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Antiviral Res. 2017 Dec;148:53-64. doi: 10.1016/j.antiviral.2017.10.015. Epub 2017 Oct 23.

A novel neutralizing human monoclonal antibody broadly abrogates hepatitis C virus infection in vitro and in vivo.

Author information

1
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium. Electronic address: Isabelle.Desombere@wiv-isp.be.
2
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium; Therapeutic Chemistry Department, National Research Centre (NRC), Dokki, Cairo, Egypt. Electronic address: Ahmed.mesalam@UGent.be.
3
School of Life Sciences, The University of Nottingham, Nottingham, NG7 2RD, UK; Nottingham Digestive Diseases Centre, National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and The University of Nottingham, Nottingham, NG7 2UH, UK. Electronic address: Richard.urbanowicz@nottingham.ac.uk.
4
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium. Electronic address: Freya.VanHoutte@UGent.be.
5
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium. Electronic address: Lieven.Verhoye@UGent.be.
6
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: Zkeck@stanford.edu.
7
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium. Electronic address: Ali.farhoudi@UGent.be.
8
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium. Electronic address: Koen.Vercauteren@UGent.be.
9
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium. Electronic address: Karin.Weening@UGent.be.
10
Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg et Pole Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. Electronic address: Thomas.baumert@unistra.fr.
11
MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, UK. Electronic address: Arvind.patel@glasgow.ac.uk.
12
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: Sfoung@stanford.edu.
13
School of Life Sciences, The University of Nottingham, Nottingham, NG7 2RD, UK; Nottingham Digestive Diseases Centre, National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and The University of Nottingham, Nottingham, NG7 2UH, UK. Electronic address: Jonathan.ball@nottingham.ac.uk.
14
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium. Electronic address: Geert.LerouxRoels@UGent.be.
15
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium. Electronic address: Philip.Meuleman@UGent.be.

Abstract

Infections with hepatitis C virus (HCV) represent a worldwide health burden and a prophylactic vaccine is still not available. Liver transplantation (LT) is often the only option for patients with HCV-induced end-stage liver disease. However, immediately after transplantation, the liver graft becomes infected by circulating virus, resulting in accelerated progression of liver disease. Although the efficacy of HCV treatment using direct-acting antivirals has improved significantly, immune compromised LT-patients and patients with advanced liver disease remain difficult to treat. As an alternative approach, interfering with viral entry could prevent infection of the donor liver. We generated a human monoclonal antibody (mAb), designated 2A5, which targets the HCV envelope. The neutralizing activity of mAb 2A5 was assessed using multiple prototype and patient-derived HCV pseudoparticles (HCVpp), cell culture produced HCV (HCVcc), and a human-liver chimeric mouse model. Neutralization levels observed for mAb 2A5 were generally high and mostly superior to those obtained with AP33, a well-characterized HCV-neutralizing monoclonal antibody. Using humanized mice, complete protection was observed after genotype 1a and 4a HCV challenge, while only partial protection was achieved using gt1b and 6a isolates. Epitope mapping revealed that mAb 2A5 binding is conformation-dependent and identified the E2-region spanning amino acids 434 to 446 (epitope II) as the predominant contact domain.

CONCLUSION:

mAb 2A5 shows potent anti-HCV neutralizing activity both in vitro and in vivo and could hence represent a valuable candidate to prevent HCV recurrence in LT-patients. In addition, the detailed identification of the neutralizing epitope can be applied for the design of prophylactic HCV vaccines.

KEYWORDS:

Chimeric mice; Envelope protein; Hepatitis C virus; Liver transplantation; Neutralizing antibody; Vaccine

PMID:
29074219
PMCID:
PMC5785094
DOI:
10.1016/j.antiviral.2017.10.015
[Indexed for MEDLINE]
Free PMC Article

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