B cell characteristics define HCV reinfection outcome

Alexander P Underwood; Money Gupta; Bing-Ru Wu; Auda A Eltahla; Irene Boo; Jing Jing Wang; David Agapiou; Arunasingam Abayasingam; Arnold Reynaldi; Elizabeth Keoshkerian; Yanran Zhao; Nicholas Brasher; Melanie R Walker; Jens Bukh; Lisa Maher; Tom Gordon; Miles P Davenport; Fabio Luciani; Heidi E Drummer; Andrew R Lloyd; Rowena A Bull

doi:10.1016/j.jhep.2024.04.004

B cell characteristics define HCV reinfection outcome

J Hepatol. 2024 Apr 9:S0168-8278(24)00271-X. doi: 10.1016/j.jhep.2024.04.004. Online ahead of print.

Authors

Alexander P Underwood¹, Money Gupta², Bing-Ru Wu², Auda A Eltahla², Irene Boo³, Jing Jing Wang⁴, David Agapiou⁵, Arunasingam Abayasingam², Arnold Reynaldi⁵, Elizabeth Keoshkerian⁵, Yanran Zhao⁵, Nicholas Brasher², Melanie R Walker², Jens Bukh⁶, Lisa Maher⁵, Tom Gordon⁴, Miles P Davenport⁵, Fabio Luciani², Heidi E Drummer⁷, Andrew R Lloyd⁵, Rowena A Bull⁸

Affiliations

¹ School of Biomedical Science, Faculty of Health and Medicine, UNSW, Sydney, NSW, Australia; The Kirby Institute, Faculty of Health and Medicine, UNSW, Sydney, NSW, Australia; Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
² School of Biomedical Science, Faculty of Health and Medicine, UNSW, Sydney, NSW, Australia; The Kirby Institute, Faculty of Health and Medicine, UNSW, Sydney, NSW, Australia.
³ Burnet Institute, Melbourne, VIC, Australia.
⁴ Department of Immunology Flinders Medical Centre and Flinders University, SA Pathology Bedford Park, SA, Australia.
⁵ The Kirby Institute, Faculty of Health and Medicine, UNSW, Sydney, NSW, Australia.
⁶ Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷ Burnet Institute, Melbourne, VIC, Australia; Department of Microbiology, Monash University, Clayton, VIC, Australia; Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.
⁸ School of Biomedical Science, Faculty of Health and Medicine, UNSW, Sydney, NSW, Australia; The Kirby Institute, Faculty of Health and Medicine, UNSW, Sydney, NSW, Australia. Electronic address: r.bull@unsw.edu.au.

PMID: 38604387
DOI: 10.1016/j.jhep.2024.04.004

Abstract

Background and aims: In individuals highly exposed to hepatitis C virus (HCV), reinfection is common, suggesting that natural development of sterilising immunity is difficult. In those that are reinfected, some will develop a persistent infection, while a small proportion repeatedly clear the virus, suggesting natural protection is possible. The aim of this study was to characterise immune responses associated with rapid natural clearance of HCV reinfection.

Methods: Broad neutralising antibodies (BnAbs) and Envelope 2 (E2)-specific memory B cell (MBCs) responses were examined longitudinally in 15 subjects with varied reinfection outcomes.

Results: BnAb responses were associated with MBC recall, but not with reinfection clearance. Strong evidence of antigen imprinting was found, and the B cell receptor repertoire showed a high level of clonality with ongoing somatic hypermutation of many clones over subsequent reinfection events. Single cell transcriptomic analyses showed that cleared reinfections featured an activated transcriptomic profile in HCV-specific B cells that rapidly expanded upon reinfection.

Conclusions: MBC quality, but not necessarily breadth of nAb responses, is important for protection against antigenically diverse variants, which is encouraging for HCV vaccine development.

Keywords: B cell; HCV; clearance; neutralizing antibody; persistence; reinfection.