Journal
HEPATOLOGY
Volume 63, Issue 4, Pages 1120-1134Publisher
WILEY
DOI: 10.1002/hep.28428
Keywords
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Categories
Funding
- Research Foundation Flanders (FWO) [G.0212.N, 1.5.009.10N]
- Ghent University [GOA 01G01712]
- Belgian state [IUAP P7/47-HEPRO-2]
- European Union (FP7, HepaMab)
- European Union [ERC-2008-AdG-HEPCENT, ERC-2014-AdG-HEPCIR]
- European Union (FP7 HepaMab)
- European Union (INTERREG-IV-Rhin Superieur-FEDER-Hepato-Regio-Net)
- ANRS [2011/132, 2012/239, 2013/108]
- ANR (Laboratoires d'excellence) [ANR-10-LABX-0028_HEPSYS]
- University of Strasbourg Foundation
- National Institute for Health Research Birmingham Liver Biomedical Research Unit
- MRC grant [G1100247]
- EU [HEALTH F3-2012-305578]
- Medical Research Council, UK
- BBSRC [BB/N008553/1] Funding Source: UKRI
- MRC [G1100247, G0400802, MC_U130184144, MC_UU_12014/2] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/N008553/1] Funding Source: researchfish
- Medical Research Council [MC_U130184144, MC_UU_12014/2, G1100247, G0400802] Funding Source: researchfish
- Agence Nationale de la Recherche (ANR) [ANR-10-LABX-0028] Funding Source: Agence Nationale de la Recherche (ANR)
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End-stage liver disease (ESLD) 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 ESLD 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 HCV pseudoparticles and cell-culture-derived HCV 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, whereas 3 of 4 AP33-treated mice were completely protected. In contrast, only one of four 3/11-treated mice remained HCV-RNA negative throughout the observation period, whereas the other 3 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. Conclusions: 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. Given that mAb AP33 efficiently neutralizes viral variants that escaped the humoral immune response and reinfected the liver graft of transplant patients, it may be a valuable candidate to prevent HCV recurrence. In addition, our data are valuable for the design of a prophylactic vaccine.
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