Broadly Neutralizing Antibody Mediated Clearance of Human Hepatitis C Virus Infection

Valerie J Kinchen; Muhammad N Zahid; Andrew I Flyak; Mary G Soliman; Gerald H Learn; Shuyi Wang; Edgar Davidson; Benjamin J Doranz; Stuart C Ray; Andrea L Cox; James E Crowe Jr; Pamela J Bjorkman; George M Shaw; Justin R Bailey

doi:10.1016/j.chom.2018.10.012

Broadly Neutralizing Antibody Mediated Clearance of Human Hepatitis C Virus Infection

Cell Host Microbe. 2018 Nov 14;24(5):717-730.e5. doi: 10.1016/j.chom.2018.10.012.

Authors

Affiliations

¹ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
³ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
⁴ Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ Integral Molecular, Inc., Philadelphia, PA 19104, USA.
⁶ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁷ Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁸ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: jbailey7@jhmi.edu.

Abstract

The role that broadly neutralizing antibodies (bNAbs) play in natural clearance of human hepatitis C virus (HCV) infection and the underlying mechanisms remain unknown. Here, we investigate the mechanism by which bNAbs, isolated from two humans who spontaneously cleared HCV infection, contribute to HCV control. Using viral gene sequences amplified from longitudinal plasma of the two subjects, we found that these bNAbs, which target the front layer of the HCV envelope protein E2, neutralized most autologous HCV strains. Acquisition of resistance to bNAbs by some autologous strains was accompanied by progressive loss of E2 protein function, and temporally associated with HCV clearance. These data demonstrate that bNAbs can mediate clearance of human HCV infection by neutralizing infecting strains and driving escaped viruses to an unfit state. These immunopathologic events distinguish HCV from HIV-1 and suggest that development of an HCV vaccine may be achievable.

Keywords: HCV clearance; antibody specificity; binding sites; hepatitis C virus; immunologic memory; neutralizing antibodies.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Monoclonal / immunology
Antibodies, Neutralizing / chemistry
Antibodies, Neutralizing / immunology*
Antibody Specificity
Base Sequence
Binding Sites
Cell Line
Cricetulus
Epitopes / immunology
Female
HEK293 Cells
HIV-1 / immunology
Hepacivirus / genetics
Hepacivirus / immunology*
Hepatitis C / immunology*
Hepatitis C Antibodies / blood
Hepatitis C Antibodies / chemistry
Hepatitis C Antibodies / immunology*
Humans
Immunologic Memory
Male
Models, Molecular
Mutagenesis, Site-Directed
Viral Envelope Proteins / genetics
Viral Envelope Proteins / immunology
Viral Load

Substances

Antibodies, Monoclonal
Antibodies, Neutralizing
Epitopes
Hepatitis C Antibodies
Viral Envelope Proteins
glycoprotein E2, Hepatitis C virus

Abstract

Publication types

MeSH terms

Substances

Grants and funding