Abstract
The high genetic diversity of hepatitis C virus (HCV) complicates effective vaccine development. We screened a cohort of 435 HCV-infected individuals and found that 2%–5% demonstrated outstanding HCV-neutralizing activity. From four of these patients, we isolated 310 HCV antibodies, including neutralizing antibodies with exceptional breadth and potency. High neutralizing activity was enabled by the use of the VH1-69 heavy-chain gene segment, somatic mutations within CDRH1, and CDRH2 hydrophobicity. Structural and mutational analyses revealed an important role for mutations replacing the serines at positions 30 and 31, as well as the presence of neutral and hydrophobic residues at the tip of the CDRH3. Based on these characteristics, we computationally created a de novo antibody with a fully synthetic VH1-69 heavy chain that efficiently neutralized multiple HCV genotypes. Our findings provide a deep understanding of the generation of broadly HCV-neutralizing antibodies that can guide the design of effective vaccine candidates.
| Original language | English |
|---|---|
| Journal | Immunity |
| Volume | 55 |
| Issue number | 2 |
| Pages (from-to) | 341-354.e7 |
| ISSN | 1074-7613 |
| DOIs | |
| Publication status | Published - 08.02.2022 |
Funding
This work was funded by grants from the European Research Council ( ERC-STG-639961 to F.K.), the German Center for Infection Research (DZIF TTU 05.817 and TTU 05.821 to F.K., T.P., T.K., and T.W.) and the German Research Foundation (DFG) (CRC 1310 to F.K.). T.P. and T.K. are funded by the DFG under Germany’s Excellence Strategy (EXC 2155 “RESIST”—project ID 39087428). This research was also supported by the U.S. National Institutes of Health ( NIH ) ( NIH grant R01 AI127469 to P.J.B.) and ( NIH grant K99 AI153465 to A.I.F.) (content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH ) and the Molecular Observatory at Caltech supported by the Gordon and Betty Moore Foundation . Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences (contract no DE-AC02-76SF00515). The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by NIHGMS (P41GM103393).
