ARTICLE: Convergent evolution and targeting of diverse E2 epitopes by human broadly neutralizing antibodies are associated with HCV clearance
AUTHORS: Clinton O Ogega, Nicole E Skinner, Marta V Schoenle, Xander E Wilcox, Nicole Frumento, Desiree A Wright, Harry T Paul, Ariadne Sinnis-Bourozikas, Kaitlyn E Clark, Alexis Figueroa, Pamela J Bjorkman, Stuart C Ray, Andrew I Flyak, Justin R Bailey
JOURNAL: Immunity. 2024 Apr 9;57(4):890-903.e6. doi: 10.1016/j.immuni.2024.03.001. Epub 2024 Mar 21.
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.
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