Basis of the host range and tissue tropism for hepatitis C virus

Lead Research Organisation: University of Glasgow

Abstract

We are investigating the properties of the protein components of the Hepatitis C virus (HCV) particles and their interactions with host proteins. Our aim is to understand exactly how the virus initiates infection of its target cell and how it interfers with the workings of the host cell to cause disease. HCV is a major cause of serious liver disease. It is estimated that approximately 200 million people globally are infected with this virus, a significant number of whom will go on to develop serious liver disease, including cirrhosis and hepatocellular carcinoma. Current worldwide projections estimate that HCV in particular will be a major source of morbidity and mortality before the end of this decade. Although new promising treatments are now becoming available, there are many unmet needs and there is as yet no vaccine available. Therefore, basic research on viral proteins to enhance our understanding of the mechanisms of virus infection is needed to develop better anti-viral therapies. Our investigations of the functions and structures of the relevant virus and host proteins will allow better understanding of the processes involved in virus life cycle and disease. The information gained will be crucial in developing novel antiviral drugs and vaccines.

Technical Summary

Hepatitis C virus (HCV) is a major cause of chronic liver disease that often leads to cirrhosis and hepatocellular carcinoma. Promising new treatments are now becoming available, but they are focused on one viral genotype. There are many unmet needs and therefore HCV will remain a serious threat for the foreseeable future. There is as yet no vaccine available. To develop new targets for a broad and more effective therapy, and preventative vaccines, it is necessary to gain greater insights into the processes involved in virus life cycle and their effects on cellular metabolism.

Our research is focused on investigating the mechanisms of HCV entry into target cells and the interactions between viral and cellular components involved in virus life cycle and pathogenesis. Specifically, we have been studying virus neutralizing antibodies and their mode of action both at structural and functional level, modes of virus transmission in cultured cells, and the functional significance of the interaction between the HCV core protein and host factors. Closely aligned to the above work, we have (1) developed several robust cell-based high-throughput screening assays that have enabled us to identify novel anti-viral compounds targeting different stages of the virus life-cycle and (2) an on-going translational project on the development of antibody-based vaccine against HCV.
My group is a member of the Glasgow HCV Network (a consortium of clinicians and scientists) and a national consortium called HCV Research UK focused on fundamental research, clinical studies and translational approaches on HCV. Our aim is to investigate molecular mechanisms that contribute to HCV-associated pathogenesis. The work performed under this programme includes whole genome transcriptome analysis in diseased liver, and investigating host factors that determine viral clearance or progression to chronicity and extrahepatic disorders.
In addition, we are studying the interaction between HCV core and the cellular DEAD-box protein, DDX3. Our data show that this interaction is dispensable for virus life cycle, but may be involved in apoptosis, oncogenesis and aspects of innate immunity. We also find that DDX3 interacts with a variety of cellular factors involved in host RNA metabolism thus implicating the core-DDX3 interaction in these processes, which may in turn contribute to viral pathogenesis. We are investigating the mechanisms for the sequestration of the host factors and their functions in infected cells. Identification of functional pathways is likely to provide novel targets for pharmacological intervention and treatment of HCV-related diseases.

Organisations

Publications

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Heerma Van Voss MR (2017) Nuclear DDX3 expression predicts poor outcome in colorectal and breast cancer. in OncoTargets and therapy

 
Description Design, Development and GMP Manufacture of a Zika vaccine - addtional funding
Amount £122,400 (GBP)
Funding ID GHR16-107-05 
Organisation Department of Health (DH) 
Sector Public
Country United Kingdom
Start 02/2018 
End 01/2021
 
Description Design, development and GMP manufacture of a Zika vaccine
Amount £2,466,148 (GBP)
Funding ID GHR 16/107/05 
Organisation Government of Catalonia 
Department Department of Health
Sector Public
Country Spain
Start 11/2016 
End 12/2020
 
Title Antiviral compounds 
Description Novel compounds inhibiting various stages of HCV infection have been generated following high-throughput screening 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Very useful tools to disect pathways and processes affecting virus life cycle. 
 
Title Generation of mouse monolconal antibodies to ZIka virus E glycoprotein 
Description To date, 2 mouse monoclonal antibodies targeting the so-called '150-loop' of Zika virus E glycoprotein have been generated. These are very unique Zika virus-specific reagents that would be very useful in our studies on vaccine development and on virus structure to be determined by electron cryo-microscopy. Also, these antibodies would likely be excellent tools for affinity purification of Zika virus E-specific antigens. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Not yet, as the reagents have just been developed. 
 
Title Generation of recombinant antibodies to HCV proteins 
Description Genes encoding antibodies of interest have been cloned and stable cell lines expressing them have been generated. 
Type Of Material Antibody 
Provided To Others? No  
Impact The antibody expressing clones and cell lines are useful tools in studies to perform sturcture-function studies on proteins of interest. Furthermore, the clones are amenable to genetic manipulation with a view to to generating higher/better affinity antibodies and to aiding above studies. 
 
Title Mutant antibodies 
Description Derivatives of the broadly neutralsing antibody AP33 carying point mutations in residues located in the antigen-binding pocket have been generated. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact These mutant antibodies are currently proving very useful reagents in assays to assess the reactivity of anti-idiotypic antibodies to AP33. 
 
Title Plasmids expressing cellular proteins 
Description Genes encoding cellular proteins of interest were generated for use in studies investigating virus-host interactions. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Extremely useful tools in studies investigating functions of host proteins in virus life cycle. 
 
Title VLPs of ZIKV, YFV, and LIV 
Description Stable drosophila cell lines inducibly expressing and secreting the Zika virus-like particles (VLPs) has been generated. Additionally, VLPs are also being produced in cells transiently transfected with plasmid constructs expressing the relevant Zika virus, yellow fever virus, and louping ill virus proteins. Methods of VLP purification have been developed and optimised. 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? No  
Impact VLPs will be used as possible vaccine candidates in animal immunisation experiments. 
 
Title Zika virus protein expession systems 
Description Both mammalian- and insect cell-based plasmid expression constructs carrying nucleotide sequences encoding the Zika virus structural proteins have been generated. Also, recombinant baculoviruses expressing the same proteins have been generated. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact These reagents have been used to produce and purify Zka virus proteins for use in vaccine and electron microscopy studies. 
 
Description Antibody-focused approaches for the development of an HCV vaccine 
Organisation University of Glasgow
Department MRC - University of Glasgow Centre for Virus Research
Country United Kingdom 
Sector Academic/University 
PI Contribution We are contributing to all experimental aspects, including animal vaccinations and experimental evaluation vaccine efficacy
Collaborator Contribution Design and generation of synthetic scaffolds tethered to peptides that mimic the virus neutralizing epitopes of interest (School of Chemistry). Identification of novel neutralising antibody epitopes using reverse vaccinology approaches (Centre for Virus Research).
Impact This is a multidisciplinary collaboration involving virologists, chemists and bioinformaticians. We have generated a first batch of synthetic scaffolds carrying a well characterised broadly neutralising epitope. This and its derivatives will be tested in immunisation experiments. Two papers published (PMID: 29382188; 31984607).
Start Year 2014
 
Description Antibody-focused approaches for the development of an HCV vaccine 
Organisation University of Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution We are contributing to all experimental aspects, including animal vaccinations and experimental evaluation vaccine efficacy
Collaborator Contribution Design and generation of synthetic scaffolds tethered to peptides that mimic the virus neutralizing epitopes of interest (School of Chemistry). Identification of novel neutralising antibody epitopes using reverse vaccinology approaches (Centre for Virus Research).
Impact This is a multidisciplinary collaboration involving virologists, chemists and bioinformaticians. We have generated a first batch of synthetic scaffolds carrying a well characterised broadly neutralising epitope. This and its derivatives will be tested in immunisation experiments. Two papers published (PMID: 29382188; 31984607).
Start Year 2014
 
Description Characterisation of neutralising antibody responses to HCV in a large cohort of acutely or chronically infected patients 
Organisation University of Glasgow
Department MRC - University of Glasgow Centre for Virus Research
Country United Kingdom 
Sector Academic/University 
PI Contribution Identification and functional characterization of HCV E1/E2 antibody responses during evolving spontaneous clearance and progression to chronicity in a cohort of HCV-infected or HIV-HCV co-infected individuals. Provided our expertise in this area of work and training to PhD student, a clinical research fellow and a post-doc.
Collaborator Contribution Characterizing diversification within the HCV E1 and E2 envelope genes over time in HIV patients co-infected with HCV that have spontaneously cleared HCV or have fluctuating viremia. Provision of patient samples
Impact Two patients with fluctuating viramia were studied using samples collected at multiple time points. In the first patient (pt100), samples from before and after the negative viral load, purifying selection was evident at multiple positions with HCV glycoproteins E1 and E2. Amino acid changes were observed outwitwith the known receptor-binding sites. An unexpected observation was that no positive selection was present within the previously well-described E2 hypervariable region 1 (HVR-1) - this region is the most extensively described target for neutralising antibodies in patients with acute HCV. It seems highly likely that there are neutralising antibodies targeting regions outwith of HVR1 and this forms the basis of further study. In the second patient (p56), the viral load never became undetectable but did drop by >1log10. The level of selection estimated across E1 and E2 appeared to be higher than that in the pt100. An amino acid change V313I was present within the same fairly conserved region of E1 as R317H in p100. This may well represent evidence of a previously undescribed B cell epitope. Again there was very little evidence of selection occurring within E2 HVR1. We are also investigating neutralizing antibody responses in spontaneous clearers and chronically-infected patients Multi-disciplinary: Fundamental and clinical science
Start Year 2013
 
Description Chimeric HCV isolates 
Organisation University of Glasgow
Department MRC - University of Glasgow Centre for Virus Research
Country United Kingdom 
Sector Academic/University 
PI Contribution Generated chimeric HCV incorporating the viral glycoproteins sequences from diverse genotypes which were supplied to us by our collaborator.
Collaborator Contribution Plasmids carrying sequences of interest supplied by our collaborator to facilitate this study
Impact The chimeric viruses are currently being characterised.
 
