Highly mutated antibodies capable of neutralizing N276 glycan-deficient HIV after a single immunization with an Env trimer

Jeong Hyun Lee, Catherine Nakao, Michael Appel, Amber Le, Elise Landais, Oleksandr Kalyuzhniy, Xiaozhen Hu, Alessia Liguori, Tina Marie Mullen, Bettina Groschel, Robert K. Abbott, Devin Sok, William R. Schief, Shane Crotty

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Elicitation of HIV broadly neutralizing antibodies (bnAbs) is challenging because unmutated bnAb precursors are rare and seldom bind HIV envelope glycoprotein (Env) trimers. One strategy to initiate bnAb responses is to use germline-targeting (GT) immunogens with high affinity to bnAb-class precursor B cells and then shepherd affinity maturation with booster immunogens that successively look more like native Env. In a mouse model where the frequency of VRC01-precursor (VRC01gHL) B cells mimics that of humans, we show that following a GT HIV Env trimer protein prime, VRC01-class B cells in the germinal center (GC) acquire high-affinity VRC01-class B cell somatic hypermutations (SHMs). Many GC-derived VRC01gHL antibodies robustly bind N276 glycan-deficient Env trimers and neutralize several N276 glycan-deficient tier 2 HIV strains. These results are encouraging for GT Env trimer vaccine designs and demonstrate accumulation of substantial SHMs, including deletions, uncommon point mutations, and functional bnAb features, after a single immunization.

Original languageEnglish (US)
Article number110485
JournalCell Reports
Volume38
Issue number10
DOIs
StatePublished - Mar 8 2022
Externally publishedYes

Keywords

  • broadly neutralizing antibody
  • envelope trimer
  • germline-targeting vaccine
  • human immunodeficiency virus

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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