroenterology

Herod MR
(2012)
Increasing rate of cleavage at boundary between non-structural proteins 4B and 5A inhibits replication of hepatitis C virus.
in The Journal of biological chemistry
Description | PHE Working Group on HCV Anti-Viral Resistance |
Geographic Reach | National |
Policy Influence Type | Membership of a guideline committee |
URL | https://www.gov.uk/government/publications/antiviral-resistance-testing-in-the-management-of-hepatit... |
Description | EC Collaborative Project |
Amount | £268,538 (GBP) |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start |
Description | MRC Developmental Pathway Funding Scheme (DPFS) |
Amount | £327,361 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start |
Description | Marie Curie Intra-European Fellowship |
Amount | £126,000 (GBP) |
Organisation | Marie Sklodowska-Curie Actions |
Sector | Charity/Non Profit |
Country | Global |
Start | 01/2006 |
End | 12/2008 |
Description | Studies on Liver Disease |
Amount | £1,924,918 (GBP) |
Funding ID | C0365 |
Organisation | Medical Research Council (MRC) |
Department | Medical Research Foundation |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2011 |
End | 03/2019 |
Title | HCV materials |
Description | My group has produced antibodies, constructs and developed biophysical approaches that have been utilised by a wide number of international groups. Characterisation of the antibodies and constructs has been completed and we continue to develop the biophysical methods. Other researchers are aware of our materials through publication of papers and presentations at conferences. A considerable number of man-years has been devoted to this area and the benefits have been acknowledged in publications from those who have received our materials. |
Type Of Material | Technology assay or reagent |
Year Produced | 2006 |
Provided To Others? | Yes |
Impact | Our materials have facilitated the ongoing development of systems for studying HCV biology and also influenced the field related to lipid disorders. |
Description | C McCormick, University of Southampton |
Organisation | University of Southampton |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Studies on the mechanism of HCV RNA replication |
Collaborator Contribution | Partner developed a novel system for examining HCV RNA replication using subgenomic replicons |
Impact | Collaboration has given rise to 1 publication with more in the pipeline. Collaborator also submitted a grant application to MRC (unsuccessful). |
Start Year | 2011 |
Description | Collaboration on apoE |
Organisation | National Institute of Health and Medical Research (INSERM) |
Department | INSERM U748 (Virus Host Interactions and Liver Diseases) |
Country | France |
Sector | Public |
PI Contribution | My group conducted imaging studies for the collaboration. |
Collaborator Contribution | The group at Strasbourg broadened our research interests to include studies on the role of apolipoproteins on assembly and release of infectious HCV. |
Impact | The collaboration resulted in 1 publication [PMID: 20014138]. |
Start Year | 2009 |
Description | Heidelberg - Virology |
Organisation | Heidelberg University |
Country | Germany |
Sector | Academic/University |
PI Contribution | My group has developed biophysical assays that have given a unique perspective on the properties of HCV proteins. This expertise was incorporated into our collaboration. |
Collaborator Contribution | The group at Heidelberg provided key reagents and knowledge that enhanced our programme of work. |
Impact | The collaboration involved a member of the team from Heidelberg visiting Glasgow to obtain training in biophysical methods. It also led to one publication (PubMed ID 17942391) with others in the process of nearing completion for submission. |
Start Year | 2006 |
Description | Impact of TRC8 on HCV RNA replication |
Organisation | University of Cambridge |
Department | Cambridge Institute for Medical Research (CIMR) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | My group provides the systems for analysis of HCV RNA replication and production of infectious virus. |
Collaborator Contribution | We have established a collaboration with a group at CIMR in Cambridge who study the role of ubiquitin ligases in virus infection. The link has expanded the range of studies in which we are engaged on interactions between HCV and cellular processes. |
Impact | As yet there are no publications arising from the collaboration but the preliminary data are potentially exciting and could lead to longer term links with Prof Lehner's group in Cambridge. |
Start Year | 2008 |
Description | Institut Pasteur |
Organisation | Pasteur Institute, Paris |
Country | France |
Sector | Charity/Non Profit |
PI Contribution | My group has provided considerable expertise to the group at Pasteur by way of methods in cell biology. |
Collaborator Contribution | Along with the group at the Pasteur Institute, we have built cell biology studies on certain aspects of HCV infection. The group at Pasteur have not provided us with reagents etc. |
Impact | This collaboration has led to the publication of 2 papers (PubMed IDs - 18489704, 19269968). It has also facilitated the French group to obtain further funding for their part in the studies. |
Start Year | 2006 |
Description | LipidomicNet Consortium |
Organisation | University Hospital Regensburg |
Country | Germany |
Sector | Hospitals |
PI Contribution | The consortium is a partnership of about 25 groups from across Europe involved in examining the relationship between human disease and lipid storage. My group is examing this relationship in the context of hepatitis C virus infection. |
Collaborator Contribution | Access to facilities for lipid analysis at the Babraham Institute in Cambridge. The institute is also providing back-up by way of training. |