Description Coronavirus molecular biology and virus-host interactions 
Organisation University of Glasgow
Department MRC - University of Glasgow Centre for Virus Research
Country United Kingdom 
Sector Academic/University 
PI Contribution Together with several CVR colleagues, we have initiated work on coronaviruses with the aim of establishing a long term programme on these viruses at the CVR. We are currently in the process of propagating the Wuhan COVID-19 virus and are expecting stocks of SARS, MERS and the hazard group 2 HCoV-229E. In addition to this we are putting in place protocols and systems to generate/rescue all these viral isolates by reverse genetics to allow mutational studies and to generate reporter viruses (such as GFP-expressing viruses). We are also generating a large number of antibodies and other reagents against different CoVs, and some of this work is being done in collaboration with the MRC Phophorylation Unit in Dundee.
Collaborator Contribution Establishment of various virological assay systems Production of antibodies
Impact The work has just begun
Start Year 2020
 
Description HCV NS4B and cellular DDX3 
Organisation University of Glasgow
Department MRC - University of Glasgow Centre for Virus Research
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided reagents for studies on NS4B. Collaborators antibodies were very useful for our studies on the dissection of the HCV core-DDX3 interaction Proteomics studies of cells infected with wild-type HCV or a viral mutant carrying a substitution in the core protein that abrogates core-DDX3 interaction. Identified a set of novel differentially expressed genes potentially implicated in processes/pathways contributing to virus-associate pathogenesis.
Collaborator Contribution Defined the role of NS4B in HCV replication and morphogenesis. Separately, provided reagents for our studies on delineating the interaction between HCV core and cellular DDX3.
Impact Publications: PMID - 19073716: 19793905 From our proteomics studies we have identified a set of novel differentially expressed genes potentially implicated in processes/pathways contributing to virus-associate pathogenesis. Experiments involving further validation of selected genes and elucidation of their functional significance remain to be performed.
Start Year 2007
 
Description HCV diversity and IFN lambda 4 
Organisation University of Glasgow
Department MRC - University of Glasgow Centre for Virus Research
Country United Kingdom 
Sector Academic/University 
PI Contribution The study relates to the impact of IFNL4 on the genetic diversity of HCV. Our contribution was to show that the E2 glycoprotein contained the highest proportion of sites affected by IFNL4 SNP rs12979860. From mapping showed that many residues were located either in the HVR1 or on the surface of the protein, with some sites coinciding with epitopes targeted by neutralising antibodies or having a role in virus entry.
Collaborator Contribution Our contribution was a part of a wider study on the role of IFNL4 in exerting genetic diversity of HCV conducted by our partners.
Impact A paper has been published on which we are co-authors (PMID: 31478835).
Start Year 2018
 
Description HCV diversity and IFN lambda 4 
Organisation University of Oxford
Department Nuffield Department of Clinical Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution The study relates to the impact of IFNL4 on the genetic diversity of HCV. Our contribution was to show that the E2 glycoprotein contained the highest proportion of sites affected by IFNL4 SNP rs12979860. From mapping showed that many residues were located either in the HVR1 or on the surface of the protein, with some sites coinciding with epitopes targeted by neutralising antibodies or having a role in virus entry.
Collaborator Contribution Our contribution was a part of a wider study on the role of IFNL4 in exerting genetic diversity of HCV conducted by our partners.
Impact A paper has been published on which we are co-authors (PMID: 31478835).
Start Year 2018
 
Description HCV entry and neutralizing antibodies 
Organisation National Institute of Health and Medical Research (INSERM)
Department INSERM U748 (Virus Host Interactions and Liver Diseases)
Country France 
Sector Public 
PI Contribution From our part, provision of training to a clinical scientist, reagents and significant intellectual input. Collaborator's reagents were very useful in our studies on synchronization of virus infection, virus neutralization assays, and functional characterization of mutant viruses
Collaborator Contribution Provided insights into host neutralizing responses to HCV infection, studied receptor functions and the role of apoE in virus infection, and supplied reagents. Identified novel entry factors. Performed in vivo analysis of the neutralizing capability of our antibody in a chimeric human liver mouse model.
Impact Publications: PMID - 16928753; 17392433; 18718838; 19100780; 20237087; 20713596; 21516087; 22414763; 24830295; 26710081; 26404951. Passive infusion of our neutralizing MAb AP33 into chimeric human liver mice afforded complete protection upon challenge with a clinical isolate of HCV. Demonstrated a role of ApoE in HCV evasion from neutralizing antibodies.
Start Year 2006
 
Description HCV entry and neutralizing antibodies 
Organisation University of Ghent
Department Center for Vaccinology
Country Belgium 
Sector Academic/University 
PI Contribution From our part, provision of training to a clinical scientist, reagents and significant intellectual input. Collaborator's reagents were very useful in our studies on synchronization of virus infection, virus neutralization assays, and functional characterization of mutant viruses
Collaborator Contribution Provided insights into host neutralizing responses to HCV infection, studied receptor functions and the role of apoE in virus infection, and supplied reagents. Identified novel entry factors. Performed in vivo analysis of the neutralizing capability of our antibody in a chimeric human liver mouse model.
Impact Publications: PMID - 16928753; 17392433; 18718838; 19100780; 20237087; 20713596; 21516087; 22414763; 24830295; 26710081; 26404951. Passive infusion of our neutralizing MAb AP33 into chimeric human liver mice afforded complete protection upon challenge with a clinical isolate of HCV. Demonstrated a role of ApoE in HCV evasion from neutralizing antibodies.
Start Year 2006
 
Description Host factors influencing HCV pathogenesis 
Organisation NHS Health Scotland
Country United Kingdom 
Sector Public 
PI Contribution We are looking at the factors influencing infection and pathogenesis of HCV infections in humans at the molecular level. To date we have looked at host responses to HCV genotypes and studied the effects of chronic HCV on the liver transcriptome. We have established a pipeline for the analysis of RNA-Seq data from archived liver biopsies. Our key findings are: (a) significant enrichment of interferon-regulated and immune pathways, (b) changes that occur during disease progression (i.e. fibrosis/cirrhosis) are not present at the early stages of chronic infection, (c) genotype 1 HCV induces a higher level of pro-inflammatory gene expression compared to genotype 3 HCV, (d) up-regulation of type I IFN inducible genes is seen in early stage chronic HCV, (e) pro-apoptotic IFN genes are not strongly induced, and (f) antiviral pathways that are able to down-regulate IFN signalling are up-regulated.
Collaborator Contribution Provided valuable patient samples; made important contributions in terms of ideas and input from clinical perspective
Impact Five studies published (PMID:23931242, PMID: 25200131, PMID: 25800823, PMID: 26912610, PMID: 27405885). Further studies on hightroughput sequencing of data patient biopsies have revealed interesting information. Briefly, HCV gentoype (gt) 1-infected biopsies displayed elevated levels of transcripts regulated by Type I and Type III interferon (IFN), including genes that predict response to IFNa therapy. In contrast, genes controlled by IFN? were induced in gt3-infected biopsies. Moreover, IFN? levels were higher in gt3 samples compared to gt1 and control biopsies. Analysis of hepatocyte-derived cell lines confirmed that the genes up-regulated in gt3 infection were predominantly induced by IFN?. The distinct interactions of the two viral genotypes with hepatic cells may explain differences in the progression of disease pathology and treatment response under both IFN-based treatments and novel direct acting antivirals. A separate study demonstrated the presence of anti-HCV envelope antibody responses in individuals at high risk of HCV who resist infection. These antibodies may be a factor that helps these individuals resist HCV infection. We are also obtaining data on antibody responses in a small cohort of patients and at-risk individuals as follows: • Studied broad cross-genotypic antibody responses in clinical cohorts, their epitope targets and clinical associations. Showed patients with broad neutralizing responses usually target multiple epitopes and they are associated with lower rates of fibrosis and may predict slower disease progression. • In collaboration with Dr Paul Kellam (University of Cambridge) we are investigating the diversity of immunoglobulin repertoire in acute and chronic infections using next generation sequencing methods. In parallel, we plan to set up assays to measure B-cell repertoire (from patients at different disease stages and infected with different genotypes) at the functional level (manuscript in prepatration). • Studied neutralising anti-envelope antibodies in unifected individuals that are repeatedly exposed to HCV (in collaboration with Matthew Cramp, University of Plymouth). This is a unique cohort of individuals who resist HCV infection despite repeated exposure. We showed that a subset of individuals produce neutralizing anti-envelope antibodies which may contribute to host immunity. Further exploring regions targeted by these antibodies may yield novel epitopes for vaccine design (manuscript published). Multi-disciplinary: Clinical and fundamental science
Start Year 2010
 
