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Structure paper

TitleHIV broadly neutralizing antibody precursors to the Apex epitope induced in nonhuman primates.
Journal, issue, pagesSci Immunol, Vol. 10, Issue 110, Page eadt6660, Year 2025
Publish dateAug 22, 2025
AuthorsKrystal M Ma / Henry J Sutton / Payal P Pratap / Jon M Steichen / Diane Carnathan / James Quinn / Oleksandr Kalyuzhniy / Alessia Liguori / Sashank Agrawal / Sabyasachi Baboo / Patrick Madden / Christopher A Cottrell / Jordan R Willis / Jeong-Hyun Lee / Elise Landais / Xiaozhen Hu / Parham Ramezani-Rad / Gabriel Ozorowski / Vanessa R Lewis / Jolene K Diedrich / Xiaoya Zhou / Tasha K Altheide / Nicole Phelps / Erik Georgeson / Nushin B Alavi / Danny Lu / Saman Eskandarzadeh / Michael Kubitz / Yumiko Adachi / Tina-Marie Mullen / Murillo Silva / Mariane B Melo / Sunny Himansu / Darrell J Irvine / Dennis R Burton / John R Yates / James C Paulson / Devin Sok / Ian A Wilson / Guido Silvestri / Andrew B Ward / Shane Crotty / William R Schief /
PubMed AbstractAn effective prophylactic HIV vaccine will likely need to induce broadly neutralizing antibodies (bnAbs). bnAbs to the Apex region of the HIV envelope glycoprotein (Env) are promising targets for ...An effective prophylactic HIV vaccine will likely need to induce broadly neutralizing antibodies (bnAbs). bnAbs to the Apex region of the HIV envelope glycoprotein (Env) are promising targets for vaccination because of their relatively low somatic hypermutation compared with other bnAbs. Most Apex bnAbs engage Env using an exceptionally long heavy-chain complementarity-determining region 3 (HCDR3) containing specific binding motifs, which reduces bnAb precursor frequency and makes priming of rare bnAb precursors a likely limiting step in the path to Apex bnAb induction. We found that adjuvanted protein or mRNA lipid nanoparticle (LNP) immunization of rhesus macaques with ApexGT6, an Env trimer engineered to bind Apex bnAb precursors, consistently induced Apex bnAb-related precursors with long HCDR3s bearing bnAb-like sequence motifs. Cryo-electron microscopy revealed that elicited Apex bnAb-related HCDR3s had structures combining elements of several prototype Apex bnAbs. These results achieve a critical HIV vaccine development milestone in outbred primates.
External linksSci Immunol / PubMed:40845127 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.88 - 3.3 Å
Structure data

44341

9b8b

EMDB-44341, PDB-9b8b:
RM038 Fab in complex with Apex-GT 6.2 trimer and RM20A3 Fab
Method: EM (single particle) / Resolution: 3.2 Å

44342

9b8c

EMDB-44342, PDB-9b8c:
RM018 Fab in complex with Apex GT 6.2 trimer and RM20A3 Fab
Method: EM (single particle) / Resolution: 3.3 Å

48523

9mqg

EMDB-48523, PDB-9mqg:
RM017 Fab in complex with Apex-GT6.2 trimer and RM20A3 Fab
Method: EM (single particle) / Resolution: 3.3 Å

PDB-9mpb:
Crystal structure of the HIV V2-apex-targeting antibody RM038, derived from macaque ApexGT6 immunization
Method: X-RAY DIFFRACTION / Resolution: 1.98 Å

PDB-9mpc:
Crystal structure of the HIV V2-apex-targeting antibody RM018 from macaque
Method: X-RAY DIFFRACTION / Resolution: 3.3 Å

PDB-9mpx:
Crystal structure of RM014, a macaque-derived HIV V2-apex-targeting antibody from ApexGT6 immunization
Method: X-RAY DIFFRACTION / Resolution: 1.88 Å

Chemicals

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

ChemComp-HOH:
WATER

ChemComp-GOL:
GLYCEROL

Source
  • macaca mulatta (Rhesus monkey)
  • human immunodeficiency virus 1
  • macaca (macaques)
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / HIV Env / immune complex / VIRAL PROTEIN / macaque antibody / VIRAL PROTEIN-IMMUNE SYSTEM complex / V1V2 apex / IMMUNE SYSTEM / HIV-1 / Germline-targeting vaccination / ApexGT6 / V2-apex antibody

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