The role of Hepatitis C virus glycoprotein-receptor polymorphism in viral pathogenesis

Lead Research Organisation: University of Birmingham
Department Name: Health and Population Sciences

Abstract

Hepatitis C virus (HCV) is a globally important virus that infects 170 million individuals world wide, resulting in progressive chronic liver disease. At present, there are limited therapies available for treating hepatitis C and there is an urgent need for the development of new agents that will cure infection. Viruses initiate infection by attaching to molecules or receptors on the cell surface, providing a target for therapeutic intervention. Recent advances have identified the cellular molecules defining HCV entry into liver cells. Studies from our laboratory have shown that HCV strains differ in their interaction with host cell receptors and this will have significant consequences for virus infectivity and spread in the liver. We hypothesise that such differences in HCV-receptor interactions will influence the ?relative fitness? of a virus to transmit and infect new individuals. We will use molecular and biological methods to study transmitting HCV strains to increase our understanding of the molecular events that define and limit virus transmission.

Technical Summary

Hepatitis C Virus (HCV) poses a global health problem, with over 170 million infected individuals worldwide at risk of developing cirrhosis and hepatocellular carcinoma. A number of anti-viral replicase molecules are in clinical development, however, drug resistance and viral genotype-specific differences will limit their efficacy, demonstrating the need for combination therapies targeting different steps of the viral replication cycle.
Recent progress in the discovery of a strain of HCV that replicates in cell culture has enabled studies on virus assembly, release and entry, offering new targets for intervention. Studies from our laboratory have contributed to the growing understanding that HCV can disseminate via direct contacts between infected and na?ve cells. Cell-to-cell transfer of HCV is resistant to the neutralising effects of antibodies targeting the viral glycoproteins, providing a strategy for the virus to escape host immune responses. Whilst the majority of studies have focused on identifying host and viral pathways required for the genesis and release of infectious cell-free particles and inhibition of their entry into na?ve cells, cell-to-cell infection is poorly understood. We hypothesise that cell-to-cell infection is the dominant route for HCV to disseminate within the infected liver. The central aim of the current proposal is to define the mechanism(s) of cell-to-cell HCV infection and its role in virus dissemination within an infected host and transmission to new hosts in two clinical settings: recurrent HCV infection of the transplanted liver and mother to child vertical infection. Identification of the selective factors that define HCV spread and transmission will have major implications for the future treatment of HCV infection.
At present it is not clear how HCV quasispecies are maintained during chronic infection. A dominant mode of cell-to-cell HCV spread will limit virus trafficking between sites and the resulting viruses will follow independent evolutionary histories, i.e. become compartmentalised. Classic genetic models predict that evolution will occur more rapidly in a series of small isolated populations than in a single homogeneous pool. We propose to study the quasispecies structure of the HCV infected liver. This information will have a major impact on our understanding of HCV pathogenesis and the mechanism(s) underlying virus escape from host immune responses and anti-viral therapies.

Publications

10 25 50
 
Description CRUK Oxford Cancer Centre
Amount £14,000 (GBP)
Organisation University of Oxford 
Sector Academic/University
Country United Kingdom
Start 09/2017 
End 08/2018
 
Description Clarendon Scholarship
Amount £240,000 (GBP)
Organisation University of Oxford 
Sector Academic/University
Country United Kingdom
Start 10/2017 
End 09/2020
 
Description Clinical Research Fellowship
Amount £242,000 (GBP)
Funding ID 200113/Z/15/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2016 
End 09/2019
 
Description Clinical Training Fellowship
Amount £241,807 (GBP)
Funding ID 200113/Z/15/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2016 
End 09/2019
 
Description Framework 7 Collaborative Funding Scheme
Amount £761,914 (GBP)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 01/2016 
End 12/2019
 
Description MRC Clinical Research Fellowship
Amount £219,640 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2012 
End 07/2016
 
Description MRC Project Grant
Amount £299,200 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2013 
End 09/2018
 
Description MRC Project grant, Understanding host factors that regulate the hepatitis B virus epigenome
Amount £650,000 (GBP)
Funding ID MR/R022011/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 07/2018 
End 04/2020
 
Description Marie Curie Fellowship (AKAP)
Amount £148,424 (GBP)
Organisation Marie Sklodowska-Curie Actions 
Sector Academic/University
Country Global
Start 05/2013 
End 04/2015
 