Description Host factors influencing HCV pathogenesis 
Organisation Plymouth Hospitals NHS Trust
Country United Kingdom 
Sector Public 
PI Contribution We are looking at the factors influencing infection and pathogenesis of HCV infections in humans at the molecular level. To date we have looked at host responses to HCV genotypes and studied the effects of chronic HCV on the liver transcriptome. We have established a pipeline for the analysis of RNA-Seq data from archived liver biopsies. Our key findings are: (a) significant enrichment of interferon-regulated and immune pathways, (b) changes that occur during disease progression (i.e. fibrosis/cirrhosis) are not present at the early stages of chronic infection, (c) genotype 1 HCV induces a higher level of pro-inflammatory gene expression compared to genotype 3 HCV, (d) up-regulation of type I IFN inducible genes is seen in early stage chronic HCV, (e) pro-apoptotic IFN genes are not strongly induced, and (f) antiviral pathways that are able to down-regulate IFN signalling are up-regulated.
Collaborator Contribution Provided valuable patient samples; made important contributions in terms of ideas and input from clinical perspective
Impact Five studies published (PMID:23931242, PMID: 25200131, PMID: 25800823, PMID: 26912610, PMID: 27405885). Further studies on hightroughput sequencing of data patient biopsies have revealed interesting information. Briefly, HCV gentoype (gt) 1-infected biopsies displayed elevated levels of transcripts regulated by Type I and Type III interferon (IFN), including genes that predict response to IFNa therapy. In contrast, genes controlled by IFN? were induced in gt3-infected biopsies. Moreover, IFN? levels were higher in gt3 samples compared to gt1 and control biopsies. Analysis of hepatocyte-derived cell lines confirmed that the genes up-regulated in gt3 infection were predominantly induced by IFN?. The distinct interactions of the two viral genotypes with hepatic cells may explain differences in the progression of disease pathology and treatment response under both IFN-based treatments and novel direct acting antivirals. A separate study demonstrated the presence of anti-HCV envelope antibody responses in individuals at high risk of HCV who resist infection. These antibodies may be a factor that helps these individuals resist HCV infection. We are also obtaining data on antibody responses in a small cohort of patients and at-risk individuals as follows: • Studied broad cross-genotypic antibody responses in clinical cohorts, their epitope targets and clinical associations. Showed patients with broad neutralizing responses usually target multiple epitopes and they are associated with lower rates of fibrosis and may predict slower disease progression. • In collaboration with Dr Paul Kellam (University of Cambridge) we are investigating the diversity of immunoglobulin repertoire in acute and chronic infections using next generation sequencing methods. In parallel, we plan to set up assays to measure B-cell repertoire (from patients at different disease stages and infected with different genotypes) at the functional level (manuscript in prepatration). • Studied neutralising anti-envelope antibodies in unifected individuals that are repeatedly exposed to HCV (in collaboration with Matthew Cramp, University of Plymouth). This is a unique cohort of individuals who resist HCV infection despite repeated exposure. We showed that a subset of individuals produce neutralizing anti-envelope antibodies which may contribute to host immunity. Further exploring regions targeted by these antibodies may yield novel epitopes for vaccine design (manuscript published). Multi-disciplinary: Clinical and fundamental science
Start Year 2010
 
Description Host factors influencing HCV pathogenesis 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We are looking at the factors influencing infection and pathogenesis of HCV infections in humans at the molecular level. To date we have looked at host responses to HCV genotypes and studied the effects of chronic HCV on the liver transcriptome. We have established a pipeline for the analysis of RNA-Seq data from archived liver biopsies. Our key findings are: (a) significant enrichment of interferon-regulated and immune pathways, (b) changes that occur during disease progression (i.e. fibrosis/cirrhosis) are not present at the early stages of chronic infection, (c) genotype 1 HCV induces a higher level of pro-inflammatory gene expression compared to genotype 3 HCV, (d) up-regulation of type I IFN inducible genes is seen in early stage chronic HCV, (e) pro-apoptotic IFN genes are not strongly induced, and (f) antiviral pathways that are able to down-regulate IFN signalling are up-regulated.
Collaborator Contribution Provided valuable patient samples; made important contributions in terms of ideas and input from clinical perspective
Impact Five studies published (PMID:23931242, PMID: 25200131, PMID: 25800823, PMID: 26912610, PMID: 27405885). Further studies on hightroughput sequencing of data patient biopsies have revealed interesting information. Briefly, HCV gentoype (gt) 1-infected biopsies displayed elevated levels of transcripts regulated by Type I and Type III interferon (IFN), including genes that predict response to IFNa therapy. In contrast, genes controlled by IFN? were induced in gt3-infected biopsies. Moreover, IFN? levels were higher in gt3 samples compared to gt1 and control biopsies. Analysis of hepatocyte-derived cell lines confirmed that the genes up-regulated in gt3 infection were predominantly induced by IFN?. The distinct interactions of the two viral genotypes with hepatic cells may explain differences in the progression of disease pathology and treatment response under both IFN-based treatments and novel direct acting antivirals. A separate study demonstrated the presence of anti-HCV envelope antibody responses in individuals at high risk of HCV who resist infection. These antibodies may be a factor that helps these individuals resist HCV infection. We are also obtaining data on antibody responses in a small cohort of patients and at-risk individuals as follows: • Studied broad cross-genotypic antibody responses in clinical cohorts, their epitope targets and clinical associations. Showed patients with broad neutralizing responses usually target multiple epitopes and they are associated with lower rates of fibrosis and may predict slower disease progression. • In collaboration with Dr Paul Kellam (University of Cambridge) we are investigating the diversity of immunoglobulin repertoire in acute and chronic infections using next generation sequencing methods. In parallel, we plan to set up assays to measure B-cell repertoire (from patients at different disease stages and infected with different genotypes) at the functional level (manuscript in prepatration). • Studied neutralising anti-envelope antibodies in unifected individuals that are repeatedly exposed to HCV (in collaboration with Matthew Cramp, University of Plymouth). This is a unique cohort of individuals who resist HCV infection despite repeated exposure. We showed that a subset of individuals produce neutralizing anti-envelope antibodies which may contribute to host immunity. Further exploring regions targeted by these antibodies may yield novel epitopes for vaccine design (manuscript published). Multi-disciplinary: Clinical and fundamental science
Start Year 2010
 
Description Host factors influencing HCV pathogenesis 
Organisation University of Glasgow
Department Institute of Health and Wellbeing
Country United Kingdom 
Sector Academic/University 
PI Contribution We are looking at the factors influencing infection and pathogenesis of HCV infections in humans at the molecular level. To date we have looked at host responses to HCV genotypes and studied the effects of chronic HCV on the liver transcriptome. We have established a pipeline for the analysis of RNA-Seq data from archived liver biopsies. Our key findings are: (a) significant enrichment of interferon-regulated and immune pathways, (b) changes that occur during disease progression (i.e. fibrosis/cirrhosis) are not present at the early stages of chronic infection, (c) genotype 1 HCV induces a higher level of pro-inflammatory gene expression compared to genotype 3 HCV, (d) up-regulation of type I IFN inducible genes is seen in early stage chronic HCV, (e) pro-apoptotic IFN genes are not strongly induced, and (f) antiviral pathways that are able to down-regulate IFN signalling are up-regulated.
Collaborator Contribution Provided valuable patient samples; made important contributions in terms of ideas and input from clinical perspective
Impact Five studies published (PMID:23931242, PMID: 25200131, PMID: 25800823, PMID: 26912610, PMID: 27405885). Further studies on hightroughput sequencing of data patient biopsies have revealed interesting information. Briefly, HCV gentoype (gt) 1-infected biopsies displayed elevated levels of transcripts regulated by Type I and Type III interferon (IFN), including genes that predict response to IFNa therapy. In contrast, genes controlled by IFN? were induced in gt3-infected biopsies. Moreover, IFN? levels were higher in gt3 samples compared to gt1 and control biopsies. Analysis of hepatocyte-derived cell lines confirmed that the genes up-regulated in gt3 infection were predominantly induced by IFN?. The distinct interactions of the two viral genotypes with hepatic cells may explain differences in the progression of disease pathology and treatment response under both IFN-based treatments and novel direct acting antivirals. A separate study demonstrated the presence of anti-HCV envelope antibody responses in individuals at high risk of HCV who resist infection. These antibodies may be a factor that helps these individuals resist HCV infection. We are also obtaining data on antibody responses in a small cohort of patients and at-risk individuals as follows: • Studied broad cross-genotypic antibody responses in clinical cohorts, their epitope targets and clinical associations. Showed patients with broad neutralizing responses usually target multiple epitopes and they are associated with lower rates of fibrosis and may predict slower disease progression. • In collaboration with Dr Paul Kellam (University of Cambridge) we are investigating the diversity of immunoglobulin repertoire in acute and chronic infections using next generation sequencing methods. In parallel, we plan to set up assays to measure B-cell repertoire (from patients at different disease stages and infected with different genotypes) at the functional level (manuscript in prepatration). • Studied neutralising anti-envelope antibodies in unifected individuals that are repeatedly exposed to HCV (in collaboration with Matthew Cramp, University of Plymouth). This is a unique cohort of individuals who resist HCV infection despite repeated exposure. We showed that a subset of individuals produce neutralizing anti-envelope antibodies which may contribute to host immunity. Further exploring regions targeted by these antibodies may yield novel epitopes for vaccine design (manuscript published). Multi-disciplinary: Clinical and fundamental science
Start Year 2010
 
Description Host factors influencing HCV pathogenesis 
Organisation University of Glasgow
Department MRC - University of Glasgow Centre for Virus Research
Country United Kingdom 
Sector Academic/University 
PI Contribution We are looking at the factors influencing infection and pathogenesis of HCV infections in humans at the molecular level. To date we have looked at host responses to HCV genotypes and studied the effects of chronic HCV on the liver transcriptome. We have established a pipeline for the analysis of RNA-Seq data from archived liver biopsies. Our key findings are: (a) significant enrichment of interferon-regulated and immune pathways, (b) changes that occur during disease progression (i.e. fibrosis/cirrhosis) are not present at the early stages of chronic infection, (c) genotype 1 HCV induces a higher level of pro-inflammatory gene expression compared to genotype 3 HCV, (d) up-regulation of type I IFN inducible genes is seen in early stage chronic HCV, (e) pro-apoptotic IFN genes are not strongly induced, and (f) antiviral pathways that are able to down-regulate IFN signalling are up-regulated.
Collaborator Contribution Provided valuable patient samples; made important contributions in terms of ideas and input from clinical perspective
Impact Five studies published (PMID:23931242, PMID: 25200131, PMID: 25800823, PMID: 26912610, PMID: 27405885). Further studies on hightroughput sequencing of data patient biopsies have revealed interesting information. Briefly, HCV gentoype (gt) 1-infected biopsies displayed elevated levels of transcripts regulated by Type I and Type III interferon (IFN), including genes that predict response to IFNa therapy. In contrast, genes controlled by IFN? were induced in gt3-infected biopsies. Moreover, IFN? levels were higher in gt3 samples compared to gt1 and control biopsies. Analysis of hepatocyte-derived cell lines confirmed that the genes up-regulated in gt3 infection were predominantly induced by IFN?. The distinct interactions of the two viral genotypes with hepatic cells may explain differences in the progression of disease pathology and treatment response under both IFN-based treatments and novel direct acting antivirals. A separate study demonstrated the presence of anti-HCV envelope antibody responses in individuals at high risk of HCV who resist infection. These antibodies may be a factor that helps these individuals resist HCV infection. We are also obtaining data on antibody responses in a small cohort of patients and at-risk individuals as follows: • Studied broad cross-genotypic antibody responses in clinical cohorts, their epitope targets and clinical associations. Showed patients with broad neutralizing responses usually target multiple epitopes and they are associated with lower rates of fibrosis and may predict slower disease progression. • In collaboration with Dr Paul Kellam (University of Cambridge) we are investigating the diversity of immunoglobulin repertoire in acute and chronic infections using next generation sequencing methods. In parallel, we plan to set up assays to measure B-cell repertoire (from patients at different disease stages and infected with different genotypes) at the functional level (manuscript in prepatration). • Studied neutralising anti-envelope antibodies in unifected individuals that are repeatedly exposed to HCV (in collaboration with Matthew Cramp, University of Plymouth). This is a unique cohort of individuals who resist HCV infection despite repeated exposure. We showed that a subset of individuals produce neutralizing anti-envelope antibodies which may contribute to host immunity. Further exploring regions targeted by these antibodies may yield novel epitopes for vaccine design (manuscript published). Multi-disciplinary: Clinical and fundamental science
Start Year 2010
 
