Antibody-dependent-cellular-cytotoxicity-inducing antibodies significantly affect the post-exposure treatment of Ebola virus infection

Qiang Liu,Lan Wang,Meng Wang,Weijin Huang,Xi Wu,Youchun Wang,Qianqian Li,Jian Ma,Changfa Fan,Chunyun Sun,Liangzhi Xie,Baowen Li,Shuya Zhou

doi:10.1038/srep45552

Abstract

Passive immunotherapy with monoclonal antibodies (mAbs) is an efficacious treatment for Ebola virus (EBOV) infections in animal models and humans. Understanding what constitutes a protective response is critical for the development of novel therapeutic strategies. We generated an EBOV-glycoprotein-pseudotyped Human immunodeficiency virus to develop sensitive neutralizing and antibody-dependent cellular cytotoxicity (ADCC) assays as well as a bioluminescent-imaging-based mouse infection model that does not require biosafety level 4 containment. The in vivo treatment efficiencies of three novel anti-EBOV mAbs at 12 h post-infection correlated with their in vitro anti-EBOV ADCC activities, without neutralizing activity. When they were treated with these mAbs, natural killer cell (NK)-deficient mice had lower viral clearance than WT mice, indicating that the anti-EBOV mechanism of the ADCC activity of these mAbs is predominantly mediated by NK cells. One potent anti-EBOV mAb (M318) displayed unprecedented neutralizing and ADCC activities (neutralization IC50, 0.018 μg/ml; ADCC EC50, 0.095 μg/ml). These results have important implications for the efficacy of antiviral drugs and vaccines as well as for pathogenicity studies of EBOV.

Highlights

Passive immunotherapy with monoclonal antibodies is an efficacious treatment for Ebola virus (EBOV) infections in animal models and humans
We found that the percentage of bioluminescence produced by the pseudovirus was not higher than 0.3% of that produced by the Jurkat effector cells in response to antibody-dependent cellular cytotoxicity (ADCC), so there was no significant difference between the ADCC activities of monoclonal antibodies (mAbs) measured with or without a pseudovirus expressing a luciferase reporter gene
Our results demonstrate that this pseudovirus-based system is suitable for evaluating the ADCC response in vitro and in vivo and that natural killer cell (NK)-cell-mediated ADCC plays a critical role in EBOV clearance

Summary

Introduction

Passive immunotherapy with monoclonal antibodies (mAbs) is an efficacious treatment for Ebola virus (EBOV) infections in animal models and humans. To facilitate the investigation of the critical events in viral infection and to identify the antiviral activity of neutralizing and ADCC-inducing antibodies, we generated a replication incompetent GP1,2-pseudotyped virus expressing the Fluc reporter protein (pHIV–ZGP–Fluc) using an envelope-defective strain of HIV-1 (strain SG3) as a way of safely and sensitively monitoring viral infections in cells and mice. These pseudovirus-infected mice are ideal models in which to evaluate antiviral efficiency in vivo in less time than is required for replication-competent EBOV assays

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