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TitleStructural and immunogenetic signatures guide CD4-mimetic HIV vaccine development.
Journal, issue, pagesCell Rep, Vol. 45, Issue 4, Page 117180, Year 2026
Publish dateApr 15, 2026
AuthorsDaniel L V Bader / Claudia T Flynn / Oleksandr Kalyuzhniy / Gabriel Ozorowski / Martin M Corcoran / Alison Burns / Pilar Altman / Romy Rouzeau / Troy Sincomb / Alessia Liguori / Monica L Fernández-Quintero / Johannes R Loeffler / Jonathan L Torres / Hannah L Turner / Erik Georgeson / Amelia Zhou / Hannah Voic / Sue Goo / Lara Shahin / Iszac Burton / Mengyu Wu / Robyn L Stanfield / Saman Eskandarzadeh / Danny Lu / Nushin Alavi / Nicole Phelps / Ryan Tingle / Katherine McKenney / John Youhanna / Sonya Amirzehni / Torben Schiffner / Jon M Steichen / Dennis R Burton / Ian A Wilson / Gunilla B Karlsson Hedestam / Elise Landais / Jeong Hyun Lee / Devin Sok / Christopher A Cottrell / Andrew B Ward / William R Schief /
PubMed AbstractHIV vaccine strategies include aims to elicit broadly neutralizing antibodies (bnAbs) targeting the CD4-binding site, that are derived from immunoglobulin heavy-chain variable genes 1-2 (V1-2) and 1- ...HIV vaccine strategies include aims to elicit broadly neutralizing antibodies (bnAbs) targeting the CD4-binding site, that are derived from immunoglobulin heavy-chain variable genes 1-2 (V1-2) and 1-46 (V1-46). Here, we present an integrated analysis of V1-46 bnAbs, including in vitro functional studies, cryo-electron microscopy structures of two V1-46 bnAbs (1-23 and 9-71) complexed with envelope trimers, and comprehensive structural and immunogenetic analyses, to help guide vaccine design. We show that V1-46-derived bnAbs use diverse light-chain variable (V/V) genes and LCDR3 lengths commonly found in human antibody repertoires, which generate unique LCDR3 signatures that influence both the antibody paratope and approach angle. We identify three V1-46 bnAb classes, 1B2530 (V1-47), CH235 (V3-15), and 561 (V3-20), with the 561 class further subdivided into types I and II. Our findings indicate that V1-46 priming immunogens should be tailored to each bnAb class, with 561-class bnAbs presenting optimal targets for germline-targeting vaccine design.
External linksCell Rep / PubMed:41996239
MethodsEM (single particle)
Resolution3.1 - 3.5 Å
Structure data

71677

9pit

EMDB-71677, PDB-9pit:
HIV-1 bnAb 1-23 in complex with BG505 MD39 SOSIP and RM19R
Method: EM (single particle) / Resolution: 3.1 Å

71678

9piv

EMDB-71678, PDB-9piv:
HIV-1 bnAb 9-71 in complex with BG505 MD39 SOSIP and RM19R
Method: EM (single particle) / Resolution: 3.5 Å

Chemicals

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

Source
  • human immunodeficiency virus 1
  • homo sapiens (human)
  • macaca mulatta (Rhesus monkey)
KeywordsVIRAL PROTEIN / HIV-1 / SOSIP / human / broadly neutralizing antibody / Fab

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