TY - JOUR
T1 - Analysis of antibodies from HCV elite neutralizers identifies genetic determinants of broad neutralization
AU - Weber, Timm
AU - Potthoff, Julian
AU - Bizu, Sven
AU - Labuhn, Maurice
AU - Dold, Leona
AU - Schoofs, Till
AU - Horning, Marcel
AU - Ercanoglu, Meryem S.
AU - Kreer, Christoph
AU - Gieselmann, Lutz
AU - Vanshylla, Kanika
AU - Langhans, Bettina
AU - Janicki, Hanna
AU - Ströh, Luisa J.
AU - Knops, Elena
AU - Nierhoff, Dirk
AU - Spengler, Ulrich
AU - Kaiser, Rolf
AU - Bjorkman, Pamela J.
AU - Krey, Thomas
AU - Bankwitz, Dorothea
AU - Pfeifer, Nico
AU - Pietschmann, Thomas
AU - Flyak, Andrew I.
AU - Klein, Florian
N1 - Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2022/2/8
Y1 - 2022/2/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85124015128&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2021.12.003
DO - 10.1016/j.immuni.2021.12.003
M3 - Journal articles
C2 - 34990590
AN - SCOPUS:85124015128
SN - 1074-7613
VL - 55
SP - 341-354.e7
JO - Immunity
JF - Immunity
IS - 2
ER -
