Two antibody germline precursors are selected for broad neutralization of hepatitis C virus.

What is it about?

One of the leading strategies to develop a vaccine against highly variable viruses focus on eliciting broadly neutralizing antibodies (bnAbs), and the antigenic site 412 (AS412, amino acids 412 to 423) represents the target of the broadest bnAbs. Although several mouse monoclonal antibodies (mAbs) targeting the viral envelope have been described, it has to be elucidated yet how the immune system selects bnAbs. To solve this fundamental question, this manuscript reports key discoveries in the virology and immunology fields as follows: 1.- We provide a genetic landscape of mAbs binding to the HCV envelope glycoprotein E2, using published mAbs and our repertoire. Analyzing this panel we discovered that two germline precursors are selected in mice for broad neutralization and recognition of AS412. In addition, our findings show that these two lineages go through different maturation pathways that focused either in the light chain or the heavy chain. 2.- Our leading bnAb showed stronger binding and neutralization breadth than what is considered the leader mice bnAb in the field. 3.- Structural analysis are key to understand how the bnAbs function. Thus, we show that two novel bnAbs bind to the same AS412 target with the similar β-hairpin conformations, but with different binding modes. 4.- Finally, in order to develop better immunogens as vaccine candidates, we present the structures of two inferred germline precursors bound to the broadly neutralizing AS412 epitope, which represent a key template for immunogen redesign.

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Why is it important?

Findings of our manuscript include the first demonstration that mice grown in different parts of the world elicit essentially the same bnAbs against AS412, and provide the first structures of a germline precursor against HCV. These structures are key templates for immunogen redesign in our efforts to obtain a vaccine.The novel findings advances our understanding of the humoral response against Hepatitis C and the conclusions may be also relevant to other variable viruses such as HIV.