Description Host factors influencing HCV pathogenesis 
Organisation University of Oxford
Department Nuffield Department of Experimental Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We are looking at the factors influencing infection and pathogenesis of HCV infections in humans at the molecular level. To date we have looked at host responses to HCV genotypes and studied the effects of chronic HCV on the liver transcriptome. We have established a pipeline for the analysis of RNA-Seq data from archived liver biopsies. Our key findings are: (a) significant enrichment of interferon-regulated and immune pathways, (b) changes that occur during disease progression (i.e. fibrosis/cirrhosis) are not present at the early stages of chronic infection, (c) genotype 1 HCV induces a higher level of pro-inflammatory gene expression compared to genotype 3 HCV, (d) up-regulation of type I IFN inducible genes is seen in early stage chronic HCV, (e) pro-apoptotic IFN genes are not strongly induced, and (f) antiviral pathways that are able to down-regulate IFN signalling are up-regulated.
Collaborator Contribution Provided valuable patient samples; made important contributions in terms of ideas and input from clinical perspective
Impact Five studies published (PMID:23931242, PMID: 25200131, PMID: 25800823, PMID: 26912610, PMID: 27405885). Further studies on hightroughput sequencing of data patient biopsies have revealed interesting information. Briefly, HCV gentoype (gt) 1-infected biopsies displayed elevated levels of transcripts regulated by Type I and Type III interferon (IFN), including genes that predict response to IFNa therapy. In contrast, genes controlled by IFN? were induced in gt3-infected biopsies. Moreover, IFN? levels were higher in gt3 samples compared to gt1 and control biopsies. Analysis of hepatocyte-derived cell lines confirmed that the genes up-regulated in gt3 infection were predominantly induced by IFN?. The distinct interactions of the two viral genotypes with hepatic cells may explain differences in the progression of disease pathology and treatment response under both IFN-based treatments and novel direct acting antivirals. A separate study demonstrated the presence of anti-HCV envelope antibody responses in individuals at high risk of HCV who resist infection. These antibodies may be a factor that helps these individuals resist HCV infection. We are also obtaining data on antibody responses in a small cohort of patients and at-risk individuals as follows: • Studied broad cross-genotypic antibody responses in clinical cohorts, their epitope targets and clinical associations. Showed patients with broad neutralizing responses usually target multiple epitopes and they are associated with lower rates of fibrosis and may predict slower disease progression. • In collaboration with Dr Paul Kellam (University of Cambridge) we are investigating the diversity of immunoglobulin repertoire in acute and chronic infections using next generation sequencing methods. In parallel, we plan to set up assays to measure B-cell repertoire (from patients at different disease stages and infected with different genotypes) at the functional level (manuscript in prepatration). • Studied neutralising anti-envelope antibodies in unifected individuals that are repeatedly exposed to HCV (in collaboration with Matthew Cramp, University of Plymouth). This is a unique cohort of individuals who resist HCV infection despite repeated exposure. We showed that a subset of individuals produce neutralizing anti-envelope antibodies which may contribute to host immunity. Further exploring regions targeted by these antibodies may yield novel epitopes for vaccine design (manuscript published). Multi-disciplinary: Clinical and fundamental science
Start Year 2010
 
Description Human monoclonal antibodies to HCV E2 
Organisation Stanford University
Country United States 
Sector Academic/University 
PI Contribution Continuing characterization of the broadly neutralizing properties of several several human human monoclonal antibodies to hepatitis C virus E2 glycoprotein. Provided reagents and made intellectual contributions. A detailed functional analyses of different HCV mutants carrying substitution mutations in a region of the viral E2 glycprotein that is a target of our broadly neutralizing antibody AP33
Collaborator Contribution Provision of antibodies and experimental data, including performing characterization of mutant viruses.
Impact Several publications: PMID: 17079294; 17990788; 18272755; 18385242; 18400849; 19321602; 22511875; 23097455; 20237087; 21697343; 22993159; 25122476
Start Year 2006
 
Description In vitro cell culture model for HBV and HCV infection 
Organisation Shantou University Medical College, China
Country China 
Sector Academic/University 
PI Contribution Following our previous collaboration, our current contribution is limited to supplying crucial reagents and providing scientific input. Our aims are to establish an in vitro human embryonic stem cell-derived hepatocyte model to investigate mechanisms of hepatitis B virus (HBV) reactivation in HBV/hepatitis C virus (HCV) co-infected patients treated with the anti-HCV direct-acting antiviral (DAA) drugs.
Collaborator Contribution Generation of stem cell-based models and testing virus infection.
Impact Studies are continuing. Collaboration is multidisciplinary involving human stem cell biology, virology and immunology
Start Year 2018
 
Description In vivo analysis of HCV neutralizing antibodies 
Organisation University of Ghent
Department Center for Vaccinology
Country Belgium 
Sector Academic/University 
PI Contribution Assessment of antibodies of interest in in vitro assays and in cultured cells infected with HCV.
Collaborator Contribution Antibodies of interest have been tested and analysed for their effects on HCV infection in the chimeric human liver uPA-SCID mouse model. Specifically, we show that our broadly neutralizing antibody AP33 is capable of protecting mice upon challenge with a clinical isolate of hepatitis C virus. Our humanised antibody AP33 is currently being tested the above uPA-SCID mouse model.
Impact Data presented preseneted at the HCV2012 and AASLD 2012 meeting. A paper published (PMID: 26710081). Two moe papers published recently (PMID: 29074219, 29128754)
Start Year 2011
 
Description In vivo analysis of HCV neutralizing antibodies 
Organisation University of Strasbourg
Country France 
Sector Academic/University 
PI Contribution Assessment of antibodies of interest in in vitro assays and in cultured cells infected with HCV.
Collaborator Contribution Antibodies of interest have been tested and analysed for their effects on HCV infection in the chimeric human liver uPA-SCID mouse model. Specifically, we show that our broadly neutralizing antibody AP33 is capable of protecting mice upon challenge with a clinical isolate of hepatitis C virus. Our humanised antibody AP33 is currently being tested the above uPA-SCID mouse model.
Impact Data presented preseneted at the HCV2012 and AASLD 2012 meeting. A paper published (PMID: 26710081). Two moe papers published recently (PMID: 29074219, 29128754)
Start Year 2011
 
Description Interaction of HBV and HDV with the host cell 
Organisation National Institute of Infectious Diseases
Country Japan 
Sector Public 
PI Contribution This is a recently established collaboration that arose from the joint initiative between the MRC and the Japanese national funder, AMED, to investigate 'infection research in a global context' which is specified as a priority field. This collaboration is underway where our specific input involves provisions of a cell lines and antibodies of interest, and establishment of an in vitro HBV/HDV infections systems, with a view to performing virus antibody neutralisation assays and studying virus-host interactions.
Collaborator Contribution Provisions of a cell lines and antibodies. Establishing in vitro HBV/HDV infections systems, and screen of interferon-stimulated genes for their ability to inhibit virus infection.
Impact No outputs yet as the work is on-going. HBV and HDV infection systems have been established.
Start Year 2017
 
Description Interaction of HBV and HDV with the host cell 
Organisation University of Glasgow
Department MRC - University of Glasgow Centre for Virus Research
Country United Kingdom 
Sector Academic/University 
PI Contribution This is a recently established collaboration that arose from the joint initiative between the MRC and the Japanese national funder, AMED, to investigate 'infection research in a global context' which is specified as a priority field. This collaboration is underway where our specific input involves provisions of a cell lines and antibodies of interest, and establishment of an in vitro HBV/HDV infections systems, with a view to performing virus antibody neutralisation assays and studying virus-host interactions.
Collaborator Contribution Provisions of a cell lines and antibodies. Establishing in vitro HBV/HDV infections systems, and screen of interferon-stimulated genes for their ability to inhibit virus infection.
Impact No outputs yet as the work is on-going. HBV and HDV infection systems have been established.
Start Year 2017
 
Description Investigating the structural basis HCV entry and neutralization by cryo-EM 
Organisation University of Glasgow
Department MRC - University of Glasgow Centre for Virus Research
Country United Kingdom 
Sector Academic/University 
PI Contribution Generation and optimization of virus particles and neutralization assays for electron tomography. Provided reagents and advice to generate recombinant hepatitis B virus (HBV) capsid carrying an hepatitis C virus (HCV) E2 glycoprotein fragment representing an epitope of our braodly neutralizing mouse monoclonal antibody (MAb) AP33.
Collaborator Contribution Developing imaging and image processing protocols, performing electron tomography protocols. Cryo-electron micrography/image reconstruction of HBV capsid carrying the MAb AP33 epitope.
Impact Work in progress. The HBV capsid particles displaying the MAb AP33 epitope will be used for vaccine development. Multi-disciplinary: Virology, molecular biology, electron microscopy, structural
Start Year 2011
 
