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TitleGermline-targeting HIV vaccination induces neutralizing antibodies to the CD4 binding site.
Journal, issue, pagesSci Immunol, Vol. 9, Issue 98, Page eadk9550, Year 2024
Publish dateAug 30, 2024
AuthorsTom G Caniels / Max Medina-Ramìrez / Shiyu Zhang / Sven Kratochvil / Yuejiao Xian / Ja-Hyun Koo / Ronald Derking / Jakob Samsel / Jelle van Schooten / Simone Pecetta / Edward Lamperti / Meng Yuan / María Ríos Carrasco / Iván Del Moral Sánchez / Joel D Allen / Joey H Bouhuijs / Anila Yasmeen / Thomas J Ketas / Jonne L Snitselaar / Tom P L Bijl / Isabel Cuella Martin / Jonathan L Torres / Albert Cupo / Lisa Shirreff / Kenneth Rogers / Rosemarie D Mason / Mario Roederer / Kelli M Greene / Hongmei Gao / Catarina Mendes Silva / Isabel J L Baken / Ming Tian / Frederick W Alt / Bali Pulendran / Michael S Seaman / Max Crispin / Marit J van Gils / David C Montefiori / Adrian B McDermott / François J Villinger / Richard A Koup / John P Moore / Per Johan Klasse / Gabriel Ozorowski / Facundo D Batista / Ian A Wilson / Andrew B Ward / Rogier W Sanders /
PubMed AbstractEliciting potent and broadly neutralizing antibodies (bnAbs) is a major goal in HIV-1 vaccine development. Here, we describe how germline-targeting immunogen BG505 SOSIP germline trimer 1.1 (GT1.1), ...Eliciting potent and broadly neutralizing antibodies (bnAbs) is a major goal in HIV-1 vaccine development. Here, we describe how germline-targeting immunogen BG505 SOSIP germline trimer 1.1 (GT1.1), generated through structure-based design, engages a diverse range of VRC01-class bnAb precursors. A single immunization with GT1.1 expands CD4 binding site (CD4bs)-specific VRC01-class B cells in knock-in mice and drives VRC01-class maturation. In nonhuman primates (NHPs), GT1.1 primes CD4bs-specific neutralizing serum responses. Selected monoclonal antibodies (mAbs) isolated from GT1.1-immunized NHPs neutralize fully glycosylated BG505 virus. Two mAbs, 12C11 and 21N13, neutralize subsets of diverse heterologous neutralization-resistant viruses. High-resolution structures revealed that 21N13 targets the same conserved residues in the CD4bs as VRC01-class and CH235-class bnAbs despite its low sequence similarity (~40%), whereas mAb 12C11 binds predominantly through its heavy chain complementarity-determining region 3. These preclinical data underpin the ongoing evaluation of GT1.1 in a phase 1 clinical trial in healthy volunteers.
External linksSci Immunol / PubMed:39213338
MethodsEM (single particle)
Resolution2.8 - 2.85 Å
Structure data

40796

8sw3

EMDB-40796, PDB-8sw3:
BG505 GT1.1 SOSIP in complex with NHP Fabs 12C11 and RM20A3
Method: EM (single particle) / Resolution: 2.8 Å

40797

8sw4

EMDB-40797, PDB-8sw4:
BG505 GT1.1 SOSIP in complex with NHP Fabs 21N13, 21M20 and RM20A3
Method: EM (single particle) / Resolution: 2.85 Å

Chemicals

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

Source
  • macaca (macaques)
  • human immunodeficiency virus 1
KeywordsVIRAL PROTEIN / germline targeting / HIV-1 Env / neutralizing antibody / non-human primate antibody / CD4 binding site / fusion peptide

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