Broadly Neutralizing Antibodies Targeting New Sites of Vulnerability in Hepatitis C Virus E1E2

Michelle D. Colbert, Andrew I. Flyak, Clinton O. Ogega, Valerie J. Kinchen, Guido Massaccesi, Mayda Hernandez, Edgar Davidson, Benjamin J. Doranz, Andrea Cox, James E. Crowe, Justin Bailey

Research output: Contribution to journalArticle

Abstract

Increasing evidence indicates that broadly neutralizing antibodies (bNAbs) play an important role in immune-mediated control of hepatitis C virus (HCV) infection, but the relative contribution of neutralizing antibodies targeting antigenic sites across the HCV envelope (E1 and E2) proteins is unclear. Here, we isolated thirteen E1E2-specific monoclonal antibodies (MAbs) from B cells of a single HCV-infected individual who cleared one genotype 1a infection and then became persistently infected with a second genotype 1a strain. These MAbs bound six distinct discontinuous antigenic sites on the E1 protein, the E2 protein, or the E1E2 heterodimer. Three antigenic sites, designated AS108, AS112 (an N-terminal E1 site), and AS146, were distinct from previously described antigenic regions (ARs) 1 to 5 and E1 sites. Antibodies targeting four sites (AR3, AR4-5, AS108, and AS146) were broadly neutralizing. These MAbs also displayed distinct patterns of relative neutralizing potency (i.e., neutralization profiles) across a panel of diverse HCV strains, which led to complementary neutralizing breadth when they were tested in combination. Overall, this study demonstrates that HCV bNAb epitopes are not restricted to previously described antigenic sites, expanding the number of sites that could be targeted for vaccine development.IMPORTANCE Worldwide, more than 70 million people are infected with hepatitis C virus (HCV), which is a leading cause of hepatocellular carcinoma and liver transplantation. Despite the development of potent direct acting antivirals (DAAs) for HCV treatment, a vaccine is urgently needed due to the high cost of treatment and the possibility of reinfection after cure. Induction of multiple broadly neutralizing antibodies (bNAbs) that target distinct epitopes on the HCV envelope proteins is one approach to vaccine development. However, antigenic sites targeted by bNAbs in individuals with spontaneous control of HCV have not been fully defined. In this study, we characterize 13 monoclonal antibodies (MAbs) from a single person who cleared an HCV infection without treatment, and we identify 3 new sites targeted by neutralizing antibodies. The sites targeted by these MAbs could inform HCV vaccine development.

Original languageEnglish (US)
JournalJournal of virology
Volume93
Issue number14
DOIs
StatePublished - Jul 15 2019

Fingerprint

Hepatitis C virus
Neutralizing Antibodies
neutralizing antibodies
Hepacivirus
monoclonal antibodies
neutralization
Monoclonal Antibodies
vaccine development
Vaccines
Virus Diseases
epitopes
Epitopes
proteins
Genotype
infection
Viral Envelope Proteins
liver transplant
Proteins
genotype
hepatoma

Keywords

  • broadly neutralizing antibodies
  • epitope
  • Flaviviridae
  • hepatitis C virus
  • hepatitis C virus clearance
  • humoral immunity
  • neutralizing antibodies

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Colbert, M. D., Flyak, A. I., Ogega, C. O., Kinchen, V. J., Massaccesi, G., Hernandez, M., ... Bailey, J. (2019). Broadly Neutralizing Antibodies Targeting New Sites of Vulnerability in Hepatitis C Virus E1E2. Journal of virology, 93(14). https://doi.org/10.1128/JVI.02070-18

Broadly Neutralizing Antibodies Targeting New Sites of Vulnerability in Hepatitis C Virus E1E2. / Colbert, Michelle D.; Flyak, Andrew I.; Ogega, Clinton O.; Kinchen, Valerie J.; Massaccesi, Guido; Hernandez, Mayda; Davidson, Edgar; Doranz, Benjamin J.; Cox, Andrea; Crowe, James E.; Bailey, Justin.

In: Journal of virology, Vol. 93, No. 14, 15.07.2019.

Research output: Contribution to journalArticle

Colbert, MD, Flyak, AI, Ogega, CO, Kinchen, VJ, Massaccesi, G, Hernandez, M, Davidson, E, Doranz, BJ, Cox, A, Crowe, JE & Bailey, J 2019, 'Broadly Neutralizing Antibodies Targeting New Sites of Vulnerability in Hepatitis C Virus E1E2', Journal of virology, vol. 93, no. 14. https://doi.org/10.1128/JVI.02070-18
Colbert MD, Flyak AI, Ogega CO, Kinchen VJ, Massaccesi G, Hernandez M et al. Broadly Neutralizing Antibodies Targeting New Sites of Vulnerability in Hepatitis C Virus E1E2. Journal of virology. 2019 Jul 15;93(14). https://doi.org/10.1128/JVI.02070-18
Colbert, Michelle D. ; Flyak, Andrew I. ; Ogega, Clinton O. ; Kinchen, Valerie J. ; Massaccesi, Guido ; Hernandez, Mayda ; Davidson, Edgar ; Doranz, Benjamin J. ; Cox, Andrea ; Crowe, James E. ; Bailey, Justin. / Broadly Neutralizing Antibodies Targeting New Sites of Vulnerability in Hepatitis C Virus E1E2. In: Journal of virology. 2019 ; Vol. 93, No. 14.
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