Description Novel anti-HCV antibodies and their analyses 
Organisation Hannover Medical School
Department Institute for Virology
Country Germany 
Sector Academic/University 
PI Contribution Generated novel mouse monoclonal antibodies targeting different regions of HCV envelope glycoprotein E2 and performed their detailed functional characterization. Two of these (MAbs DAO1 and DAO3) were found to target novel conformation-sensitive epitopes on E2. We also identified one antibody (MAb DAO5) that bound to a major virus receptor binding site (aa 523-540) which forms part of the central immunoglobulin (Ig)-like domain within HCV E2. A detailed epitope mapping experiments identified aa D535 to be crucial for DAO5 recognition of E2. Interestingly, D535 is also critical for the interation between HCV E2 and CD81, a host factor essential for virus entry. Curiously though, MAb DAO5 did not neutralize virus infection. We have now obtained a crystal structure of the epitope peptide in compelx with MAb DAO5 in collaboration with scientists at Pasteur Inst, Paris. Together, our results suggest that the E2 segment spanning aa 529-540 is structurally flexible.
Collaborator Contribution Determined the crystal structure of analysis of MAb DAO5 in complex with a peptide representing its epitope (E2 aa 529-540). These data showed that the peptide in complex with DAO5 adopted a helical conformation that is in stark contrast to the extended conformation observed in the E2 core structure. It was also observed that MAb DAO5 binds to soluble E2 (sE2) in a temperature-dependent manner and despite the lack of neutralizing activity it directly cross-competes with the virus receptor CD81 and other conformational neutralizing mAbs recognizing a critical epitope residue (D535). These results suggest that mAb DAO5 recognizes natively folded sE2 locally displaying a high degree of flexibility in this crucial CD81 binding region.
Impact A manuscript describing the structural basis of the conformational flexibility in the central Ig-like domain of E2 is published in mBio (PMID: 28512091). Multidisciplinary: Virology, molecular biology, immunology, protein structure and function
Start Year 2010
 
Description Novel anti-HCV antibodies and their analyses 
Organisation Pasteur Institute, Paris
Country France 
Sector Charity/Non Profit 
PI Contribution Generated novel mouse monoclonal antibodies targeting different regions of HCV envelope glycoprotein E2 and performed their detailed functional characterization. Two of these (MAbs DAO1 and DAO3) were found to target novel conformation-sensitive epitopes on E2. We also identified one antibody (MAb DAO5) that bound to a major virus receptor binding site (aa 523-540) which forms part of the central immunoglobulin (Ig)-like domain within HCV E2. A detailed epitope mapping experiments identified aa D535 to be crucial for DAO5 recognition of E2. Interestingly, D535 is also critical for the interation between HCV E2 and CD81, a host factor essential for virus entry. Curiously though, MAb DAO5 did not neutralize virus infection. We have now obtained a crystal structure of the epitope peptide in compelx with MAb DAO5 in collaboration with scientists at Pasteur Inst, Paris. Together, our results suggest that the E2 segment spanning aa 529-540 is structurally flexible.
Collaborator Contribution Determined the crystal structure of analysis of MAb DAO5 in complex with a peptide representing its epitope (E2 aa 529-540). These data showed that the peptide in complex with DAO5 adopted a helical conformation that is in stark contrast to the extended conformation observed in the E2 core structure. It was also observed that MAb DAO5 binds to soluble E2 (sE2) in a temperature-dependent manner and despite the lack of neutralizing activity it directly cross-competes with the virus receptor CD81 and other conformational neutralizing mAbs recognizing a critical epitope residue (D535). These results suggest that mAb DAO5 recognizes natively folded sE2 locally displaying a high degree of flexibility in this crucial CD81 binding region.
Impact A manuscript describing the structural basis of the conformational flexibility in the central Ig-like domain of E2 is published in mBio (PMID: 28512091). Multidisciplinary: Virology, molecular biology, immunology, protein structure and function
Start Year 2010
 
Description Novel in vitro model for HCV infection and replication 
Organisation Shantou University Medical College, China
Country China 
Sector Academic/University 
PI Contribution This study led to the establishment of a novel human embryonic stem cell-derived hepatocyte system for propagation of hepatitis C virus in my lab. We also showed that this system is phenotypically closer to human liver hepatocytes and as such has allowed us to identify novel virus-host interactions that are not seen in the existing widely used hepatoma-based cell culture system for studying HCV life cycle. This work was funded by the MRC UK-China Stem Cell partnership Development Initiative (PI - Edinburgh partner; Co-PI - myself).
Collaborator Contribution University of Edinburgh partner provided the stem cell-derived hepatocytes and related functional characterization. Shantou partners performed the work stem cell-related work at Edinburgh (differentiation into human hepatocytes and phenotypic characterization) and virus-related study (in vitro infection, virus spread assays, virus-host interaction) in my lab.
Impact PMID: 24201130 PMID: 25068132 Multidisciplinary: Regenerative medicine, stem cell biology, virology, molecular biology
Start Year 2011
 
Description Novel in vitro model for HCV infection and replication 
Organisation University of Edinburgh
Department MRC Centre for Regenerative Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution This study led to the establishment of a novel human embryonic stem cell-derived hepatocyte system for propagation of hepatitis C virus in my lab. We also showed that this system is phenotypically closer to human liver hepatocytes and as such has allowed us to identify novel virus-host interactions that are not seen in the existing widely used hepatoma-based cell culture system for studying HCV life cycle. This work was funded by the MRC UK-China Stem Cell partnership Development Initiative (PI - Edinburgh partner; Co-PI - myself).
Collaborator Contribution University of Edinburgh partner provided the stem cell-derived hepatocytes and related functional characterization. Shantou partners performed the work stem cell-related work at Edinburgh (differentiation into human hepatocytes and phenotypic characterization) and virus-related study (in vitro infection, virus spread assays, virus-host interaction) in my lab.
Impact PMID: 24201130 PMID: 25068132 Multidisciplinary: Regenerative medicine, stem cell biology, virology, molecular biology
Start Year 2011
 
Description Oncogenic role of DDX3 
Organisation Johns Hopkins Medicine
Department Department of Radiology and Radiological Sciences
Country United States 
Sector Academic/University 
PI Contribution Provided significant intellectual input and supplied relevant reagents
Collaborator Contribution Defined the role of DDX3 in promoting growth, proliferation and neoplastic transformation of breast epithelial cells.
Impact Publications: PMID - 18264132; 21448281; 23696831; 28761359 Our recent studies indicate that nuclear DDX3 is partially CRM1-mediated and predicts worse survival in colorectal and breast cancers, putting it forward as a target for therapeutic intervention with DDX3 inhibitors under development in these cancer types.
Start Year 2006
 
Description Predicting effectiveness of HCV NAbs using HCV-GLUE platform 
Organisation University of Glasgow
Department MRC - University of Glasgow Centre for Virus Research
Country United Kingdom 
Sector Academic/University 
PI Contribution We have used HCV-GLUE, a bioinformatics resource for HCV sequence data, to investigate the major epitopes targeted by well-characterized broadly neutralizing antibodies (bNAbs) to hepatitis C virus. A functional analysis emerging from the bioinformatics studies is under progress.
Collaborator Contribution The partners developed and provided the HCV-GLUE platform and their bioinformatics expertise in data analyses.
Impact A manuscript published (PMID: 30013555). The HCV GLUE platform is being used to analyse the epitope residues of a new anti-HCV E2 antibody we have generated. Our current data indicate that the epitope of this antibody is unique and discontinuous. Further biochemical experiments are underway to gain a better insight into the epitope.
Start Year 2017
 
Description Role of natural killer cell receptors in HCV infection 
Organisation University of Southampton
Country United Kingdom 
Sector Academic/University 
PI Contribution Generating and provision of cell lines co-expressing HCV replicons and different human HLA alleles of interest.
Collaborator Contribution Performing all immunology and cell killing experiments.
Impact A paper published in Science Immunology (PMID: 28916719 ).
Start Year 2014
 
Description SFTSV vaccine development 
Organisation Chinese Academy of Sciences
Country China 
Sector Public 
PI Contribution Our contribution involves provision of scientific input on vaccine development, monoclonal antibody production, virus neutralisation assays, animal models to assess in vivo efficacy of novel vaccines, and animal pathogenesis studies. The work is funded by the BBSRC grant (BB/R019800/1) on which I am a co-applicant.
Collaborator Contribution Our partner is a Principle Applicant. There are several partners on this project. Their collective contribution is to perform the planned experiments.
Impact Work is multidisciplinary involving cell biology, virology, structural biology, vaccine development, and animal pathogenesis. Animal infection models have been set up and prelinary results are encouraging.
Start Year 2018
 
Description SFTSV vaccine development 
Organisation University of Glasgow
Department MRC - University of Glasgow Centre for Virus Research
Country United Kingdom 
Sector Academic/University 
PI Contribution Our contribution involves provision of scientific input on vaccine development, monoclonal antibody production, virus neutralisation assays, animal models to assess in vivo efficacy of novel vaccines, and animal pathogenesis studies. The work is funded by the BBSRC grant (BB/R019800/1) on which I am a co-applicant.
Collaborator Contribution Our partner is a Principle Applicant. There are several partners on this project. Their collective contribution is to perform the planned experiments.
Impact Work is multidisciplinary involving cell biology, virology, structural biology, vaccine development, and animal pathogenesis. Animal infection models have been set up and prelinary results are encouraging.
Start Year 2018
 
Description Screening of antiviral compounds 
Organisation King's College School
Country United Kingdom 
Sector Academic/University 
PI Contribution Acquired state-of-the art robotic systems to establish high-throughput screening facility within the CVR. Developed and validated HTS assays to investigate the different stages of HCV life cycle (requiring work under containment levels 2 and 3). Compound library screens identified several novel hits inhibiting different stages of HCV entry and post-entry events. These compounds are proving very useful in our studies to dissect viral processes at the mechanistic level, and their antiviral potential is being further developed for treatment to control and eliminate infection.
Collaborator Contribution Provision of novel DNA minor groove compounds, nucleoside analogues and estrogens. A large part of the study involving the latter was performed at Università del Piemonte Orientale, Novara, Italy. More recently, compounds developed by our King's College partners were evaluated.
Impact Identified novel inhibitors acting at different stages of HCV life cycle (e.g. virus entry, genome translation & amp; replication, virus assembly and secretion). 4 papers published to date (PMID: 26428870, 27406141, 27885811, 30661824).
Start Year 2011
 
