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

Desombere, Isabelle and Mesalam, Ahmed Atef and Urbanowicz, Richard A. and Van Houtte, Freya and Verhoye, Lieven and Keck, Zhen-Yong and Farhoudi, Ali and Vercauteren, Koen and Weening, Karin E. and Baumert, Thomas F. and Patel, Arvind H. and Foung, Steven K.H. and Ball, Jonathan and Leroux-Roels, Geert and Meuleman, Philip (2017) A novel neutralizing human monoclonal antibody broadly abrogates hepatitis C virus infection in vitro and in vivo. Antiviral Research, 148 . pp. 53-64. ISSN 1872-9096

[img]
Preview
PDF - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
Download (1MB) | Preview

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 effi cacy 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.

Item Type: Article
Keywords: Hepatitis C virus; envelope protein; neutralizing antibody; chimeric mice; liver transplantation; vaccine
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine > Nottingham Digestive Diseases Centre
University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences
Identification Number: 10.1016/j.antiviral.2017.10.015
Depositing User: Eprints, Support
Date Deposited: 24 Nov 2017 09:07
Last Modified: 24 Nov 2017 10:11
URI: http://eprints.nottingham.ac.uk/id/eprint/48357

Actions (Archive Staff Only)

Edit View Edit View