Early T follicular helper cell activity accelerates hepatitis C virus-specific B cell expansion
Eduardo Salinas, … , Naglaa H. Shoukry, Arash Grakoui
Eduardo Salinas, … , Naglaa H. Shoukry, Arash Grakoui
Published January 19, 2021
Citation Information: J Clin Invest. 2021;131(2):e140590. https://doi.org/10.1172/JCI140590.
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Early T follicular helper cell activity accelerates hepatitis C virus-specific B cell expansion

Abstract

Early appearance of neutralizing antibodies during acute hepatitis C virus (HCV) infection is associated with spontaneous viral clearance. However, the longitudinal changes in antigen-specific memory B cell (MBCs) associated with divergent HCV infection outcomes remain undefined. We characterized longitudinal changes in E2 glycoprotein-specific MBCs from subjects who either spontaneously resolved acute HCV infection or progressed to chronic infection, using single-cell RNA-seq and functional assays. HCV-specific antibodies in plasma from chronically infected subjects recognized multiple E2 genotypes, while those from spontaneous resolvers exhibited variable cross-reactivity to heterotypic E2. E2-specific MBCs from spontaneous resolvers peaked early after infection (4–6 months), following expansion of activated circulating T follicular helper cells (cTfh) expressing interleukin 21. In contrast, E2-specific MBCs from chronically infected subjects, enriched in VH1-69, expanded during persistent infection (> 1 year), in the absence of significantly activated cTfh expansion. Early E2-specific MBCs from spontaneous resolvers produced monoclonal antibodies (mAbs) with fewer somatic hypermutations and lower E2 binding but similar neutralization as mAbs from late E2-specific MBCs of chronically infected subjects. These findings indicate that early cTfh activity accelerates expansion of E2-specific MBCs during acute infection, which might contribute to spontaneous clearance of HCV.

Authors

Eduardo Salinas, Maude Boisvert, Amit A. Upadhyay, Nathalie Bédard, Sydney A. Nelson, Julie Bruneau, Cynthia A. Derdeyn, Joseph Marcotrigiano, Matthew J. Evans, Steven E. Bosinger, Naglaa H. Shoukry, Arash Grakoui

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Figure 5

E2-specific mAbs from resolvers neutralize HCVpp as efficiently as mAbs from chronically infected subjects despite weaker J6 E2 binding.

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E2-specific mAbs from resolvers neutralize HCVpp as efficiently as mAbs ...
(A) Relative binding strength of pooled mAbs from resolvers (SR, black circles, n = 3 subjects, 10 mAbs per subject) and CI subjects (red squares, n = 3 subjects, 10 mAbs per subject) to J6 E2 protein, quantified by biolayer interferometry and expressed as mean log EC50–1 ± SD. (B and C) Neutralization against J6/JFH1 (B) or H77 (C) HCVpp of pooled mAbs from resolvers or CI subjects. Dotted line indicates the threshold of IC50–1 = 0.02. (D and E) Comparison of neutralizing activity against H77 and J6/JFH1 by individual mAbs from resolvers (D) and CI subjects (E). (F and G) Correlation between J6/JFH1 HCVpp neutralization and binding abilities by individual mAbs of resolvers (F) or CI subjects (G). Results for binding experiments represent means of pooled mAbs and error bars represent SD. Results for neutralization experiments represent the mean of 3 independent experiments. Unpaired, Mann-Whitney U test (A–D), Spearman’s correlation (E–H). **P < 0.01; ***P < 0.001; NS, P > 0.05. In all graphs, each dot represents a single mAb.