Impact | Inclusion in the consortium has allowed us access to state-of-the-art technology and expert on lipid profiling and cell biology imaging. For the consortium, we add a unique dimension as no other groups studying viruses are part of LipidomicNet. |
Start Year | 2008 |
Description | Provision of antibodies |
Organisation | AstraZeneca |
Department | Arrow Therapeutics |
Country | United Kingdom |
Sector | Private |
PI Contribution | The antibodies were unique reagents that were to be used in screening assays to identify unique compounds with anti-HCV activity. |
Impact | The company has not divulged any data from their screens. |
Start Year | 2007 |
Description | Structural studies on the IFNL4 protein |
Organisation | Aarhus University |
Country | Denmark |
Sector | Academic/University |
PI Contribution | We have provided data on the antiviral activities of natural variants of the human IFNL4 protein (both partners). |
Collaborator Contribution | The team at Stanford has modelled predictive structures of IFNL4 and natural variants based on their previous publications on other IFNL proteins. The group in Aarhus has created constructs aimed at producing authentically folded IFNL4 proteins for structural studies. |
Impact | A manuscript describing the findings of the collaboration will be submitted imminently and a pre-publication version of the paper has been published in Bioarchive. |
Start Year | 2016 |
Description | Structural studies on the IFNL4 protein |
Organisation | Howard Hughes Medical Institute |
Country | United States |
Sector | Charity/Non Profit |
PI Contribution | We have provided data on the antiviral activities of natural variants of the human IFNL4 protein (both partners). |
Collaborator Contribution | The team at Stanford has modelled predictive structures of IFNL4 and natural variants based on their previous publications on other IFNL proteins. The group in Aarhus has created constructs aimed at producing authentically folded IFNL4 proteins for structural studies. |
Impact | A manuscript describing the findings of the collaboration will be submitted imminently and a pre-publication version of the paper has been published in Bioarchive. |
Start Year | 2016 |
Description | Studies on Lipid Metabolism in HCV-Infected Patients |
Organisation | Newcastle University |
Department | Institute of Cellular Medicine |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | My group has provided the tissue culture systems that produce infectious HCV to correlate effects of a high fat supplement in natural HCV infection with effects on virus infectivity seen in vitro. |
Collaborator Contribution | Interaction with the group at Newcastle University has enabled us to establish a link with studies on human subjects in the area of lipid metabolism and HCV infection. |
Impact | The collaboration has given rise to 1 paper (PMID: 20682323). |
Start Year | 2009 |
Description | UTMB, Institut Pasteur |
Organisation | University of Texas |
Country | United States |
Sector | Academic/University |
PI Contribution | My group produced all of the mutants and performed all of the cell-based analysis for the study. |
Collaborator Contribution | The group at UTMB, along with a group at the Pasteur Institute, provided animals for key parts of a study on GB virus-B, whichis a close genetic relative of HCV. |
Impact | The collaboration yielded a publication (PubMed ID 16882659). |
Description | Industrial workshop (Helena Biosciences) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited speaker to the launch of a new liver for liver disease that was aimed primarily at medical practitioners who provide clinical care to patients. This led to potential future avenues of research with the company involved. |
Year(s) Of Engagement Activity | 2019 |
Description | Interviews |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | I have given interviews to journalists for newspapers. There was no further contact with the journalists and so it is difficult to judge any impact. |
Year(s) Of Engagement Activity | 2006,2007 |
Description | Invited speaker at UK Clinical Pharmacists Workshop |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | This was the third workshop by the UK Clinical Pharmacists to which I had been invited. The group wished to learn about the new therapies for treating hepatitis C virus infection and the success achieved by these therapies. |
Year(s) Of Engagement Activity | 2018 |
Description | PCR workshop - Glasgow Science Centre |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | The workshop was organised by Dr D Bhella from the Unit and he will no doubt provide more comprehensive details. Both of the CDFs employed on the project volunteered their time and expertise for the workshop. As noted above, Dr D Bhella will most likely address this question on behalf of the Unit. |
Year(s) Of Engagement Activity | 2009 |
Description | PHE HCV Drug Resistance Group for DAA Therapy |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Public Health England (PHE) created a working group to establish guidelines for retreatment of HCV-infected patients who had been treated with novel all-oral therapy but treatment was not successful. |
Year(s) Of Engagement Activity | 2018,2019,2020 |
URL | https://www.gov.uk/government/publications/antiviral-resistance-testing-in-the-management-of-hepatit... |
Description | presentation |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | I have given a presentation to a HepC support group and been involved in fund-raising activities. Support groups are more aware of the activities funded by MRC to study HCV infection |
Year(s) Of Engagement Activity | 2006 |
Description | presentations |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | I have given practical demonstrations and talks at open days for schools. There are now well-established contacts with local schools and teachers. Students have expressed a greater interest in pursuing a scientific career after the open day events. |
Year(s) Of Engagement Activity | 2006,2007,2008 |