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TitlePotent and broad HIV-1 neutralization in fusion peptide-primed SHIV-infected macaques.
Journal, issue, pagesCell, Vol. 187, Issue 25, Page 7214-7231.e23, Year 2024
Publish dateDec 12, 2024
AuthorsHua Wang / Cheng Cheng / James L Dal Santo / Chen-Hsiang Shen / Tatsiana Bylund / Amy R Henry / Colin A Howe / Juyun Hwang / Nicholas C Morano / Daniel J Morris / Sergei Pletnev / Ryan S Roark / Tongqing Zhou / Bryan T Hansen / Forrest H Hoyt / Timothy S Johnston / Shuyi Wang / Baoshan Zhang / David R Ambrozak / Jordan E Becker / Michael F Bender / Anita Changela / Ridhi Chaudhary / Martin Corcoran / Angela R Corrigan / Kathryn E Foulds / Yicheng Guo / Myungjin Lee / Yingying Li / Bob C Lin / Tracy Liu / Mark K Louder / Marco Mandolesi / Rosemarie D Mason / Krisha McKee / Vinod Nair / Sijy O'Dell / Adam S Olia / Li Ou / Amarendra Pegu / Nagarajan Raju / Reda Rawi / Jesmine Roberts-Torres / Edward K Sarfo / Mallika Sastry / Andrew J Schaub / Stephen D Schmidt / Chaim A Schramm / Cindi L Schwartz / Sarah C Smith / Tyler Stephens / Jonathan Stuckey / I-Ting Teng / John-Paul Todd / Yaroslav Tsybovsky / David J Van Wazer / Shuishu Wang / Nicole A Doria-Rose / Elizabeth R Fischer / Ivelin S Georgiev / Gunilla B Karlsson Hedestam / Zizhang Sheng / Ruth A Woodward / Daniel C Douek / Richard A Koup / Theodore C Pierson / Lawrence Shapiro / George M Shaw / John R Mascola / Peter D Kwong /
PubMed AbstractAn antibody-based HIV-1 vaccine will require the induction of potent cross-reactive HIV-1-neutralizing responses. To demonstrate feasibility toward this goal, we combined vaccination targeting the ...An antibody-based HIV-1 vaccine will require the induction of potent cross-reactive HIV-1-neutralizing responses. To demonstrate feasibility toward this goal, we combined vaccination targeting the fusion-peptide site of vulnerability with infection by simian-human immunodeficiency virus (SHIV). In four macaques with vaccine-induced neutralizing responses, SHIV infection boosted plasma neutralization to 45%-77% breadth (geometric mean 50% inhibitory dilution [ID] ∼100) on a 208-strain panel. Molecular dissection of these responses by antibody isolation and cryo-electron microscopy (cryo-EM) structure determination revealed 15 of 16 antibody lineages with cross-clade neutralization to be directed toward the fusion-peptide site of vulnerability. In each macaque, isolated antibodies from memory B cells recapitulated the plasma-neutralizing response, with fusion-peptide-binding antibodies reaching breadths of 40%-60% (50% inhibitory concentration [IC] < 50 μg/mL) and total lineage-concentrations estimates of 50-200 μg/mL. Longitudinal mapping indicated that these responses arose prior to SHIV infection. Collectively, these results provide in vivo molecular examples for one to a few B cell lineages affording potent, broadly neutralizing plasma responses.
External linksCell / PubMed:39471811 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.09 - 4.03 Å
Structure data

EMDB-41309: CRYO-EM STRUCTURE OF HIV-1 BG505DS-SOSIP.664 ENV TRIMER BOUND TO HERH-c.01 FAB
PDB-8tjr: CRYO-EM STRUCTURE OF HIV-1 BG505DS-SOSIP.664 ENV TRIMER BOUND TO HERH-a.01 FAB
Method: EM (single particle) / Resolution: 3.29 Å

EMDB-41310, PDB-8tjs:
CRYO-EM STRUCTURE OF HIV-1 BG505DS-SOSIP.664 ENV TRIMER BOUND TO GPZ6-a.01 FAB
Method: EM (single particle) / Resolution: 3.31 Å

EMDB-41346, PDB-8tkc:
CRYO-EM STRUCTURE OF HIV-1 BG505DS-SOSIP.664 ENV TRIMER BOUND TO DJ85-b.01 FAB
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-41359, PDB-8tl2:
CRYO-EM STRUCTURE OF HIV-1 BG505DS-SOSIP.664 ENV TRIMER BOUND TO DJ85-c.01 FAB
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-41360, PDB-8tl3:
CRYO-EM STRUCTURE OF HIV-1 BG505DS-SOSIP.664 ENV TRIMER BOUND TO DJ85-d.01 FAB
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-41361, PDB-8tl4:
CRYO-EM STRUCTURE OF HIV-1 BG505DS-SOSIP.664 ENV TRIMER BOUND TO DJ85-e.01 FAB
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-41362, PDB-8tl5:
CRYO-EM STRUCTURE OF HIV-1 BG505DS-SOSIP.664 ENV TRIMER BOUND TO HERH-c.01 FAB
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-41426, PDB-8tnu:
Cryo-EM structure of TRNM-b*01 Fab in complex with HIV-1 Env trimer BG505.DS SOSIP
Method: EM (single particle) / Resolution: 3.36 Å

EMDB-41438, PDB-8to7:
Cryo-EM structure of HERH-b*01 Fab in complex with HIV-1 Env trimer BG505.DS SOSIP
Method: EM (single particle) / Resolution: 3.39 Å

EMDB-41440, PDB-8to9:
Cryo-EM structure of TRNM-f*01 Fab in complex with HIV-1 Env trimer ConC SOSIP
Method: EM (single particle) / Resolution: 4.03 Å

EMDB-41459, PDB-8top:
Cryo-EM structure of HIV-1 Env BG505 DS-SOSIP in complex with antibody GPZ6-b.01 targeting the fusion peptide
Method: EM (single particle) / Resolution: 3.52 Å

PDB-8tdx:
TRNM-b.01 in complex with HIV Env fusion peptide
Method: X-RAY DIFFRACTION / Resolution: 2.09 Å

PDB-8te7:
Structure of TRNM-f.01
Method: X-RAY DIFFRACTION / Resolution: 3.18 Å

Chemicals

ChemComp-HOH:
WATER

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

Source
  • homo sapiens (human)
  • macaca (macaques)
  • human immunodeficiency virus 1
  • macaca mulatta (Rhesus monkey)
KeywordsIMMUNE SYSTEM / HIV-1 / Fusion Peptide / Antibody / Fab / CD4 Binding Site / Viral Protein/Immune System / SHIV / Viral Protein-Immune System complex / broadly neutralizing antibody / glycoprotein / viral protein / FP-targeting vaccines / Vaccination / HIV-1 Envelope / GPZ6-b.01 / BG505 DS-SOSIP / neutralization / immunization

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