Description Marie Curie Fellowship (Recoin)
Amount £154,840 (GBP)
Funding ID 299674 
Organisation Marie Sklodowska-Curie Actions 
Sector Academic/University
Country Global
Start 04/2012 
End 03/2014
 
Description Research Grant (FP7 PathCo)
Amount £1,253,354 (GBP)
Funding ID 305578 
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 11/2012 
End 10/2017
 
Description Research grant
Amount £390,000 (GBP)
Funding ID BB/N008553/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 04/2016 
End 03/2019
 
Description Research studentship
Amount £85,000 (GBP)
Organisation University of Birmingham 
Sector Academic/University
Country United Kingdom
Start 10/2015 
End 09/2018
 
Description Senior Investigator Award
Amount £1,600,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2017 
End 07/2022
 
Description TUM Fellowship scheme
Amount € 247,000 (EUR)
Organisation Technical University of Munich 
Sector Academic/University
Country Germany
Start 03/2015 
End 02/2017
 
Description Wellcome Trust ISSF
Amount £42,542 (GBP)
Organisation University of Oxford 
Sector Academic/University
Country United Kingdom
Start 03/2018 
End 02/2019
 
Description Wellcome Trust ISSF Award
Amount £49,760 (GBP)
Organisation University of Oxford 
Sector Academic/University
Country United Kingdom
Start 09/2018 
End 08/2021
 
Description Antonio Bertoletti - To study the role of immune cells in hepatitis C entry and infection 
Organisation Duke University
Country United States 
Sector Academic/University 
PI Contribution Provide viral hepatitis expertise
Collaborator Contribution Provide immunological expertise and access to liver perfusate.
Impact Fletcher, N.F., Sutaria, R., Juandy, J., Barnes, A., Blahova, M., Hu, K., Cosset, F-L., Balfe, P., Adams, D.H., Curbishley, S,M., Bertoletti, A. and McKeating, J.A. Activated macrophages promote hepatitis C virus entry in a tutor necrosis factor-dependent manner. Hepatology. 59: 1320-30, 2014.
Start Year 2010
 
Description Ellie Barnes - To study the role of neutralizing antibodies in hepatitis C virus infection. 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Viral hepatitis expertise.
Collaborator Contribution Immunology expertise
Impact Stratified Medicine to Optimise the Treatment of Patients with Hepatitis C Virus Infection (STOP-HCV). Investigators: Consortium of UK investigators, led by Ellie Barnes (Oxford University). Awarding body: MRC. Funds: £6.3M. Dates: 01/5/13 - 31/4/18.
Start Year 2009
 
Description The role of HIFs in hepatitis B virus infection 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Mala Maini - UCL, London.
Collaborator Contribution The role of HIFs in hepatitis B virus infection
Impact None yet
Start Year 2013
 
Description The role of autotaxin-lysophosphatidic acid receptor signaling in hepatitis B and C virus replication. 
Organisation Babraham Institute
Country United Kingdom 
Sector Private 
PI Contribution The role of autotaxin-lysophosphatidic acid receptor signaling in hepatitis B and C virus replication.
Collaborator Contribution The role of autotaxin-lysophosphatidic acid receptor signaling in hepatitis B and C virus replication.
Impact None yet
Start Year 2013
 
