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Cross-genotype AR3-specific neutralizing antibodies confer long-term protection in injecting drug users after HCV clearance

Merat, Sabrina J.; Bru, Camille; van de Berg, Dorien; Molenkamp, Richard; Tarr, Alexander W.; Koekkoek, Sylvie; Kootstra, Neeltje A.; Prins, Maria; Ball, Jonathan K.; Bakker, Arjen Q.; de Jong, Menno D.; Spits, Hergen; Beaumont, Tim; Schinkel, Janke

Authors

Sabrina J. Merat

Camille Bru

Dorien van de Berg

Richard Molenkamp

Sylvie Koekkoek

Neeltje A. Kootstra

Maria Prins

JONATHAN BALL jonathan.ball@nottingham.ac.uk
Professor of Molecular Virology

Arjen Q. Bakker

Menno D. de Jong

Hergen Spits

Tim Beaumont

Janke Schinkel



Abstract

Background & Aims
Understanding immune protection against hepatitis C virus (HCV) infection is necessary for designing an effective vaccine. A number of broadly-reactive, neutralizing antibodies have been isolated from B cells of HCV-infected subjects. However, it remains unclear whether B cells producing such antibodies contribute to the clearance and long-term immune protection against HCV.

Methods
We analysed the B-cell repertoire of thirteen participants from the Amsterdam Cohort Study among injecting drug users with a median follow-up of 17.5 years. Five subjects ultimately became chronically infected either after primary infection or after reinfection. Eight subjects, at the end of study follow-up, were HCV RNA negative following spontaneous clearance of one or multiple infections. From each subject, 10,000 CD27+IgG+ B cells, collected 0.75 year after HCV infection, were cultured to characterize the antibody repertoire.

Results
Using a multiplex flow cytometry-based assay to study the antibody binding to E1E2 from genotype 1 to 6, we found that a high frequency of cross-genotype antibodies was associated with spontaneous clearance of one or multiple infections (p-value=0.03). Epitope specificity of these cross-genotype antibodies was determined by alanine mutant scanning in four subjects, who were HCV RNA negative following spontaneous clearance of one or multiple infections. Interestingly, the cross-genotype antibodies were mainly AR3-specific and showed cross-neutralizing activity against HCV. In addition to AR3 antibodies, three subjects developed antibodies recognizing AR4 of which one monoclonal antibody showed cross-neutralizing capacity.

Conclusions
Together, these data suggest that a strong B-cell response producing cross-genotype and neutralizing antibodies, especially targeting AR3, contribute to HCV clearance and long-term immune protection against HCV.

Journal Article Type Article
Publication Date Jul 1, 2019
Journal Journal of Hepatology
Print ISSN 0168-8278
Electronic ISSN 1600-0641
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 71
Issue 1
Pages 14-24
APA6 Citation Merat, S. J., Bru, C., van de Berg, D., Molenkamp, R., Tarr, A. W., Koekkoek, S., …Schinkel, J. (2019). Cross-genotype AR3-specific neutralizing antibodies confer long-term protection in injecting drug users after HCV clearance. Journal of Hepatology, 71(1), 14-24. https://doi.org/10.1016/j.jhep.2019.02.013
DOI https://doi.org/10.1016/j.jhep.2019.02.013
Keywords Injecting drug user; HCV infection; Spontaneous clearance; Memory B cell; Broadly neutralizing antibody
Publisher URL https://www.sciencedirect.com/science/article/pii/S016882781930128X?via%3Dihub

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