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TitleVaccination generates broadly cross-neutralizing antibodies to the HIV Env apex.
Journal, issue, pagesNature, Year 2026
Publish dateApr 29, 2026
AuthorsJavier Guenaga / Monika Ádori / Shridhar Bale / Swastik Phulera / Ioannis Zygouras / Fabian-Alexander Schleich / Xaquin Castro Dopico / Sashank Agrawal / Miyo Ota / Richard Wilson / Jocelyn Cluff / Tamar Dzvelaia / Marco Mandolesi / Wen-Hsin Lee / Agnes A Walsh / Mariane B Melo / Laurent Verkoczy / Darrell J Irvine / Martin Corcoran / Ian A Wilson / Diane Carnathan / Guido Silvestri / Andrew B Ward / Gabriel Ozorowski / Gunilla B Karlsson Hedestam / Richard T Wyatt /
PubMed AbstractAs a chronically replicating virus, HIV has evolved extreme sequence variability and effective shielding of functionally constrained spike protein determinants by host-derived glycans. Broadly ...As a chronically replicating virus, HIV has evolved extreme sequence variability and effective shielding of functionally constrained spike protein determinants by host-derived glycans. Broadly neutralizing antibodies, although rare, can be isolated from people living with HIV, revealing conserved envelope glycoprotein (Env) sites as key targets for vaccine development. One such target is the apex of the Env spike. Here we identify a vaccination strategy using heterologous HIV Env trimers covalently coupled to liposomes for multivalent display that resulted in the elicitation of cross-neutralizing HIV serum antibody responses in all trimer-liposome-immunized non-human primates. Critically, we isolated monoclonal antibodies from multiple macaques that cross-neutralize divergent HIV clinical isolates. High-resolution cryogenic electron microscopy structural analyses of monoclonal antibodies from four different macaques demonstrate that they target the Env trimer apex in a manner highly similar to that of the human-infection-elicited, apex-directed broadly neutralizing antibody PG9, representing a substantial advance in HIV vaccine development.
External linksNature / PubMed:42056526
MethodsEM (single particle) / X-ray diffraction
Resolution1.544 - 30.0 Å
Structure data

EMDB-72009, PDB-9py5:
Q10M-055 Fab in complex with HIV-1 Env Q23 NFL TD CC3+
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-72031, PDB-9pyd:
Q12QBM-007 Fab in complex with HIV-1 Env BG505 NFL TD CC3+
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-72033, PDB-9pyh:
Q9M-023 Fab in complex with HIV-1 Env BG505 NFL TD CC3+
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-72035, PDB-9pyk:
Q12BBM-069 Fab in complex with HIV-1 Env BG505 NFL TD CC3+
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-72735: HIV-1 Env Q23 NFL TD CC3+ in complex with NHP Q9 V2-apex polyclonal antibody Fabs isolated post-2 immunizations
Method: EM (single particle) / Resolution: 30.0 Å

EMDB-72736: HIV-1 Env Q23 NFL TD CC3+ in complex with NHP Q10 V2-apex polyclonal antibody Fabs isolated post-2 immunizations
Method: EM (single particle) / Resolution: 30.0 Å

EMDB-72737: HIV-1 Env Q23 NFL TD CC3+ in complex with NHP Q12 V2-apex polyclonal antibody Fabs isolated post-2 immunizations
Method: EM (single particle) / Resolution: 30.0 Å

EMDB-72738: HIV-1 Env 16055 NFL TD CC2+ in complex with pooled NHP Q8-Q9-Q12 V2-apex polyclonal antibody Fabs isolated post-4 immunizations
Method: EM (single particle) / Resolution: 25.0 Å

EMDB-72739: HIV-1 Env BG505 NFL TD CC3+ in complex with pooled NHP Q8-Q9-Q12 V2-apex polyclonal antibody Fabs isolated post-4 immunizations
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-74449: Q7M-675 Fab in complex with HIV-1 Env WITO NFL TD CC3+
Method: EM (single particle) / Resolution: 4.3 Å

PDB-9pyn:
Crystal structure of HIV Apex fab Q9M-023
Method: X-RAY DIFFRACTION / Resolution: 2.34 Å

PDB-9pyy:
Crystal structure of HIV Apex Fab Q10M_055
Method: X-RAY DIFFRACTION / Resolution: 1.63 Å

PDB-9pz2:
Crystal structure of HIV Apex neutralizing Fab Q12QBM-007
Method: X-RAY DIFFRACTION / Resolution: 1.544 Å

PDB-9pz3:
Crystal structure of HIV Apex targeting neutralizing antibody Q12BBM-069
Method: X-RAY DIFFRACTION / Resolution: 1.79 Å

Chemicals

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

ChemComp-HOH:
WATER

Source
  • human immunodeficiency virus 1
  • macaca mulatta (Rhesus monkey)
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / HIV-1 / macaque / non-human primate / NHP / V2-apex / neutralizing antibody / VIRAL PROTEIN-IMMUNE SYSTEM complex / vaccine / IMMUNE SYSTEM / HIV / Apex targeting neutralizing antibody / Apex mAb / NHPs / HIV Apex neutralizing antibody / Apex neutralizing antibody

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