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TitleVaccination induces broadly neutralizing antibody precursors to HIV gp41.
Journal, issue, pagesNat Immunol, Vol. 25, Issue 6, Page 1073-1082, Year 2024
Publish dateMay 30, 2024
AuthorsTorben Schiffner / Ivy Phung / Rashmi Ray / Adriana Irimia / Ming Tian / Olivia Swanson / Jeong Hyun Lee / Chang-Chun D Lee / Ester Marina-Zárate / So Yeon Cho / Jiachen Huang / Gabriel Ozorowski / Patrick D Skog / Andreia M Serra / Kimmo Rantalainen / Joel D Allen / Sabyasachi Baboo / Oscar L Rodriguez / Sunny Himansu / Jianfu Zhou / Jonathan Hurtado / Claudia T Flynn / Katherine McKenney / Colin Havenar-Daughton / Swati Saha / Kaitlyn Shields / Steven Schulze / Melissa L Smith / Chi-Hui Liang / Laura Toy / Simone Pecetta / Ying-Cing Lin / Jordan R Willis / Fabian Sesterhenn / Daniel W Kulp / Xiaozhen Hu / Christopher A Cottrell / Xiaoya Zhou / Jennifer Ruiz / Xuesong Wang / Usha Nair / Kathrin H Kirsch / Hwei-Ling Cheng / Jillian Davis / Oleksandr Kalyuzhniy / Alessia Liguori / Jolene K Diedrich / Julia T Ngo / Vanessa Lewis / Nicole Phelps / Ryan D Tingle / Skye Spencer / Erik Georgeson / Yumiko Adachi / Michael Kubitz / Saman Eskandarzadeh / Marc A Elsliger / Rama R Amara / Elise Landais / Bryan Briney / Dennis R Burton / Diane G Carnathan / Guido Silvestri / Corey T Watson / John R Yates / James C Paulson / Max Crispin / Gevorg Grigoryan / Andrew B Ward / Devin Sok / Frederick W Alt / Ian A Wilson / Facundo D Batista / Shane Crotty / William R Schief /
PubMed AbstractA key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design ...A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. We developed germline-targeting epitope scaffolds with affinity for 10E8-class precursors and engineered nanoparticles for multivalent display. Scaffolds exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens, protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. Thus, germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features.
External linksNat Immunol / PubMed:38816615 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.98 - 4.0 Å
Structure data

40825

8sx3

EMDB-40825, PDB-8sx3:
10E8-GT10.2 immunogen in complex with human Fab 10E8 and mouse Fab W6-10
Method: EM (single particle) / Resolution: 4.0 Å

PDB-8tzn:
Crystal structure of 10E8-GT10.2 HIV-1 MPER scaffold in complex with a non-human primate W3-01 Fab
Method: X-RAY DIFFRACTION / Resolution: 3.11 Å

PDB-8tzw:
Crystal structure of 10E8-GT4 scaffold in complex with a human 10E8 inferred germline (10E8-iGL1)
Method: X-RAY DIFFRACTION / Resolution: 2.66 Å

PDB-8u03:
Crystal structure of non-glycosylated 10E8-GT10.1 scaffold in complex with a human 10E8 NGS precursor (10E8-NGS-03)
Method: X-RAY DIFFRACTION / Resolution: 2.72 Å

PDB-8u08:
Crystal structure of 10E8-GT11 scaffold in complex with a human 10E8 inferred germline (10E8-iGL1)
Method: X-RAY DIFFRACTION / Resolution: 1.98 Å

PDB-8v2e:
Crystal structure of B055 scaffold boost immunogen in complex with a mature 10E8 Fab
Method: X-RAY DIFFRACTION / Resolution: 2.62 Å

Chemicals

ChemComp-HOH:
WATER / Water

ChemComp-1PE:
PENTAETHYLENE GLYCOL / precipitant*YM / Polyethylene glycol

ChemComp-IMD:
IMIDAZOLE / Imidazole

ChemComp-GOL:
GLYCEROL / Glycerol

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

Source
  • mus musculus (house mouse)
  • synthetic construct (others)
  • homo sapiens (human)
  • unidentified monkey (mammal)
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / HIV / Germline targeting / MPER / broadly neutralizing antibody / vaccine design / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex / IMMUNE SYSTEM / HIV-1 / NHP / 10E8 / scaffold / GP41 / Vaccine / epitope-scaffold / boost immunogen / antigen-antibody complex

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