Description Screening of antiviral compounds 
Organisation Northumbria University
Country United Kingdom 
Sector Academic/University 
PI Contribution Acquired state-of-the art robotic systems to establish high-throughput screening facility within the CVR. Developed and validated HTS assays to investigate the different stages of HCV life cycle (requiring work under containment levels 2 and 3). Compound library screens identified several novel hits inhibiting different stages of HCV entry and post-entry events. These compounds are proving very useful in our studies to dissect viral processes at the mechanistic level, and their antiviral potential is being further developed for treatment to control and eliminate infection.
Collaborator Contribution Provision of novel DNA minor groove compounds, nucleoside analogues and estrogens. A large part of the study involving the latter was performed at Università del Piemonte Orientale, Novara, Italy. More recently, compounds developed by our King's College partners were evaluated.
Impact Identified novel inhibitors acting at different stages of HCV life cycle (e.g. virus entry, genome translation & amp; replication, virus assembly and secretion). 4 papers published to date (PMID: 26428870, 27406141, 27885811, 30661824).
Start Year 2011
 
Description Screening of antiviral compounds 
Organisation Russian Academy of Sciences
Department Engelhardt Institute of Molecular Biology (EIMB)
Country Russian Federation 
Sector Academic/University 
PI Contribution Acquired state-of-the art robotic systems to establish high-throughput screening facility within the CVR. Developed and validated HTS assays to investigate the different stages of HCV life cycle (requiring work under containment levels 2 and 3). Compound library screens identified several novel hits inhibiting different stages of HCV entry and post-entry events. These compounds are proving very useful in our studies to dissect viral processes at the mechanistic level, and their antiviral potential is being further developed for treatment to control and eliminate infection.
Collaborator Contribution Provision of novel DNA minor groove compounds, nucleoside analogues and estrogens. A large part of the study involving the latter was performed at Università del Piemonte Orientale, Novara, Italy. More recently, compounds developed by our King's College partners were evaluated.
Impact Identified novel inhibitors acting at different stages of HCV life cycle (e.g. virus entry, genome translation & amp; replication, virus assembly and secretion). 4 papers published to date (PMID: 26428870, 27406141, 27885811, 30661824).
Start Year 2011
 
Description Screening of antiviral compounds 
Organisation University of Eastern Piedmont
Country Italy 
Sector Academic/University 
PI Contribution Acquired state-of-the art robotic systems to establish high-throughput screening facility within the CVR. Developed and validated HTS assays to investigate the different stages of HCV life cycle (requiring work under containment levels 2 and 3). Compound library screens identified several novel hits inhibiting different stages of HCV entry and post-entry events. These compounds are proving very useful in our studies to dissect viral processes at the mechanistic level, and their antiviral potential is being further developed for treatment to control and eliminate infection.
Collaborator Contribution Provision of novel DNA minor groove compounds, nucleoside analogues and estrogens. A large part of the study involving the latter was performed at Università del Piemonte Orientale, Novara, Italy. More recently, compounds developed by our King's College partners were evaluated.
Impact Identified novel inhibitors acting at different stages of HCV life cycle (e.g. virus entry, genome translation & amp; replication, virus assembly and secretion). 4 papers published to date (PMID: 26428870, 27406141, 27885811, 30661824).
Start Year 2011
 
Description Screening of antiviral compounds 
Organisation University of Strathclyde
Department Strathclyde Institute of Pharmacy & Biomedical Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Acquired state-of-the art robotic systems to establish high-throughput screening facility within the CVR. Developed and validated HTS assays to investigate the different stages of HCV life cycle (requiring work under containment levels 2 and 3). Compound library screens identified several novel hits inhibiting different stages of HCV entry and post-entry events. These compounds are proving very useful in our studies to dissect viral processes at the mechanistic level, and their antiviral potential is being further developed for treatment to control and eliminate infection.
Collaborator Contribution Provision of novel DNA minor groove compounds, nucleoside analogues and estrogens. A large part of the study involving the latter was performed at Università del Piemonte Orientale, Novara, Italy. More recently, compounds developed by our King's College partners were evaluated.
Impact Identified novel inhibitors acting at different stages of HCV life cycle (e.g. virus entry, genome translation & amp; replication, virus assembly and secretion). 4 papers published to date (PMID: 26428870, 27406141, 27885811, 30661824).
Start Year 2011
 
Description Screening of antiviral compounds 
Organisation Volgograd State Medical University
Country Russian Federation 
Sector Academic/University 
PI Contribution Acquired state-of-the art robotic systems to establish high-throughput screening facility within the CVR. Developed and validated HTS assays to investigate the different stages of HCV life cycle (requiring work under containment levels 2 and 3). Compound library screens identified several novel hits inhibiting different stages of HCV entry and post-entry events. These compounds are proving very useful in our studies to dissect viral processes at the mechanistic level, and their antiviral potential is being further developed for treatment to control and eliminate infection.
Collaborator Contribution Provision of novel DNA minor groove compounds, nucleoside analogues and estrogens. A large part of the study involving the latter was performed at Università del Piemonte Orientale, Novara, Italy. More recently, compounds developed by our King's College partners were evaluated.
Impact Identified novel inhibitors acting at different stages of HCV life cycle (e.g. virus entry, genome translation & amp; replication, virus assembly and secretion). 4 papers published to date (PMID: 26428870, 27406141, 27885811, 30661824).
Start Year 2011
 
Description Structure of AP33 and related vaccine studies 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Generated and purified large quantities of the hepatitis C virus (HCV) monoclonal antibody (MAb) AP33 Fab fragment (a pan-genotypic virus neutralizing antibody) and supplied appropriate peptides to University of St Andrews for co-crystallisation studies. We used MAb AP33 as a template to reverse engineer an immunogen that induces similar antibodies upon vaccination. To our knowledge, this is the first time in the HCV vaccine field, the success of such a focused, structure-based approach has been demonstrated. We have supplied this candidate vaccine to our University of St Andrews collaborator for structural studies. We recently established collaoartion with ICL to validate this vaccine in vivo in an HCV infection small animal model In collaboration with the group at University of Naples Federico II, Naples we characterised monoclonal antibodies generated in animals following immunisation with a cyclic peptide representing the AP33 epitope for binding to the HCV glycoprotein E2 and for virus neutralising activity. In collaboration with the Intercollegiate Faculty of Biotechnology , Gdansk, analysed sera from animals immunised with the hepatitis B virus surface antigen-based virus-like particles displaying the AP33 epitope.
Collaborator Contribution Determined the crystal structure of the antibody AP33 bound to its epitope peptide and just recently recently, that of our vaccine candidate in complex with AP33. Further structural analysis of the latter is currently in progress. The University of Naples Federico II group generated antibodies to the cyclic variant of the peptide corresponding to the AP33 epitope and performed their structural analyses when bound to the peptide. Intercollegiate Faculty of Biotechnology , Gdansk, developed a hepatitis B virus surface antigen-based virus-like particles displaying the AP33 epitope for vaccine research Our collaborators at the ICL have shown protection from HCV infection in a chimeric human live mouse model following passive immunization with serum IgGs derived from mice vaccinated with our anti-idiotype antibody vaccine. This work is currently being prepared for submission for publication.
Impact We have recently crystallized MAb AP33 bound to its cognate epitope sequence which identified antibody residues essential for this interaction. Based on this we are generated mutated derivatives of this antibody which are proving very useful in our on-going studies on understanding the antigen-antibody interactions at both structural and biochemical levels (Paper published: PMID 22993159). As an extension to this work, we have a novel vaccine candidate capable of eliciting MAb AP33-like anitbodies in immunized animals. Furthermore, a crystal structure of this antibody-based vaccine candidate in complex with its ligand has just been generated. Further work (including in vivo evaluation of the vaccine) is in progress. Indeed, more recently our collaborators at the ICL have shown protection from HCV infection in a chimeric human live mouse model following passive immunization with serum IgGs derived from mice vaccinated with our anti-idiotype antibody vaccine. We explored the potential of cyclic peptides mimicking the AP33 epitope structure to elicit anti-HCV antibodies. Antibodiess that specifically recognize a cyclic variant of the epitope bound to soluble E2 with a lower affinity than other blocking antibodies and do not neutralize virus. The structure of the complex between one such antibody and the cyclic epitope, together with new structural data showing the linear peptide bound to neutralizing antibodies in extended conformations, suggests that the epitope displays a conformational flexibility that contributes to neutralization escape. Such features can be of major importance for the design of epitope-based anti-HCV vaccines (published PMID:26819303). Collaboration is multidisciplinary involving Protein biochemistry, molecular biology, structural biology and virology.
Start Year 2009
 