Description Thomas Baumert - To study the mechanism of hepatitis C virus entry into polarized hepatocytes. 
Organisation National Institute of Health and Medical Research (INSERM)
Country France 
Sector Public 
PI Contribution Provide imaging expertise of viral receptor trafficking.
Collaborator Contribution Complementary viral expertise.
Impact Zona, L., Lupberger, J., Thumann, C., Ahmed-Adrar, N.S., Thumann, C., Harris, H.J., Barnes, A., Florentin, J., Taware, R.G., Xiao, F., Turek, M., Durand, S.C., Duong, F.H., Heim, M.H., Cosset, F-L., Hirsch, I., Brino, L., Zeisel, M.B., Le Naour, F., McKeating, J.A. and Baumert, T.F. (2013). HRas signal transduction mediates hepatitis C virus entry by triggering the assembly of the host tetraspanin receptor complex. Host Cell and Microb 13: 302-13. Fofana, I., Zona, L., Thumann, C., Heydmann, L., Durand, S.C., Lupberger, J., Blum, H.E., Pessaux, P, Gondeau, C., Reynolds, G.M., McKeating, J.A., Grunert, F., Thompson, J., Zeisel, M.B., and Baumert, T.F. Functional analysis of claudin-6 and claudin-9 as entry factors for hepatitis C virus infection of human hepatocytes using monoclonal antibodies. J Virol, in press. Farquhar, M. J., Hu, K., Harris, H.J., Davis, C., Brimacombe, C.L., Baumert, T.F., Rappoport, J.Z., Balfe, P., and McKeating, J.A. (2012). Hepatitis C virus promotes CD81 and claudin-1 endocytosis. J Virology 86: 4305-16. Fletcher, N.F., Wilson, G.K., Murray, J., Hu, K., Lewis, A., Reynolds, G., Stamataki, Z., Meredith, L.W., Rowe, I.A., Luo, G., Lopez-Ramirez, M.A., Baumert, T. F., Weksler, B., Couraud, P.O., Kim, S.K., Romero, I.A., Jopling, C., Morgello, S., Balfe, P., and McKeating, J.A. (2012). Hepatitis C virus infection of blood brain barrier endothelial cells. Gastroenterology 142: 634-643. Lupberger, J., Zeisel, M.B., Xiao, F., Thumann, C., Fofana, I., Zona, L., Davis, C., Mee, C.J., Turek, M., Gorke, S., Royer, C., Fischer, B., Zahid, M.N., Lavillette, D., Fresquet, J., Cosset, F-L., Rothenberg, S.M., Pietschmann, T., Patel, A.H., Pessaux, P., Doffeol, M., Raffelsberger, W., Poch, O., McKeating, J.A., Brino, L., and Baumert, T.F. (2011). EGF receptor and EphA2 are hepatitis C virus host entry factors and targets for antiviral therapy. Nat Med, 17: 589-95. Syder, A.J, Lee, H., Zeisel, M.B., Grove, J., Soulier, E., Macdonald, J., Chow, S., Chang, J., Baumert, T.F., McKeating, J.A., McKelvy, J., Wong-Staal, F. (2011). Small molecule scavenger receptor B1 antagonists are potent HCV entry Inhibitors. J. Hepatology, 54, 48-55. Brimacombe, C., Grove, J., Meredith, L., Hu, K., Syder, A.J., Flores, M.F., Timpe, J., Krieger, S.E., Baumert, T.F., Tellinghuisen, T.L., Wong-Staal, F., Balfe, P., and McKeating, J.A. (2011). Neutralizing antibody resistant hepatitis C virus cell-to-cell transmission. J.Virology, 85, 596-605. Fletcher, N.F., Yang, J.P., Farquahr, M.F., Hu, K., Davis, C., He, Q., Dowd, K., Ray, S.C., Krieger, S.E., Baumert, T.F., Balfe, P., Wong-Staal, F., and McKeating, J.A. (2010). Hepatitis C virus infection of neuroepithelioma cell lines. Gastroenterology, 139: 1365-1374. Fofana, I., Krieger, S.E., Grunert, F., Glauben, S., Xiao, F., Fafi-Kremer, S., Soulier, E., Royer, C., Mee, C.J., McKeating J.A., Dragic, T., Schuster, C., Thompson, J., and Baumert, T.F. (2010). Monoclonal anti-Claudin 1 antibodies for the prevention of hepatitis C virus infection. Gastroenterology, 139:953-64. Krieger, S.E., Zeisel, M.B, Davis, C., Thumann, C., Harris, H.J., Schnober, E.K., Mee, C.J., Soulier, E., Lambotin, M., Grunert, F., Loan Dao Thi, V., Dreux, M., Cosset, F-L., McKeating, J.A., Schuster, C., and Baumert, T.F (2010). Inhibition of hepatitis C virus infection by anti Claudin antibodies is mediated by neutralization of E2-CD81-Claudin 1 association(s). Hepatology, 51:1144-57. Kapadia, S. B., Barth, H., Baumert, T., McKeating, J. A. & Chisari, F. V. (2007). Initiation of hepatitis C virus infection is dependent on cholesterol and cooperativity between CD81 and scavenger receptor B type I. J Virology 81, 374-383.
Start Year 2009
 
Description To study the role of circadian clocks in HIV infection. 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution Andrew Loudon - Institute for Human Development,
Collaborator Contribution To study the role of circadian clocks in HIV infection.
Impact None yet
Start Year 2014
 
