ABSTRACT

Hepatitis C virus (HCV) is a member of the Flaviviridae family; however, unlike other family members, the HCV virion has an unusually high lipid content. HCV has two envelope glycoproteins, E1 and E2. E2 contributes to receptor binding, cell membrane attachment, and immune evasion. In contrast, the functions of E1 are poorly characterized due, in part, to challenges in producing the protein. This manuscript describes the expression and purification of a soluble E1 ectodomain (eE1) that is recognized by conformational, human monoclonal antibodies. eE1 forms a complex with apolipoproteins AI and AII, cholesterol, and phospholipids by recruiting high-density lipoprotein (HDL) from the extracellular media. We show that HDL binding is a function specific to eE1 and HDL hinders recognition of E1 by a neutralizing monoclonal antibody. Either low-density lipoprotein or HDL increases the production and infectivity of cell culture-produced HCV, but E1 preferentially selects HDL, influencing both viral life cycle and antibody evasion.

IMPORTANCE

Hepatitis C virus (HCV) infection is a significant burden on human health, but vaccine candidates have yet to provide broad protection against this infection. We have developed a method to produce high quantities of soluble E1 or E2, the viral proteins located on the surface of HCV. HCV has an unusually high lipid content due to the recruitment of apolipoproteins. We found that E1 (and not E2) preferentially recruits host high-density lipoprotein (HDL) extracellularly. This recruitment of HDL by E1 prevents binding of E1 by a neutralizing antibody and furthermore prevents antibody-mediated neutralization of the virus. By comparison, low-density lipoprotein does not protect the virus from antibody-mediated neutralization. Our findings provide mechanistic insight into apolipoprotein recruitment, which may be critical for vaccine development.

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Information & Contributors

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Published In

cover image Journal of Virology
Journal of Virology
Volume 98Number 123 January 2024
eLocator: e00849-23
Editor: J.-H. James Ou, University of Southern California, Los Angeles, California, USA
PubMed: 38174935

History

Received: 6 June 2023
Accepted: 28 November 2023
Published online: 4 January 2024

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Keywords

  1. hepatitis C virus
  2. envelope glycoprotein 1
  3. high-density lipoprotein
  4. apolipoproteins

Contributors

Authors

Jennifer Casiano Matos
Structural Virology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
Author Contributions: Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, and Writing – review and editing.
Kaneemozhe Harichandran
Structural Virology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
Author Contributions: Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, and Writing – review and editing.
Jingrong Tang
Lipoprotein Metabolism Laboratory, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA
Author Contributions: Resources and Writing – review and editing.
Denis O. Sviridov
Lipoprotein Metabolism Laboratory, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA
Author Contributions: Formal analysis, Methodology, and Writing – review and editing.
Translational Immunobiology Unit, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
Author Contributions: Data curation, Methodology, and Writing – review and editing.
Motoshi Suzuki
Protein Chemistry Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA
Author Contributions: Data curation, Formal analysis, Investigation, Methodology, and Writing – review and editing.
Lisa R. Olano
Protein Chemistry Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA
Author Contributions: Data curation, Formal analysis, and Writing – review and editing.
Alvaro Hobbs
Structural Virology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
Ashish Kumar
Structural Virology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
Author Contributions: Investigation, Methodology, and Writing – review and editing.
Myeisha U. Paskel
Structural Virology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
Author Contributions: Investigation, Methodology, and Writing – review and editing.
Translational Immunobiology Unit, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
Author Contributions: Formal analysis and Writing – review and editing.
Structural Virology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
Author Contributions: Conceptualization, Data curation, Formal analysis, Supervision, Writing – original draft, and Writing – review and editing.
Lipoprotein Metabolism Laboratory, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA
Author Contributions: Conceptualization, Funding acquisition, Project administration, Resources, Supervision, and Writing – review and editing.
Structural Virology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
Author Contributions: Conceptualization, Formal analysis, Funding acquisition, Project administration, Resources, Writing – original draft, and Writing – review and editing.

Editor

J.-H. James Ou
Editor
University of Southern California, Los Angeles, California, USA

Notes

Jennifer Casiano Matos and Kaneemozhe Harichandran contributed equally to this article. The co-first authors are listed alphabetically by last name.
The authors declare no conflict of interest.

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