Description Structure of AP33 and related vaccine studies 
Organisation Medical University of Gdansk
Department Intercollegiate Faculty of Biotechnology
Country Poland 
Sector Academic/University 
PI Contribution Generated and purified large quantities of the hepatitis C virus (HCV) monoclonal antibody (MAb) AP33 Fab fragment (a pan-genotypic virus neutralizing antibody) and supplied appropriate peptides to University of St Andrews for co-crystallisation studies. We used MAb AP33 as a template to reverse engineer an immunogen that induces similar antibodies upon vaccination. To our knowledge, this is the first time in the HCV vaccine field, the success of such a focused, structure-based approach has been demonstrated. We have supplied this candidate vaccine to our University of St Andrews collaborator for structural studies. We recently established collaoartion with ICL to validate this vaccine in vivo in an HCV infection small animal model In collaboration with the group at University of Naples Federico II, Naples we characterised monoclonal antibodies generated in animals following immunisation with a cyclic peptide representing the AP33 epitope for binding to the HCV glycoprotein E2 and for virus neutralising activity. In collaboration with the Intercollegiate Faculty of Biotechnology , Gdansk, analysed sera from animals immunised with the hepatitis B virus surface antigen-based virus-like particles displaying the AP33 epitope.
Collaborator Contribution Determined the crystal structure of the antibody AP33 bound to its epitope peptide and just recently recently, that of our vaccine candidate in complex with AP33. Further structural analysis of the latter is currently in progress. The University of Naples Federico II group generated antibodies to the cyclic variant of the peptide corresponding to the AP33 epitope and performed their structural analyses when bound to the peptide. Intercollegiate Faculty of Biotechnology , Gdansk, developed a hepatitis B virus surface antigen-based virus-like particles displaying the AP33 epitope for vaccine research Our collaborators at the ICL have shown protection from HCV infection in a chimeric human live mouse model following passive immunization with serum IgGs derived from mice vaccinated with our anti-idiotype antibody vaccine. This work is currently being prepared for submission for publication.
Impact We have recently crystallized MAb AP33 bound to its cognate epitope sequence which identified antibody residues essential for this interaction. Based on this we are generated mutated derivatives of this antibody which are proving very useful in our on-going studies on understanding the antigen-antibody interactions at both structural and biochemical levels (Paper published: PMID 22993159). As an extension to this work, we have a novel vaccine candidate capable of eliciting MAb AP33-like anitbodies in immunized animals. Furthermore, a crystal structure of this antibody-based vaccine candidate in complex with its ligand has just been generated. Further work (including in vivo evaluation of the vaccine) is in progress. Indeed, more recently our collaborators at the ICL have shown protection from HCV infection in a chimeric human live mouse model following passive immunization with serum IgGs derived from mice vaccinated with our anti-idiotype antibody vaccine. We explored the potential of cyclic peptides mimicking the AP33 epitope structure to elicit anti-HCV antibodies. Antibodiess that specifically recognize a cyclic variant of the epitope bound to soluble E2 with a lower affinity than other blocking antibodies and do not neutralize virus. The structure of the complex between one such antibody and the cyclic epitope, together with new structural data showing the linear peptide bound to neutralizing antibodies in extended conformations, suggests that the epitope displays a conformational flexibility that contributes to neutralization escape. Such features can be of major importance for the design of epitope-based anti-HCV vaccines (published PMID:26819303). Collaboration is multidisciplinary involving Protein biochemistry, molecular biology, structural biology and virology.
Start Year 2009
 
Description Structure of AP33 and related vaccine studies 
Organisation University of Naples
Department Institute of Biostructures and Bioimaging
Country Italy 
Sector Academic/University 
PI Contribution Generated and purified large quantities of the hepatitis C virus (HCV) monoclonal antibody (MAb) AP33 Fab fragment (a pan-genotypic virus neutralizing antibody) and supplied appropriate peptides to University of St Andrews for co-crystallisation studies. We used MAb AP33 as a template to reverse engineer an immunogen that induces similar antibodies upon vaccination. To our knowledge, this is the first time in the HCV vaccine field, the success of such a focused, structure-based approach has been demonstrated. We have supplied this candidate vaccine to our University of St Andrews collaborator for structural studies. We recently established collaoartion with ICL to validate this vaccine in vivo in an HCV infection small animal model In collaboration with the group at University of Naples Federico II, Naples we characterised monoclonal antibodies generated in animals following immunisation with a cyclic peptide representing the AP33 epitope for binding to the HCV glycoprotein E2 and for virus neutralising activity. In collaboration with the Intercollegiate Faculty of Biotechnology , Gdansk, analysed sera from animals immunised with the hepatitis B virus surface antigen-based virus-like particles displaying the AP33 epitope.
Collaborator Contribution Determined the crystal structure of the antibody AP33 bound to its epitope peptide and just recently recently, that of our vaccine candidate in complex with AP33. Further structural analysis of the latter is currently in progress. The University of Naples Federico II group generated antibodies to the cyclic variant of the peptide corresponding to the AP33 epitope and performed their structural analyses when bound to the peptide. Intercollegiate Faculty of Biotechnology , Gdansk, developed a hepatitis B virus surface antigen-based virus-like particles displaying the AP33 epitope for vaccine research Our collaborators at the ICL have shown protection from HCV infection in a chimeric human live mouse model following passive immunization with serum IgGs derived from mice vaccinated with our anti-idiotype antibody vaccine. This work is currently being prepared for submission for publication.
Impact We have recently crystallized MAb AP33 bound to its cognate epitope sequence which identified antibody residues essential for this interaction. Based on this we are generated mutated derivatives of this antibody which are proving very useful in our on-going studies on understanding the antigen-antibody interactions at both structural and biochemical levels (Paper published: PMID 22993159). As an extension to this work, we have a novel vaccine candidate capable of eliciting MAb AP33-like anitbodies in immunized animals. Furthermore, a crystal structure of this antibody-based vaccine candidate in complex with its ligand has just been generated. Further work (including in vivo evaluation of the vaccine) is in progress. Indeed, more recently our collaborators at the ICL have shown protection from HCV infection in a chimeric human live mouse model following passive immunization with serum IgGs derived from mice vaccinated with our anti-idiotype antibody vaccine. We explored the potential of cyclic peptides mimicking the AP33 epitope structure to elicit anti-HCV antibodies. Antibodiess that specifically recognize a cyclic variant of the epitope bound to soluble E2 with a lower affinity than other blocking antibodies and do not neutralize virus. The structure of the complex between one such antibody and the cyclic epitope, together with new structural data showing the linear peptide bound to neutralizing antibodies in extended conformations, suggests that the epitope displays a conformational flexibility that contributes to neutralization escape. Such features can be of major importance for the design of epitope-based anti-HCV vaccines (published PMID:26819303). Collaboration is multidisciplinary involving Protein biochemistry, molecular biology, structural biology and virology.
Start Year 2009
 
Description Structure of AP33 and related vaccine studies 
Organisation University of St Andrews
Department Centre for Biomolecular Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Generated and purified large quantities of the hepatitis C virus (HCV) monoclonal antibody (MAb) AP33 Fab fragment (a pan-genotypic virus neutralizing antibody) and supplied appropriate peptides to University of St Andrews for co-crystallisation studies. We used MAb AP33 as a template to reverse engineer an immunogen that induces similar antibodies upon vaccination. To our knowledge, this is the first time in the HCV vaccine field, the success of such a focused, structure-based approach has been demonstrated. We have supplied this candidate vaccine to our University of St Andrews collaborator for structural studies. We recently established collaoartion with ICL to validate this vaccine in vivo in an HCV infection small animal model In collaboration with the group at University of Naples Federico II, Naples we characterised monoclonal antibodies generated in animals following immunisation with a cyclic peptide representing the AP33 epitope for binding to the HCV glycoprotein E2 and for virus neutralising activity. In collaboration with the Intercollegiate Faculty of Biotechnology , Gdansk, analysed sera from animals immunised with the hepatitis B virus surface antigen-based virus-like particles displaying the AP33 epitope.
Collaborator Contribution Determined the crystal structure of the antibody AP33 bound to its epitope peptide and just recently recently, that of our vaccine candidate in complex with AP33. Further structural analysis of the latter is currently in progress. The University of Naples Federico II group generated antibodies to the cyclic variant of the peptide corresponding to the AP33 epitope and performed their structural analyses when bound to the peptide. Intercollegiate Faculty of Biotechnology , Gdansk, developed a hepatitis B virus surface antigen-based virus-like particles displaying the AP33 epitope for vaccine research Our collaborators at the ICL have shown protection from HCV infection in a chimeric human live mouse model following passive immunization with serum IgGs derived from mice vaccinated with our anti-idiotype antibody vaccine. This work is currently being prepared for submission for publication.
Impact We have recently crystallized MAb AP33 bound to its cognate epitope sequence which identified antibody residues essential for this interaction. Based on this we are generated mutated derivatives of this antibody which are proving very useful in our on-going studies on understanding the antigen-antibody interactions at both structural and biochemical levels (Paper published: PMID 22993159). As an extension to this work, we have a novel vaccine candidate capable of eliciting MAb AP33-like anitbodies in immunized animals. Furthermore, a crystal structure of this antibody-based vaccine candidate in complex with its ligand has just been generated. Further work (including in vivo evaluation of the vaccine) is in progress. Indeed, more recently our collaborators at the ICL have shown protection from HCV infection in a chimeric human live mouse model following passive immunization with serum IgGs derived from mice vaccinated with our anti-idiotype antibody vaccine. We explored the potential of cyclic peptides mimicking the AP33 epitope structure to elicit anti-HCV antibodies. Antibodiess that specifically recognize a cyclic variant of the epitope bound to soluble E2 with a lower affinity than other blocking antibodies and do not neutralize virus. The structure of the complex between one such antibody and the cyclic epitope, together with new structural data showing the linear peptide bound to neutralizing antibodies in extended conformations, suggests that the epitope displays a conformational flexibility that contributes to neutralization escape. Such features can be of major importance for the design of epitope-based anti-HCV vaccines (published PMID:26819303). Collaboration is multidisciplinary involving Protein biochemistry, molecular biology, structural biology and virology.
Start Year 2009
 
Description ZIka virus vaccine development 
Organisation International Centre for Genetic Engineering and Biotechnology
Country Italy 
Sector Academic/University 
PI Contribution Generation and evaluation of protein subunit-based Zika virus vaccine candidates. Generation and characterisation of immunological tools (polyclonal and monoclonal antibodies) that would be crucial for structure-function analyses of Zika viral envelope glycoprotein. Establishing small animal infection model. Demonstration the efficacy of our novel vaccine candidates in both animal and cell culture models.
Collaborator Contribution Provision of patient serum samples; in silico analysis of a Zika virus E glycoprotein-specific peptide (Oswaldo Cruz Foundation). Generation and evaluation of viral vector-based Zika virus vaccine candidates (Oxford). Provision of reagents and specific experimental assays (ICGEB-Trieste). EM structural studies of Zika virus particles bound with antibodies of interest (Centre for Virus Research). Establishment of virus transmission via mosquito bites into our in vivo virus-challenge model
Impact A manuscript entitled "Rational Zika vaccine design via the modulation of antigen membrane anchors in chimpanzee adenoviral vectors" published in Nat. Commun. 9(1):2441. doi: 10.1038/s41467-018-04859-5. PMID: 29934593. Another manuscript on our VLP-based vaccine is currently under review.
Start Year 2016
 
