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TitleHuman immunoglobulin repertoire analysis guides design of vaccine priming immunogens targeting HIV V2-apex broadly neutralizing antibody precursors.
Journal, issue, pagesImmunity, Vol. 55, Issue 11, Page 2149-22167.e9, Year 2022
Publish dateNov 8, 2022
AuthorsJordan R Willis / Zachary T Berndsen / Krystal M Ma / Jon M Steichen / Torben Schiffner / Elise Landais / Alessia Liguori / Oleksandr Kalyuzhniy / Joel D Allen / Sabyasachi Baboo / Oluwarotimi Omorodion / Jolene K Diedrich / Xiaozhen Hu / Erik Georgeson / Nicole Phelps / Saman Eskandarzadeh / Bettina Groschel / Michael Kubitz / Yumiko Adachi / Tina-Marie Mullin / Nushin B Alavi / Samantha Falcone / Sunny Himansu / Andrea Carfi / Ian A Wilson / John R Yates / James C Paulson / Max Crispin / Andrew B Ward / William R Schief /
PubMed AbstractBroadly neutralizing antibodies (bnAbs) to the HIV envelope (Env) V2-apex region are important leads for HIV vaccine design. Most V2-apex bnAbs engage Env with an uncommonly long heavy-chain ...Broadly neutralizing antibodies (bnAbs) to the HIV envelope (Env) V2-apex region are important leads for HIV vaccine design. Most V2-apex bnAbs engage Env with an uncommonly long heavy-chain complementarity-determining region 3 (HCDR3), suggesting that the rarity of bnAb precursors poses a challenge for vaccine priming. We created precursor sequence definitions for V2-apex HCDR3-dependent bnAbs and searched for related precursors in human antibody heavy-chain ultradeep sequencing data from 14 HIV-unexposed donors. We found potential precursors in a majority of donors for only two long-HCDR3 V2-apex bnAbs, PCT64 and PG9, identifying these bnAbs as priority vaccine targets. We then engineered ApexGT Env trimers that bound inferred germlines for PCT64 and PG9 and had higher affinities for bnAbs, determined cryo-EM structures of ApexGT trimers complexed with inferred-germline and bnAb forms of PCT64 and PG9, and developed an mRNA-encoded cell-surface ApexGT trimer. These methods and immunogens have promise to assist HIV vaccine development.
External linksImmunity / PubMed:36179689 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.64 - 26.0 Å
Structure data

EMDB-25622: Negative Stain EM reconstruction of ApexGT3 in complex with two copies of PG9 Fab
Method: EM (single particle) / Resolution: 26.0 Å

EMDB-25732, PDB-7t73:
HIV-1 Envelope ApexGT2.2MUT in complex with PCT64.LMCA Fab
Method: EM (single particle) / Resolution: 4.0 Å

EMDB-25733, PDB-7t74:
HIV-1 Envelope ApexGT2 in complex with PCT64.35S Fab and RM20A3 Fab
Method: EM (single particle) / Resolution: 3.35 Å

EMDB-25734, PDB-7t75:
HIV-1 Envelope ApexGT2 in complex with RM20A3 Fab
Method: EM (single particle) / Resolution: 2.7 Å

EMDB-25735, PDB-7t76:
HIV-1 Envelope ApexGT3 in complex with PG9.iGL Fab
Method: EM (single particle) / Resolution: 4.43 Å

EMDB-25736, PDB-7t77:
HIV-1 Envelope ApexGT3.N130 in complex with PG9 Fab
Method: EM (single particle) / Resolution: 4.75 Å

PDB-7ti6:
Crystal structure of the wild-type least mutated common ancestor (LMCA) of the HIV-targeting PCT64 antibody lineage
Method: X-RAY DIFFRACTION / Resolution: 2.64 Å

Chemicals

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

ChemComp-EPE:
4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / pH buffer*YM

ChemComp-HOH:
WATER

Source
  • human immunodeficiency virus 1
  • homo sapiens (human)
  • macaca mulatta (Rhesus monkey)
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / HIV / germline targeting vaccine / VIRAL PROTEIN-IMMUNE SYSTEM complex / IMMUNE SYSTEM / Antibody / Broadly Neutralizing / HIV-1 / V2 Apex

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