RT Journal Article
SR Electronic
T1 Hepatitis C reference viruses highlight potent antibody responses and diverse viral functional interactions with neutralising antibodies
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1734
OP 1745
DO 10.1136/gutjnl-2020-321190
VO 70
IS 9
A1 Bankwitz, Dorothea
A1 Bahai, Akash
A1 Labuhn, Maurice
A1 Doepke, Mandy
A1 Ginkel, Corinne
A1 Khera, Tanvi
A1 Todt, Daniel
A1 Ströh, Luisa J
A1 Dold, Leona
A1 Klein, Florian
A1 Klawonn, Frank
A1 Krey, Thomas
A1 Behrendt, Patrick
A1 Cornberg, Markus
A1 McHardy, Alice C
A1 Pietschmann, Thomas
YR 2021
UL http://gut.bmj.com/content/70/9/1734.abstract
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.