Description ZIka virus vaccine development 
Organisation Oswaldo Cruz Foundation (Fiocruz)
Department Research Center Aggeu Magalhães
Country Brazil 
Sector Academic/University 
PI Contribution Generation and evaluation of protein subunit-based Zika virus vaccine candidates. Generation and characterisation of immunological tools (polyclonal and monoclonal antibodies) that would be crucial for structure-function analyses of Zika viral envelope glycoprotein. Establishing small animal infection model. Demonstration the efficacy of our novel vaccine candidates in both animal and cell culture models.
Collaborator Contribution Provision of patient serum samples; in silico analysis of a Zika virus E glycoprotein-specific peptide (Oswaldo Cruz Foundation). Generation and evaluation of viral vector-based Zika virus vaccine candidates (Oxford). Provision of reagents and specific experimental assays (ICGEB-Trieste). EM structural studies of Zika virus particles bound with antibodies of interest (Centre for Virus Research). Establishment of virus transmission via mosquito bites into our in vivo virus-challenge model
Impact A manuscript entitled "Rational Zika vaccine design via the modulation of antigen membrane anchors in chimpanzee adenoviral vectors" published in Nat. Commun. 9(1):2441. doi: 10.1038/s41467-018-04859-5. PMID: 29934593. Another manuscript on our VLP-based vaccine is currently under review.
Start Year 2016
 
Description ZIka virus vaccine development 
Organisation University of Glasgow
Department School of Geographical and Earth Sciences Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution Generation and evaluation of protein subunit-based Zika virus vaccine candidates. Generation and characterisation of immunological tools (polyclonal and monoclonal antibodies) that would be crucial for structure-function analyses of Zika viral envelope glycoprotein. Establishing small animal infection model. Demonstration the efficacy of our novel vaccine candidates in both animal and cell culture models.
Collaborator Contribution Provision of patient serum samples; in silico analysis of a Zika virus E glycoprotein-specific peptide (Oswaldo Cruz Foundation). Generation and evaluation of viral vector-based Zika virus vaccine candidates (Oxford). Provision of reagents and specific experimental assays (ICGEB-Trieste). EM structural studies of Zika virus particles bound with antibodies of interest (Centre for Virus Research). Establishment of virus transmission via mosquito bites into our in vivo virus-challenge model
Impact A manuscript entitled "Rational Zika vaccine design via the modulation of antigen membrane anchors in chimpanzee adenoviral vectors" published in Nat. Commun. 9(1):2441. doi: 10.1038/s41467-018-04859-5. PMID: 29934593. Another manuscript on our VLP-based vaccine is currently under review.
Start Year 2016
 
Description ZIka virus vaccine development 
Organisation University of Oxford
Department Nuffield Department of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Generation and evaluation of protein subunit-based Zika virus vaccine candidates. Generation and characterisation of immunological tools (polyclonal and monoclonal antibodies) that would be crucial for structure-function analyses of Zika viral envelope glycoprotein. Establishing small animal infection model. Demonstration the efficacy of our novel vaccine candidates in both animal and cell culture models.
Collaborator Contribution Provision of patient serum samples; in silico analysis of a Zika virus E glycoprotein-specific peptide (Oswaldo Cruz Foundation). Generation and evaluation of viral vector-based Zika virus vaccine candidates (Oxford). Provision of reagents and specific experimental assays (ICGEB-Trieste). EM structural studies of Zika virus particles bound with antibodies of interest (Centre for Virus Research). Establishment of virus transmission via mosquito bites into our in vivo virus-challenge model
Impact A manuscript entitled "Rational Zika vaccine design via the modulation of antigen membrane anchors in chimpanzee adenoviral vectors" published in Nat. Commun. 9(1):2441. doi: 10.1038/s41467-018-04859-5. PMID: 29934593. Another manuscript on our VLP-based vaccine is currently under review.
Start Year 2016
 
Title ?C??????????????? 
Description ?????AP33?????????????????????????????????????????????????????????????1?????2??????23???????????VL CDR1(L1)?VL CDR2(L2)??VL CDR3(L3)????????????????24?????25??????26???????????VH CDR1(H1)?VH CDR2(H2)??VH CDR3(H3)?????????????????????????????? 
IP Reference JP2017527279 
Protection Patent granted
Year Protection Granted 2017
Licensed No
Impact None to date
 
Title ANTI-HEPATITIS C ANTIBODIES AND ANTIGEN BINDING FRAGMENTS THEREOF 
Description The invention provides an antibody or antigen binding fragment thereof capable of binding to the antigen binding pocket of the AP33 antibody, wherein said antibody or antigen binding fragment thereof comprises VL CDR1 (L1), VL CDR2 (L2), and VL CDR3 (L3) consisting of the amino acid sequences of SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:23 respectively, and comprises VH CDR1 (H1), VH CDR2 (H2), and VH CDR3 (H3) consisting of the amino acid sequences of SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26 respectively. The invention also provides compositions, methods, nucleic acids and uses. 
IP Reference US2017283484 
Protection Patent granted
Year Protection Granted 2017
Licensed No
Impact None to date
 
Title Anti-Hepatitis C antibodies and antigen binding fragments thereof 
Description The invention provides an antibody or antigen binding fragment thereof capable of binding to the antigen binding pocket of the AP 
IP Reference AU2015310671 
Protection Patent granted
Year Protection Granted 2017
Licensed No
Impact None to date
 
Title Humanised AP33 - MRCT10 
Description This is the humanized version of AP33 which was developed in collaboration with MRC Technology's Therapeutic Antibody Group 
IP Reference WO2009081285 
Protection Patent application published
Year Protection Granted 2009
Licensed Yes
Impact This antibody has therapeutic potential against HCV. Indeed, it has been recently licenced by the MRCT to a pharma in China.
 
Title Mouse monoclonal antibody (MAb) AP33 and its humanized derivative, MRCT10 
Description MAb AP33 recognizes a highly conserved linear region of the hepatitis C virus E2 glycoprotein which is essential for virus entry into target cells. This antibody blocks the interaction of E2 with CD81, a cellular receptor essential for virus entry. It also neutralizes infection of cells with diverse viral genotypes and subtypes. Given its broadly neutralizing properties, MAb AP33 was humanized in collaboration with the MRCT Therapeutic Antibody Group. The latter has recently been licenced to a pharma for therapeutic development. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2007
Development Status Actively seeking support
Impact The humanised MAb AP33, called MRCT10, is expected to be of direct clinical benefit for passive immunotherapy to reduce the risk of HCV infection after needlestick or other accidental exposure, and in the liver-transplant setting to reduce the incidence of graft re-infection. Furthermore, given its broadly neutralising properties, the epitope recognised by MAb AP33/MRCT10 can be considered a valid lead for vaccine design. 
 
Title Potential prophylactic vaccine, B2.1A 
Description B2.1A is an anti-idiotype antibody-based vaccine that is capable of eliciting antibodies target an epitope recognised by our broadly neutralizing antibody AP33 in vaccinated animals. A GB patent application (reference 1415714.3) was filed in 5th September 2014. Further data were added in the priority year. The efficacy of B2.1A is currently being evaluated in an immunocompetent mouse model of HCV via a collaborative study with Marcus Dorner at Imperial College. There is a collaborative agreement in place between the institutions (i.e. MRCT, GU, and Imperial), which addresses matters such as IP management and commercialisation. The intension is to market the technology once further data has been added to the patent application, as a licence and / or collaborative opportunity. Funding: MRC 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Initial development
Year Development Stage Completed 2015
Development Status Under active development/distribution
Impact Not yet, as the product is till under assessment 
 
Title ZIKV vaccine 
Description We have developed two candidate vaccines that, exposing ZIKV envelope protein locked in a dimeric conformation, are able to fully protect from ZIKV infection in mouse model. These vaccines are currently undergoing further pre-clinical evaluations. Our plan is to then forward our best candidate vaccine for GMP manufacture and subsequent clinical trials. This project is funded by the UK Department of Health. Further funding is being sought to advance our vaccine towards its clinical end-use. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2019
Development Status Under active development/distribution
Impact Our aim was to develop protein-based ZIKV vaccine candidates, e.g. virus-like particles (VLPs) and viral subunits like soluble Envelope protein (sE). We generated a mutant E sequence that creates a disulphide bridge between E dimers. This covalent stabilisation abrogates E trimerization avoiding the exposure of epitopes recognized by cross-reactive poorly neutralizing antibodies and forcing the viral protein to reveal Envelope Dimer Epitopes (EDE) instead. Our purpose is to focus the immune response against EDE, in order to elicit highly specific neutralizing antibodies, hopefully overcoming the risk of Antibody-Dependent Enhancement (ADE) of other Flavivirus infection. We used E covalent dimers (cvD) in form of soluble protein (sE-cvD) and VLPs (VLP-cvD). sE-cvD elicited high titres of anti-E antibodies with good neutralizing capacity against ZIKV in vaccinated mice. Two doses of vaccine fully protected the vaccinated mice from lethal challenge with no detectable viremia in blood and peripheral organs as brain, spleen, testis and ovaries. Similarly, VLP-cvD also elicited anti-E antibodies that were dimer-specific and were protective in our animal challenge model. The sera from immunized mice are currently being tested for passive protection and ADE of Dengue. Altogether, our results suggest that ZIKV E covalent dimers are a promising element for an effective ZIKV vaccine. 
 
Description Glasgow Science Festival - 'Outbreak' 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Schools
Results and Impact Since 2012, approximately 80 high school students have attended a workshop where they investigate a fictional virus outbreak using molecular biology and diagnostic methods.

The workshop received excellent evaluation feedback from participants.
Year(s) Of Engagement Activity 2012,2013
 
Description MRC Centenary Celebrations 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Over the course of two events in June 2013, we interacted with approximately 350 children and their families. We used these interactions to communicate some basic facts about viruses - focussing on their size, structure, routes of transmission and how to limit spread.

As part of the activity, we asked participants to consider the question 'If you were a virology researcher what would you study?' and collected responses using post-it note feedback. This provided a good opportunity to discuss the impact of medical research (we often used vaccines as an example), and the importance of the support of the Medical Research Council to help scientists tackle some of the greatest health problems facing humanity.

We have been invited to display the timeline at local schools and science centres across Scotland.
Year(s) Of Engagement Activity 2013
URL http://www.virusesacenturayofdiscovery.org.uk