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TitleAntibody elicited by HIV-1 immunogen vaccination in macaques displaces Env fusion peptide and destroys a neutralizing epitope.
Journal, issue, pagesNPJ Vaccines, Vol. 6, Issue 1, Page 126, Year 2021
Publish dateOct 25, 2021
AuthorsMorgan E Abernathy / Harry B Gristick / Jost Vielmetter / Jennifer R Keeffe / Priyanthi N P Gnanapragasam / Yu E Lee / Amelia Escolano / Rajeev Gautam / Michael S Seaman / Malcolm A Martin / Michel C Nussenzweig / Pamela J Bjorkman /
PubMed AbstractHIV-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. We report ...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. We report characterization of Ab1245, an off-target antibody against the Env gp120-gp41 interface, from V3-glycan patch immunogen-primed and boosted macaques. A 3.7 Å 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, raising the possibility 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.
External linksNPJ Vaccines / PubMed:34697307 / PubMed Central
MethodsEM (single particle)
Resolution3.7 Å
Structure data

24072

7mxe

EMDB-24072, PDB-7mxe:
Ab1245 Fab in complex with BG505 SOSIP.664 and 8ANC195 Fab
Method: EM (single particle) / Resolution: 3.7 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
  • macaca mulatta (Rhesus monkey)
  • human immunodeficiency virus 1
KeywordsANTIVIRAL PROTEIN/VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex / non-neutralizing / ANTIVIRAL PROTEIN / ANTIVIRAL PROTEIN-VIRAL PROTEIN complex

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