Publications
ImmunityMar 2024 DOI:
10.1016/j.immuni.2024.03.001

Convergent evolution and targeting of diverse E2 epitopes by human broadly neutralizing antibodies are associated with HCV clearance

Ogega, Clinton O; Skinner, Nicole E; Schoenle, Marta V; Wilcox, Xander E; Frumento, Nicole; Wright, Desiree A; Paul, Harry T; Sinnis-Bourozikas, Ariadne; Clark, Kaitlyn E; Figueroa, Alexis; Bjorkman, Pamela J; Ray, Stuart C; Flyak, Andrew I; Bailey, Justin R
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Genes
Abstract
The early appearance of broadly neutralizing antibodies (bNAbs) in serum is associated with spontaneous hepatitis C virus (HCV) clearance, but to date, the majority of bNAbs have been isolated from chronically infected donors. Most of these bNAbs use the VH1-69 gene segment and target the envelope glycoprotein E2 front layer. Here, we performed longitudinal B cell receptor (BCR) repertoire analysis on an elite neutralizer who spontaneously cleared multiple HCV infections. We isolated 10,680 E2-reactive B cells, performed BCR sequencing, characterized monoclonal B cell cultures, and isolated bNAbs. In contrast to what has been seen in chronically infected donors, the bNAbs used a variety of VH genes and targeted at least three distinct E2 antigenic sites, including sites previously thought to be non-neutralizing. Diverse front-layer-reactive bNAb lineages evolved convergently, acquiring breadth-enhancing somatic mutations. These findings demonstrate that HCV clearance-associated bNAbs are genetically diverse and bind distinct antigenic sites that should be the target of vaccine-induced bNAbs.
Product Used
Genes

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