Monoclonal anti-envelope antibody AP33 protects humanized mice against a patient-derived hepatitis C virus challenge

Desombere, I. et al. (2016) Monoclonal anti-envelope antibody AP33 protects humanized mice against a patient-derived hepatitis C virus challenge. Hepatology, 63(4), pp. 1120-1134. (doi:10.1002/hep.28428) (PMID:26710081)

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Abstract

End-stage liver disease caused by hepatitis C virus (HCV) infection is a major indication for liver transplantation. However, immediately after transplantation the liver graft of viremic patients universally becomes infected by circulating virus, resulting in accelerated liver disease progression. Currently available direct-acting antiviral therapies have reduced efficacy in patients with end-stage liver disease and prophylactic strategies to prevent HCV recurrence are still highly needed. In this study we compared the ability of two broadly reactive monoclonal antibodies (mAbs), designated 3/11 and AP33, recognizing a distinct but overlapping epitope in the viral E2 glycoprotein to protect humanized mice from a patient-derived HCV challenge. Their neutralizing activity was assessed using the HCVpp and HCVcc systems expressing multiple patient-derived envelopes and a human-liver chimeric mouse model. HCV RNA was readily detected in all control mice challenged with a patient-derived HCV genotype 1b isolate, while three out of four AP33-treated mice were completely protected. In contrast, only one out of four 3/11-treated mice remained HCV RNA negative throughout the observation period, while the other three had a viral load that was indistinguishable from that in the control group. The increased in vivo efficacy of AP33 was in line with its higher affinity and neutralizing capacity observed in vitro. Conclusion: Although mAbs AP33 and 3/11 target the same region in E2, only mAb AP33 can efficiently protect from challenge with a heterologous HCV population in vivo. Since mAb AP33 efficiently neutralizes viral variants that escaped the humoral immune response and re-infected the liver graft of transplant patients, it may be a valuable candidate to prevent HCV recurrence. In addition our data is valuable for the design of a prophylactic vaccine.

Item Type:Articles
Additional Information:This is the peer reviewed version of the following article: Desombere, I., Fafi-Kremer, S., Van Houtte, F., Pessaux, P., Farhoudi, A., Heydmann, L., Verhoye, L., Cole, S., McKeating, J. A., Leroux-Roels, G., Baumert, T. F., Patel, A. H. and Meuleman, P. (2015), Monoclonal anti-envelope antibody AP33 protects humanized mice against a patient-derived hepatitis C virus challenge. Hepatology., which has been published in final form at 10.1002/hep.28428 . This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cole, Mrs Sarah and Patel, Professor Arvind
Authors: Desombere, I., Fafi-Kremer, S., Van Houtte, F., Pessaux, P., Farhoudi, A., Heydmann, L., Verhoye, L., Cole, S., McKeating, J. A., Leroux-Roels, G., Baumert, T. F., Patel, A. H., and Meuleman, P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Hepatology
Publisher:John Wiley & Sons, Inc.
ISSN:0270-9139
ISSN (Online):1527-3350
Published Online:22 February 2016
Copyright Holders:Copyright © 2015 John Wiley and Sons
First Published:First published in Hepatology 63(4):1120-1134
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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