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TitleNeutralizing antibodies induced in immunized macaques recognize the CD4-binding site on an occluded-open HIV-1 envelope trimer.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 732, Year 2022
Publish dateFeb 8, 2022
AuthorsZhi Yang / Kim-Marie A Dam / Michael D Bridges / Magnus A G Hoffmann / Andrew T DeLaitsch / Harry B Gristick / Amelia Escolano / Rajeev Gautam / Malcolm A Martin / Michel C Nussenzweig / Wayne L Hubbell / Pamela J Bjorkman /
PubMed AbstractBroadly-neutralizing antibodies (bNAbs) against HIV-1 Env can protect from infection. We characterize Ab1303 and Ab1573, heterologously-neutralizing CD4-binding site (CD4bs) antibodies, isolated from ...Broadly-neutralizing antibodies (bNAbs) against HIV-1 Env can protect from infection. We characterize Ab1303 and Ab1573, heterologously-neutralizing CD4-binding site (CD4bs) antibodies, isolated from sequentially-immunized macaques. Ab1303/Ab1573 binding is observed only when Env trimers are not constrained in the closed, prefusion conformation. Fab-Env cryo-EM structures show that both antibodies recognize the CD4bs on Env trimer with an 'occluded-open' conformation between closed, as targeted by bNAbs, and fully-open, as recognized by CD4. The occluded-open Env trimer conformation includes outwardly-rotated gp120 subunits, but unlike CD4-bound Envs, does not exhibit V1V2 displacement, 4-stranded gp120 bridging sheet, or co-receptor binding site exposure. Inter-protomer distances within trimers measured by double electron-electron resonance spectroscopy suggest an equilibrium between occluded-open and closed Env conformations, consistent with Ab1303/Ab1573 binding stabilizing an existing conformation. Studies of Ab1303/Ab1573 demonstrate that CD4bs neutralizing antibodies that bind open Env trimers can be raised by immunization, thereby informing immunogen design and antibody therapeutic efforts.
External linksNat Commun / PubMed:35136084 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.51 - 4.1 Å
Structure data

25877

7tfn

EMDB-25877, PDB-7tfn:
Cryo-EM structure of CD4bs antibody Ab1303 in complex with HIV-1 Env trimer BG505 SOSIP.664
Method: EM (single particle) / Resolution: 4.0 Å

25878

7tfo

EMDB-25878, PDB-7tfo:
Cryo-EM structure of HIV-1 Env trimer BG505 SOSIP.664 in complex with CD4bs antibody Ab1573
Method: EM (single particle) / Resolution: 4.1 Å

PDB-7ryu:
Anti-HIV neutralizing antibody Ab1303 Fab isolated from sequentially immunized mcaques
Method: X-RAY DIFFRACTION / Resolution: 1.51 Å

PDB-7ryv:
Anti-HIV neutralizing antibody Ab1573 Fab isolated from sequentially immunized macaques
Method: X-RAY DIFFRACTION / Resolution: 2.5 Å

Chemicals

ChemComp-HOH:
WATER

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

ChemComp-MAN:
alpha-D-mannopyranose

Source
  • human immunodeficiency virus 1
  • macaca mulatta (Rhesus monkey)
KeywordsIMMUNE SYSTEM / anti-HIV neutralizing antibody; antibody Fab; / anti-HIV antibody; neutralizing antibody; immunogen design / VIRAL PROTEIN/IMMUNE SYSTEM / HIV-1 Env / neutralizing antibody / CD4 binding site antibody / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex / Cryo-EM structure of the trimeric HIV-1 Env ecto-domain BG505 SOSIP.664 in complex with CD4 binding site antibody Ab1573

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