Description To study the role of glucocorticoid signaling in the hepatitis B and C virus lifecycle. 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution David Ray - Institute for Human Development, University of Manchester
Collaborator Contribution To study the role of glucocorticoid signaling in the hepatitis B and C virus lifecycle.
Impact None yet
Start Year 2014
 
Description Ulla Protzer - Mechanism of hepatitis B virus entry. 
Organisation Technical University of Munich
Department Institute of Virology
Sector Academic/University 
PI Contribution Ulrike Protzer - Institute of Virology, University of Munich, Germany. Mechanism of hepatitis B virus entry.
Collaborator Contribution Mechanism of hepatitis B virus entry.
Impact 'Lentiviral hepatitis B pseudotype entry requires sodium taurocholate co-transporting polypeptide and additional hepatocyte-specific factors.'  Meredith LW, Hu K, Cheng X, Howard CR, Baumert TF, Balfe P, van de Graaf KF, Protzer U, McKeating JA, J Gen Virol, 97: 121-7, 2016.
Start Year 2013
 
Description Big Bang Fair 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Ran activity at the "Big Bang Fair" - a national science fair at the Birmingham NEC targeted to School years 7 - 11 with > 15,000 attendees.
Also acted as Judge for national science scheme entries.
Year(s) Of Engagement Activity 2014
 
Description Careers fairs 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Schools
Results and Impact Had several students apply to UoB on the basis of our presentations. To date these careers talks have been give to over 500 17-18 year olds

Repeat visits invitations from all schools involved. several work experience students have applied for time in our department on the basis of these activities.
Year(s) Of Engagement Activity 2010,2011,2012
 
Description Flak International Meeting, basic science to clinical practice 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Plenary session at policy forum
Year(s) Of Engagement Activity 2016
 
Description Hep-CAR Symposium 
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 Organiser, chair and speaker at international symposium
Year(s) Of Engagement Activity 2018
 
Description HepCar Kick off meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Address to Meeting, chair of Research committee
Year(s) Of Engagement Activity 2016
 
Description Invited speaker 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Plenary speaker at Conference
Year(s) Of Engagement Activity 2016
 
Description Oxford Immunology Symposium 
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 Organiser, Chair and speaker at international meeting
Year(s) Of Engagement Activity 2018
 
Description PathCo Meeting, Sienna 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Chair of Scientific session and presenter
Year(s) Of Engagement Activity 2016
 
Description Pint of Science lectures 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Pint of Science is an international initiative to enhance public understanding of science. We took part in the inaugural series in Birmingham in 2015.
Year(s) Of Engagement Activity 2015
 
Description Research Seminar, Freiburg 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Research seminar and collaborative meeting
Year(s) Of Engagement Activity 2016
 
Description Research Seminar, IAS, TUM, Munich 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Research seminar
Year(s) Of Engagement Activity 2016
 
Description Research Seminar, Institute Pasteur 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited speaker
Year(s) Of Engagement Activity 2016
 
Description Research Seminar, King's College London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited research Seminar
Year(s) Of Engagement Activity 2016
 
Description Research Seminar, WIMM, Oxford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Research Seminar
Year(s) Of Engagement Activity 2016
 
Description STEMnet ambassador scheme 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Schools
Results and Impact >20 ambassadors from MDS are now actvively engaged in visits to West Midlands Schools and MDS has become the largest group at UoB to send people out on these visits. In the last year 45 visits were made and we estimate >1,000 children (and their teachers) were visited.

Several of our ambassadors are visiting schools for the third year running and the schools appreciate the presence of UoB in their community
Year(s) Of Engagement Activity 2010,2011,2012
 
Description School prize giving & lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Gave talk on women in science, careers and research. Presented School prizes

School reported strengthening of science curriculum
Year(s) Of Engagement Activity 2009
 
Description School science weeks 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact Series of hands on experience of microbiology for primary school children.

School reports improved KS2 results and better understanding of health among children
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
 
Description School visits and lectures 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Virology talks to 6th form students, with description of research career and role of women in science.

Teachers reported that several students chose to study Biology or Medicine as a result of these talks (indeed one of these students is now on our course in Birmingham).
Year(s) Of Engagement Activity 2007,2008,2009,2010,2011
 
Description Seminar, Imperial College, London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Research Seminar
Year(s) Of Engagement Activity 2017
 
Description Seminar, University of Bristol 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Research Seminar
Year(s) Of Engagement Activity 2018