The role of neutralising antibodies in hepatitis C virus infection

Lead Research Organisation: University of Birmingham
Department Name: Immunity and Infection

Abstract

Hepatitis C virus (HCV) is the major etiological agent of liver disease in most regions of the world. The majority of new infections become chronic and these individuals are at high risk for developing progressive liver disease. However, a minority of individuals (20%) resolve their infection and clear HCV to undetectable levels. We are interested in studying the immune parameters that distinguish these individuals from those where the virus persists. We will study the role of antibodies that have the potential to bind virus and prevent infection of new cells within the liver. Research findings from this proposal with immediate clinical relevance will be translated to the general public by interviews with the local press and through the MRC web site.

Technical Summary

Hepatitis C virus (HCV) is the major etiological agent of liver disease in most regions of the world, with approximately 170 million individuals infected. Chronic HCV infection is also associated with disturbances in B lymphocyte function, including mixed cryoglobulinemia and B-cell lymphoma. Cellular and humoral immune responses are generated during HCV infection, however they are insufficient to effect viral clearance in the majority of individuals, with approximately 80% of new infections becoming chronic. However, the 20% of patients who resolve their infection provide an invaluable resource for studying the immune correlates of virus clearance. Recent studies of acute resolving infection provide compelling evidence that protective immunity exists: however, the immune factors that determine resolution versus chronic infection are poorly defined. The presence of an early and strong intrahepatic CD4+/CD8+ T-cell response appears to associate with early control of acute HCV infection. However, the role of nAbs in HCV infection and disease progression is unclear, largely due to the lack of assays that measure and quantify their activity. The recent discovery that retroviral pseudotypes bearing HCV envelope glycoproteins are infectious for cultured liver cell lines makes it possible to study the role of nAbs in HCV infection. Our current research shows that the majority of individuals who resolve acute HCV infection demonstrate a cross-reactive nAb response within the first year of infection, whereas, chronically infected patients develop nAb responses much later. We hypothesize that development of an early cross-reactive nAb response contributes to the immune control and clearance of HCV. To test this, we will study the evolution and specificity of the HCV specific nAb response in acute infection, comparing individuals who resolve HCV to those who progress to chronic infection. We will also study autologous nAb responses and determine if HCV evolves escape variants, with the goal of identifying the key differences in the early nAb response in patients who resolve acute HCV compared to those with persistent infection. These data will be critical both for the interpretation of current HCV env gp vaccine trials and for the future design of prophylactic and therapeutic vaccine immunogens. Finally, we will develop model systems to study HCV-B cell interaction(s) to address the mechanism(s) underlying the delayed appearance of nAbs in persistently infected patients and to elucidate the general B-cell abnormalities observed in chronically infected patients.

Publications

10 25 50
 
Description BCH Research Studentship
Amount £69,633 (GBP)
Funding ID BCHRF253 
Organisation BCH Charities 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2010 
End 12/2013
 
Description Biomedical Research Unit
Amount £5,500,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Birmingham Liver Biomedical Research Unit
Sector Public
Country United Kingdom
Start 05/2008 
End 04/2012
 
Description Clarendon Scholarship
Amount £240,000 (GBP)
Organisation University of Oxford 
Sector Academic/University
Country United Kingdom
Start 10/2017 
End 09/2020
 
Description MRC Project Grant
Amount £419,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2009 
End 03/2012
 
Description MRC Project Grant
Amount £363,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2009 
End 09/2012
 
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 (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 Merit Award
Amount £50,000 (GBP)
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 01/2006 
End 12/2011
 
Description Programme grant
Amount £1,248,546 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2012 
End 06/2017
 
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 (FP7, Hepacute)
Amount £329,505 (GBP)
Funding ID 260844 
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 11/2010 
End 04/2014
 
Description Research Grant (ROTRF)
Amount £189,694 (GBP)
Organisation Roche Organ Transplantation Research Foundation (ROTRF) 
Sector Charity/Non Profit
Country Switzerland
Start 01/2011 
End 12/2014
 
Description Research Studentship (WT)
Amount £201,043 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2011 
End 09/2014
 
Description Research grant (FP6, Hepacivac)
Amount £172,000 (GBP)
Funding ID 37435 
Organisation Sixth Framework Programme (FP6) 
Sector Public
Country European Union (EU)
Start 04/2008 
End 03/2012
 
Description Research grant (Pfizer)
Amount £241,000 (GBP)
Organisation Pfizer Ltd 
Sector Private
Country United Kingdom
Start 10/2008 
End 04/2010
 
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 Wellcome Trust Programme grant (Model systems to study hepatitis C virus tropism for the liver)
Amount £767,361 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2006 
End 04/2011
 
Title Assay for cell to cell transmission of HCV 
Description An assay was developed to quantify the degree of direct cell to cell transfer of HCV in the presence of neutralising antibodies 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact These experiments have led to several groups re-assessing the likely efficacy of mAb based therapies 
 
Title Polarized HepG2 infection system 
Description A culture system to evaluate HCV infection of polarized hepatoma cell lines 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2009 
Provided To Others? Yes  
Impact Several groups are now re-assessing their infection models to take into account the effects of cell polarization. 
 
