title: Broad Anti-Hepatitis C Virus (HCV) Antibody Responses Are Associated with Improved Clinical Disease Parameters in Chronic HCV Infection.
abstract: During hepatitis C virus (HCV) infection, broadly neutralizing antibody (bNAb) responses targeting E1E2 envelope glycoproteins are generated in many individuals. It is unclear if these antibodies play a protective or a pathogenic role during chronic infection. In this study, we investigated whether bNAb responses in individuals with chronic infection were associated with differences in clinical presentation. Patient-derived purified serum IgG was used to assess the breadth of HCV E1E2 binding and the neutralization activity of HCV pseudoparticles. The binding and neutralization activity results for two panels bearing viral envelope proteins representing either an intergenotype or an intragenotype 1 group were compared. We found that the HCV load was negatively associated with strong cross-genotypic E1E2 binding (P= 0.03). Overall, we observed only a modest correlation between total E1E2 binding and neutralization ability. The breadth of intergenotype neutralization did not correlate with any clinical parameters; however, analysis of individuals with genotype 1 (gt1) HCV infection (n= 20), using an intragenotype pseudoparticle panel, found a strong association between neutralization breadth and reduced liver fibrosis (P= 0.006). A broad bNAb response in our cohort with chronic infection was associated with a single nucleotide polymorphism (SNP) in theHLA-DQB1 gene (P= 0.038), as previously reported in a cohort with acute disease. Furthermore, the bNAbs in these individuals targeted more than one region of E2-neutralizing epitopes, as assessed through cross-competition of patient bNAbs with well-characterized E2 antibodies. We conclude that the bNAb responses in patients with chronic gt1 infection are associated with lower rates of fibrosis and host genetics may play a role in the ability to raise such responses.
  
  
  OBJECTIVE
  Globally, there are 130 million to 150 million people with chronic HCV infection. Typically, the disease is progressive and is a major cause of severe liver cirrhosis and hepatocellular carcinoma. While it is known that neutralizing antibodies have a role in spontaneous clearance during acute infection, little is known about their role in chronic infection. In the present work, we investigated the antibody response in a cohort of chronically infected individuals and found that a broadly neutralizing antibody response is protective and is associated with reduced levels of liver fibrosis and cirrhosis. We also found an association between SNPs in class II HLA genes and the presence of a broadly neutralizing response, indicating that antigen presentation may be important for the production of HCV-neutralizing antibodies.
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Rachael E
authors.initials: RE
authors.lastname: Swann
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Cowton
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, United Kingdom.|School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Robinson
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Cole
authors.affiliation: Walton Liver Clinic, Glasgow Royal Infirmary, Glasgow, United Kingdom.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Barclay
authors.affiliation: Department of Gastroenterology, Gartnavel General Hospital, Glasgow, United Kingdom.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Mills
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Thomson
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: McLauchlan
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, United Kingdom Arvind.Patel@glasgow.ac.uk.
authors.forename: Arvind H
authors.initials: AH
authors.lastname: Patel
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology; D002460:Cell Line; D003429:Cross Reactions; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology; D005260:Female; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics; D016174:Hepacivirus / Q000145:classification / Q000235:genetics / Q000276:immunology*; D018937:Hepatitis C Antibodies / Q000097:blood / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000097:blood / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000821:virology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008103:Liver Cirrhosis / Q000209:etiology; D008297:Male; D008875:Middle Aged; D010802:Phylogeny; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology; D019562:Viral Load
chemical_list: D057134:Antibodies, Neutralizing; C087035:E1 protein, Hepatitis C virus; D000939:Epitopes; D006683:HLA-DQ Antigens; D018937:Hepatitis C Antibodies; D007074:Immunoglobulin G; D014759:Viral Envelope Proteins