Forskning ved Københavns Universitet - Københavns Universitet


Functional convergence of a germline-encoded neutralizing antibody response in rhesus macaques immunized with HCV envelope glycoproteins

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  • Fang Chen
  • Netanel Tzarum
  • Xiaohe Lin
  • Erick Giang
  • Rodrigo Velázquez-Moctezuma
  • Augestad, Elias Honerød
  • Kenna Nagy
  • Linling He
  • Mayda Hernandez
  • Mallorie E. Fouch
  • Ariadna Grinyó
  • Deborah Chavez
  • Benjamin J. Doranz
  • Prentø, Jannick
  • Robyn L. Stanfield
  • Robert Lanford
  • Bukh, Jens
  • Ian A. Wilson
  • Jiang Zhu
  • Mansun Law

Human IGHV1-69-encoded broadly neutralizing antibodies (bnAbs) that target the hepatitis C virus (HCV) envelope glycoprotein (Env) E2 are important for protection against HCV infection. An IGHV1-69 ortholog gene, VH1.36, is preferentially used for bnAbs isolated from HCV Env-immunized rhesus macaques (RMs). Here, we studied the genetic, structural, and functional properties of VH1.36-encoded bnAbs generated by vaccination, in comparison to IGHV1-69-encoded bnAbs from HCV patients. Global B cell repertoire analysis confirmed the expansion of VH1.36-derived B cells in immunized animals. Most E2-specific, VH1.36-encoded antibodies cross-neutralized HCV. Crystal structures of two RM bnAbs with E2 revealed that the RM bnAbs engaged conserved E2 epitopes using similar molecular features as human bnAbs but with a different binding mode. Longitudinal analyses of the RM antibody repertoire responses during immunization indicated rapid lineage development of VH1.36-encoded bnAbs with limited somatic hypermutation. Our findings suggest functional convergence of a germline-encoded bnAb response to HCV Env with implications for vaccination in humans.

Udgave nummer4
Sider (fra-til)781-796.e4
StatusUdgivet - 2021

ID: 260546954