Description Adam Cunningham - Viral-bacterial coinfection 
Organisation University of Birmingham
Country United Kingdom 
Sector Academic/University 
PI Contribution virology expertise
Collaborator Contribution anti-bacterial immunology
Impact Grant : Establishing model systems to study viral-bacterial co-infection. Investigators: Adam Cunningham and Jane McKeating. Awarding Body: MRC Centre for Immune Regulation, UoB. Funds: £85,000.Dates: 01/10/12 -31/9/16.
Start Year 2010
 
Description Alex Tarr - To study the role of neutralising antibodies in hepatitis C virus infection. 
Organisation University of Nottingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Viral hepatitis expertise.
Collaborator Contribution Immunology expertise
Impact Tarr, A.W., Lafayem P., Meredith, L., Damier-Piolle, L., Urbanowicz, R.A., Meola, A., Jestin, J-L., Brown, R.J.P., McKeating, J.A., Rey, F.A., Ball, J.K. and Krey,T. (2013). A recombinant nano body inhibits hepatitis C virus entry and cell-to-cell transmission. Hepatology. 58: 932-9. Brown, R.J.P., Hudson, N., Wilson, G., Rehman, S.U., Jabbari, S., Tarr, A.W., Borrow, P., Joyce, M. Lewis, J., Zhu L.F., Law, M., Kneteman, N., Tyrell, D.L., McKeating, J.A. and Ball, J. (2012). Hepatitis C virus envelope glycoprotein fitness defines virus population composition following transmission to a new host. J.Virol 86: 119566 - 66. Tarr, A.W., Urbanowicz, R.A., Jayaraj, D., Brown, R.J.P., McKeating, J.A., Irving, W.L., and Ball, J.K. (2012). Naturally occurring antibodies recognizing linear epitopes in the amino-terminus of the hepatitis C virus E2 protein confer non-interfering, additive neutralization. J.Virol 86: 2739-49. Law, M., Maruyama, T., Lewis, J., Giang, E., Tarr, A. W., Stamataki, Z., Gastaminza, P., Chisari, F. V., Jones, I. M., Fox, R. I., Ball, J. K., McKeating, J. A., Kneteman, N. M. & Burton, D. R. (2008). Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge. Nat Med 14, 25-27. Submitted MRC project application in 2013 that was unsuccessful despite excellent scores - plan to re-submit.
Start Year 2009
 
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 Dan Tennant - To study the role of hypoxia on hepatitis C and B replication. 
Organisation University of Birmingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Provide viral hepatitis expertise and clinical material.
Collaborator Contribution Provision of hypoxia expertise.
Impact Wilson, G., Tennant, D and McKeating J.A (2013). Hypoxia, viruses and liver injury. J Hepatology, invited review. A manuscript is currently under preparation and planning to submit MRC Project grant next year.
Start Year 2013
 
Description David Adams - To study hepatitis C virus pathogenesis 
Organisation University of Birmingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Viral hepatitis Expertise.
Collaborator Contribution Immunological expertise
Impact Stamataki, Z., Tilakaratne, S., Adams, D.H., and McKeating, J.A. (2011). Rituximab treatment in hepatitis C infection: an in vitro model to study the impact of B cell depletion on virus infectivity. PLoS One 6(9):e25789. Rowe, I.A., Wilson, G.K., Galsinh, S.K., Durrant, S., Lazar, C., Branza-Nichita, N., Bicknell, R., Adams, D.H., Balfe,P., and McKeating, J.A. (2013). Paracrine signals from liver sinusoidal endothelium regulate HCV replication. Hepatology, in press. 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 tumor necrosis factor-dependent manner. Hepatology, in press. Stamataki, Z., Shannon-Lowe, C., Shaw, J., Mutimer, D., Rickinson, A. B., Gordon, J., Adams, D. H., Balfe, P. & McKeating, J. A. (2009). Hepatitis C virus association with peripheral blood B lymphocytes potentiates viral infection of liver-derived hepatoma cells. Blood 113, 585-593. Reynolds, G. M., Harris, H. J., Jennings, A., Hu, K., Grove, J., Lalor, P. F., Adams, D. H., Balfe, P., Hubscher, S. G. & McKeating, J. A. (2008). Hepatitis C virus receptor expression in normal and diseased liver tissue. Hepatology 47, 418-427. Lai, W. K., Curbishley, S. M., Goddard, S., Alabraba, E., Shaw, J., Youster, J., McKeating, J. A & Adams, D. H. (2007). Hepatitis C is associated with perturbation of intrahepatic myeloid and plasmacytoid dendritic cell function. J Hepatology 47, 338-347. Grants: Liver Biomedical Research Unit to study Immune and cell therapy of liver disease. Investigators: Adams, McKeating, Newsome, Stewart, Johnson, Young. Awarding Body: National Institute of Health Research (UK). Funds: £6.35 million. Dates: 2012-2017.
Start Year 2006
 
