PT  - JOURNAL ARTICLE
AU  - Bankwitz, Dorothea
AU  - Bahai, Akash
AU  - Labuhn, Maurice
AU  - Doepke, Mandy
AU  - Ginkel, Corinne
AU  - Khera, Tanvi
AU  - Todt, Daniel
AU  - Ströh, Luisa J
AU  - Dold, Leona
AU  - Klein, Florian
AU  - Klawonn, Frank
AU  - Krey, Thomas
AU  - Behrendt, Patrick
AU  - Cornberg, Markus
AU  - McHardy, Alice C
AU  - Pietschmann, Thomas
TI  - Hepatitis C reference viruses highlight potent antibody responses and diverse viral functional interactions with neutralising antibodies
AID  - 10.1136/gutjnl-2020-321190
DP  - 2021 Sep 01
TA  - Gut
PG  - 1734--1745
VI  - 70
IP  - 9
4099  - http://gut.bmj.com/content/70/9/1734.short
4100  - http://gut.bmj.com/content/70/9/1734.full
SO  - Gut2021 Sep 01; 70
AB  - Objective Neutralising antibodies are key effectors of infection-induced and vaccine-induced immunity. Quantification of antibodies’ breadth and potency is critical for understanding the mechanisms of protection and for prioritisation of vaccines. Here, we used a unique collection of human specimens and HCV strains to develop HCV reference viruses for quantification of neutralising antibodies, and to investigate viral functional diversity.Design We profiled neutralisation potency of polyclonal immunoglobulins from 104 patients infected with HCV genotype (GT) 1–6 across 13 HCV strains representing five viral GTs. Using metric multidimensional scaling, we plotted HCV neutralisation onto neutralisation maps. We employed K-means clustering to guide virus clustering and selecting representative strains.Results Viruses differed greatly in neutralisation sensitivity, with J6 (GT2a) being most resistant and SA13 (GT5a) being most sensitive. They mapped to six distinct neutralisation clusters, in part composed of viruses from different GTs. There was no correlation between viral neutralisation and genetic distance, indicating functional neutralisation clustering differs from sequence-based clustering. Calibrating reference viruses representing these clusters against purified antibodies from 496 patients infected by GT1 to GT6 viruses readily identified individuals with extraordinary potent and broadly neutralising antibodies. It revealed comparable antibody cross-neutralisation and diversity between specimens from diverse viral GTs, confirming well-balanced reporting of HCV cross-neutralisation across highly diverse human samples.Conclusion Representative isolates from six neutralisation clusters broadly reconstruct the functional HCV neutralisation space. They enable high resolution profiling of HCV neutralisation and they may reflect viral functional and antigenic properties important to consider in HCV vaccine design.Data sharing not applicable as no datasets generated and/or analysed for this study. Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Sequences of the reporter viruses were submitted to the NCBI GenBank database.