RT Journal Article
SR Electronic
T1 Antibody elicited by HIV-1 immunogen vaccination in macaques displaces Env fusion peptide and destroys a neutralizing epitope
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.03.17.435265
DO 10.1101/2021.03.17.435265
A1 Morgan E. Abernathy
A1 Harry B. Gristick
A1 Jost Vielmetter
A1 Jennifer R. Keeffe
A1 Priyanthi NP Gnanapragasam
A1 Yu E. Lee
A1 Amelia Escolano
A1 Rajeev Gautam
A1 Michael S. Seaman
A1 Malcolm A. Martin
A1 Michel C. Nussenzweig
A1 Pamela J. Bjorkman
YR 2021
UL http://biorxiv.org/content/early/2021/03/17/2021.03.17.435265.abstract
AB HIV-1 vaccine design aims to develop an immunogen that elicits broadly neutralizing antibodies against a desired epitope, while eliminating responses to off-target regions of HIV-1 Env. Here we report isolation and characterization of Ab1245, an off-target antibody against the Env gp120-gp41 interface, from V3-glycan patch immunogen-primed and boosted macaques. A 3.7Å cryo-EM structure of an Ab1245-Env complex reveals one Ab1245 Fab binding asymmetrically to Env trimer at the gp120-gp41 interface using its long CDRH3 to mimic regions of gp41. The mimicry includes positioning of a CDRH3 methionine into the gp41 tryptophan clasp, resulting in displacement of the fusion peptide and fusion peptide-proximal region. Despite fusion peptide displacement, Ab1245 is non-neutralizing even at high concentrations, implying that only two fusion peptides per trimer are required for viral–host membrane fusion. These structural analyses facilitate immunogen design to prevent elicitation of Ab1245-like antibodies that block neutralizing antibodies against the fusion peptide.Competing Interest StatementThe authors have declared no competing interest.