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 Freek van Eeden - In vitro validation of HIF-GR cross-talk. 
Organisation University of Sheffield
Country United Kingdom 
Sector Academic/University 
PI Contribution Provide viral hepatitis expertise and clinical material to study HIF-1a/GR cross-talk and functional consequences for viral persistence .
Collaborator Contribution Provision of VHL null zebrafish model.
Impact A manuscript is currently under review.
Start Year 2012
 
Description HEPacute 
Organisation Technical University of Munich
Country Germany 
Sector Academic/University 
PI Contribution FP7 network to investigate corrrelates of viral clearance in acute infection
Collaborator Contribution Access to European HCV samples
Impact None to date
Start Year 2010
 
Description Hepacivac (FP6 programme) 
Organisation European Commission
Department EC FP6 Collaborative Projects
Country European Union (EU) 
Sector Academic/University 
PI Contribution Test in vitro neutralising antibody responses in pre-clinical evaluations of candidate HCV vaccines
Collaborator Contribution This network provides us with expertise in vaccine preparation, cell mediated immunity and animal models, all of which have strengthened our work.
Impact Relevant publications include 17941058, 18838615, 18829747, 19052239 and 19321602.
Start Year 2008
 
Description Jeremy Tomlinson - To study the effect of HCV on insulin signaling. 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Provide viral hepatitis expertise
Collaborator Contribution Provide endocrinology expertise
Impact Co-sponsors of Clinical Training Fellowship to Reina Lim. Hepatic steatosis and insulin resistance in hepatitis C infection. Awarding body: MRC. Funds: £356,000. Dates: 01/10/12 - 31/9/15. Linking Glucocorticoid Receptor Activation and Lipid Metabolism in the Pathogenesis of Hepatocellular Carcinoma. Investigators: Jeremy Tomlinson and Jane McKeating. Awarding Body: CMDS University of Birmingham. Funds: £85,000. Dates: 01/10/14 -31/9/17. A paper is currently in preparation.
Start Year 2009
 
Description MRC centre for Immune Regulation 
Organisation University of Birmingham
Department MRC Centre for Immune Regulation
Country United Kingdom 
Sector Public 
PI Contribution Access to shared facilities and provision of expertise
Collaborator Contribution Provision of key core technologies and expertise
Impact Many of the publications we generated between 2006 and 2012 used the MRC centre facilities.
Start Year 2006
 
Description Margaret Ashcroft - To study the role of hypoxia on hepatitis C and B replication. 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution Provide viral hepatitis expertise and clinical material.
Collaborator Contribution Provision of HIF-1a expression vectors and inhibitors.
Impact Wilson, G., Brimacombe, C.L., Rowe, I.A., Reynolds, G.M., Fletcher, N.F., Stamataki, Z., Bhogal, R., Simoes, M., Ashcroft, M., Afford, S.C., Mitry, R., Dhawan, A., Mee, C.J., Hubscher, S.G., Balfe, P., and McKeating, J.A. (2012). A dual role for hypoxia factor 1-a in the hepatitis C virus lifecycle and hepatoma migration. J. Hepatology 56: 803-9.
Start Year 2009
 
Description Stan van der Graaf - To study the role of NTCP bile salt transporter in hepatitis B virus entry 
Organisation Academic Medical Center
Country Netherlands 
Sector Academic/University 
PI Contribution Development of lentiviral pseudotypes expressing hepatitis B virus (HBV) glycoproteins and to study the role of NTCP in mediating viral infection.
Collaborator Contribution Provision of stable cell lines expressing wild type and mutant NTCP.
Impact Meredith, L.M., Hu, K., Cheng, X., Howard, C.R., Baumert, T.F., Balfe, P., van de Graaf, S.F., Protzer, U., and McKeating, J.A. Lentiviral hepatitis B pseudotypes uncover a role for NTCP and additional hepatocyte specific factors in virus entry. J Gen Virol. 97: 121-7, 2016. Plus other manuscripts in preparation.
Start Year 2011
 
