Broad anti-hepatitis C virus (HCV) antibody responses are associated with improved clinical disease parameters in chronic HCV infection

Swann, R. E. , Cowton, V. M., Robinson, M. W., Cole, S. J., Barclay, S. T., Mills, P. R., Thomson, E. C. , McLauchlan, J. and Patel, A. (2016) Broad anti-hepatitis C virus (HCV) antibody responses are associated with improved clinical disease parameters in chronic HCV infection. Journal of Virology, 90(9), pp. 4530-4543. (doi:10.1128/JVI.02669-15) (PMID:26912610) (PMCID:PMC4836347)

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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 neutralization activity of HCV pseudoparticles. Two panels were compared, bearing viral envelope proteins representing either an inter-genotype or an intra-genotype (gt) 1 group. We found that HCV viral load was negatively associated with strong cross-genotypic E1E2 binding (P=0.03). Overall we observed only modest correlation between total E1E2 binding and neutralizing ability. The breadth of inter-genotype neutralization did not correlate with any clinical parameters, however, analysis of individuals with gt 1 HCV infection (n=20), using an intra-genotype pseudoparticle panel, found a strong association between neutralization breadth and reduced liver fibrosis (P=0.006). Broad bNAb response in our chronic cohort was associated with a single nucleotide polymorphism (SNP) in the HLA-DQB1 gene (P=0.038) as previously reported in an acute cohort. Furthermore 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 bNAb responses in chronic gt1 infection are associated with lower rates of fibrosis and host genetics may play a role in the ability to raise such responses. IMPORTANCE: Globally there are 130-150 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 investigate the antibody response in a cohort of chronically infected individuals and find that a broad neutralizing antibody response is protective, with reduced levels of liver fibrosis and cirrhosis. We also find an association with SNPs in class II HLA genes and the presence of a broad neutralizing response indicating that antigen presentation may be important for production of HCV neutralizing antibodies.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Robinson, Dr Mark and Cowton, Dr Vanessa and Swann, Rachael and Cole, Mrs Sarah and Thomson, Professor Emma and Patel, Professor Arvind and McLauchlan, Professor John
Authors: Swann, R. E., Cowton, V. M., Robinson, M. W., Cole, S. J., Barclay, S. T., Mills, P. R., Thomson, E. C., McLauchlan, J., and Patel, A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Virology
Publisher:American Society for Microbiology
ISSN (Online):1098-5514
Published Online:29 February 2016
Copyright Holders:Copyright © 2016 American Society for Microbiology
First Published:First published in Journal of Virology 90(9):4530-4543
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
656491Basis of the host range and tissue tropism for hepatitis C virusArvind PatelMedical Research Council (MRC)MC_UU_12014/2MVLS III - CENTRE FOR VIRUS RESEARCH
501441Centre for Integrated VirologyMassimo PalmariniMedical Research Council (MRC)G0801822MVLS III - CENTRE FOR VIRUS RESEARCH
645101T-cell mediated evolution of hepatitis C virus during acute infectionEmma ThomsonWellcome Trust (WELLCOME)102789/Z/13/ZMVLS III - CENTRE FOR VIRUS RESEARCH