Plasma deconvolution identifies broadly neutralizing antibodies associated with hepatitis C virus clearance
Valerie J. Kinchen, … , James E. Crowe Jr, Justin R. Bailey
Valerie J. Kinchen, … , James E. Crowe Jr, Justin R. Bailey
Published August 13, 2019
Citation Information: J Clin Invest. 2019;129(11):4786-4796. https://doi.org/10.1172/JCI130720.
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Research Article Immunology Virology

Plasma deconvolution identifies broadly neutralizing antibodies associated with hepatitis C virus clearance

Abstract

A vaccine for hepatitis C virus (HCV) is urgently needed. Development of broadly neutralizing plasma antibodies during acute infection is associated with HCV clearance, but the viral epitopes of these plasma antibodies are unknown. Identifying these epitopes could define the specificity and function of neutralizing antibodies (NAbs) that should be induced by a vaccine. Here, we present the development and application of a high-throughput method that deconvolutes polyclonal anti-HCV NAbs in plasma, delineating the epitope specificities of anti-HCV NAbs in acute-infection plasma of 44 humans with subsequent clearance or persistence of HCV. Remarkably, we identified multiple broadly neutralizing antibody combinations that were associated with greater plasma neutralizing breadth and with HCV clearance. These studies have the potential to inform new strategies for vaccine development by identifying broadly neutralizing antibody combinations in plasma associated with the natural clearance of HCV, while also providing a high-throughput assay that could identify these responses after vaccination trials.

Authors

Valerie J. Kinchen, Guido Massaccesi, Andrew I. Flyak, Madeleine C. Mankowski, Michelle D. Colbert, William O. Osburn, Stuart C. Ray, Andrea L. Cox, James E. Crowe Jr, Justin R. Bailey

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Figure 5

Plasma NAb deconvolution predicts mAbs subsequently isolated from B cells of the same subject.

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Plasma NAb deconvolution predicts mAbs subsequently isolated from B cell...
(A) NAb deconvolution of subject C18 plasma. Plasma neutralization profile was averaged from 2 independent experiments. Reference mAb profiles were averaged from 5 independent experiments. Wedge sizes are proportional to the plasma response attributed to each reference mAb. P value is from the Pearson correlation of the C18 plasma neutralization profile with a combined neutralization profile comprising the indicated proportion of each reference mAb. (B) Pearson correlations between neutralization profiles and number of shared probable E1/E2-binding residues, as determined by alanine-scanning mutagenesis–E1/E2-binding analysis, between 12 mAbs isolated from subject C18 B cells and best-match reference mAbs. C18 mAb neutralization profiles were determined in a single experiment, with neutralization of each HCVpp measured in duplicate. (C) Examples of concordance between binding residues of reference mAbs identified in plasma and 3 best-match mAbs isolated from C18 B cells. Colored spheres indicated main chain atoms of probable binding residues, superimposed on the crystallized structure of the HCV E2 protein ectodomain, strain 1b09, PDB accession 6MEI (15), with colors modified in PyMOL, v1.8.6.2. Shared putative E1 binding residues of HEPC130 and AR4A (Y201, N205) are not shown.