Description Stephan Urban - the role of NTCP bile salt transporter in hepatitis B virus entry 
Organisation Heidelberg University
Country Germany 
Sector Academic/University 
PI Contribution Development of lentiviral pseudotypes expressing hepatitis B virus (HBV) glycoproteins and to study the effect of a synthetic peptide that mimics viral encoded Pre-S1 glycoprotein (Myrcludex), currently under clinical evaluation, for it's effect on HBV entry.
Collaborator Contribution Provision of hepatitis B virus molecular clones and Myrcludex.
Impact Baumert, T.F., Meredith, L., Yi, N., Felmlee, D.J., McKeating, J.A. and Urban, S. 2013. Entry of hepatitis B and C viruses - recent progress and future impact. Current Opinions in Virology, 2014.
Start Year 2012
 
Description Sven IJzendoorn - To study the role of hepatocyte polarity in hepatitis C virus infection. 
Organisation University of Groningen
Country Netherlands 
Sector Academic/University 
PI Contribution Viral hepatitis expertise.
Collaborator Contribution Hepatocyte polarity expertise
Impact Harris, H.J., Clerte, C., Fraquhar, M,J., Goodall, M., Hu, K., Rassam, P., Dosset, P., Wilson, G.K., Balfe, P., IJzendoorn, S.C., Milhiet, P.E. and McKeating, J.A. (2013). Hepatoma polarization limits CD81 and hepatitis C virus dynamics. Cellular Micro 15: 430-45. Mee, C. J., Harris, H. J., Farquhar, M. J., Wilson, G., Reynolds, G., Davis, C., van, IJzendoorn, S. C., Balfe, P. & McKeating, J. A. (2009). Polarization restricts hepatitis C virus entry into HepG2 hepatoma cells. J. Virology 83, 6211-6221. Farquhar, M. J., Harris, H. J., Diskar, M., Jones, S., Mee, C. J., Nielsen, S. U., Brimacombe, C. L., Molina, S., Toms, G. L., Maurel, P., Howl, J., Herberg, F. W., van Ijzendoorn, S. C., Balfe, P. & McKeating, J. A. (2008). Protein kinase A-dependent step(s) in hepatitis C virus entry and infectivity. J Virology 82, 8797-8811.
Start Year 2009
 
Description Tao Dong - To study the immunology of HIV-HCV coinfection 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution viral hepatitis expertise.
Collaborator Contribution HIV T cell immunity
Impact Pathogen Co-infection "PathCo": HIV, Tuberculosis, Malaria and hepatitis C virus Investigators: McKeating as a consortium member. Awarding Body: FP7. Funds: £280,000. Dates: 01/11/13 - 31/10/2017.
Start Year 2011
 
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 Thomas Krey - To study the mechanism of hepatitis C virus neutralization. 
Organisation Pasteur Institute, Paris
Country France 
Sector Academic/University 
PI Contribution Viral hepatitis Expertise.
Collaborator Contribution Structural biologist
Impact 'Structural flexibility of a conserved antigenic region in hepatitis C virus glycoprotein E2 recognized by broadly neutralizing antibodies.'  Meola A, Tarr AW, England P, Meredith LW, McClure CP, Foung SK, McKeating JA, Ball JK, Rey FA, Krey T, J Virol, 89: 2170-81, 2015. 'An alpaca nanobody inhibits hepatitis C virus entry and cell-to-cell transmission.'  Tarr AW, Lafaye P, Meredith L, Damier-Piolle L, Urbanowicz RA, Meola A, Jestin JL, Brown RJ, McKeating JA, Rey FA, Ball JK, Krey T, Hepatology, 58: 932-9, 2013.
Start Year 2009
 
Description Ulla Protzer - To study the mechanism of hepatitis B virus entry 
Organisation Heinrich Heine University Düsseldorf
Department Institute of Virology
Country Germany 
Sector Academic/University 
PI Contribution Development of lentiviral pseudotypes expressing hepatitis B virus glycoproteins and to characterise their infectivity for a range of cell types
Collaborator Contribution Provision of hepatitis B virus molecular clones and to advise on differentiation protocols for the bipotent HepaRG cell line.
Impact WT ISSF application to fund a training visit for Dr Luke Meredith to visit Protzer lab. Currently preparing a manuscript and MRC project grant with Protzer as a named collaborator.
Start Year 2011
 
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 Darwin day lectures 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Gave keynote presentation on processes of viral evolution, with a focus on HCV

Invited to present again. Positive feedback from audience evaluation forms.
Year(s) Of Engagement Activity 2006
 
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