| Reference | ||
|---|---|---|
| Reference Type | Literature | IEDB_Reference:1035419 |
| Title | Antibody Lineages with Vaccine-Induced Antigen-Binding Hotspots Develop Broad HIV Neutralization. | |
| Authors | Rui Kong; Hongying Duan; Zizhang Sheng; Kai Xu; Priyamvada Acharya; Xuejun Chen; Cheng Cheng; Adam S Dingens; Jason Gorman; Mallika Sastry; Chen-Hsiang Shen; Baoshan Zhang; Tongqing Zhou; Gwo-Yu Chuang; Cara W Chao; Ying Gu; Alexander J Jafari; Mark K Louder; Sijy O'Dell; Ariana P Rowshan; Elise G Viox; Yiran Wang; Chang W Choi; Martin M Corcoran; Angela R Corrigan; Venkata P Dandey; Edward T Eng; Hui Geng; Kathryn E Foulds; Yicheng Guo; Young D Kwon; Bob Lin; Kevin Liu; Rosemarie D Mason; Martha C Nason; Tiffany Y Ohr; Li Ou; Reda Rawi; Edward K Sarfo; Arne Schön; John P Todd; Shuishu Wang; Hui Wei; Winston Wu; NISC Comparative Sequencing Program; James C Mullikin; Robert T Bailer; Nicole A Doria-Rose; Gunilla B Karlsson Hedestam; Diana G Scorpio; Julie Overbaugh; Jesse D Bloom; Bridget Carragher; Clinton S Potter; Lawrence Shapiro; Peter D Kwong; John R Mascola | |
| Affiliations | Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA; National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY 10027, USA; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98195, USA; Molecular and Cellular Biology PhD Program, University of Washington, Seattle, WA 98195, USA; Division of Human Biology and Epidemiology Program, Seattle, WA 98195, USA; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm 17177, Sweden; Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA; NIH Intramural Sequencing Center, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; Howard Hughes Medical Institute, S... | |
| Journal | Cell | |
| Year | 2019 | |
| Abstract | The vaccine-mediated elicitation of antibodies (Abs) capable of neutralizing diverse HIV-1 strains has been a long-standing goal. To understand how broadly neutralizing antibodies (bNAbs) can be elicited, we identified, characterized, and tracked five neutralizing Ab lineages targeting the HIV-1-fusion peptide (FP) in vaccinated macaques over time. Genetic and structural analyses revealed two of these lineages to belong to a reproducible class capable of neutralizing up to 59% of 208 diverse viral strains. B cell analysis indicated each of the five lineages to have been initiated and expanded by FP-carrier priming, with envelope (Env)-trimer boosts inducing cross-reactive neutralization. These Abs had binding-energy hotspots focused on FP, whereas several FP-directed Abs induced by immunization with Env trimer-only were less FP-focused and less broadly neutralizing. Priming with a conserved subregion, such as FP, can thus induce Abs with binding-energy hotspots coincident with the target subregion and capable of broad neutralization. | |
| Curation Last Updated | 2023-08-19 00:45:59 | |
| Epitope | ||
|---|---|---|
| Epitope ID | 780270 | IEDB_epitope:780270 |
| Chemical Type | Linear peptide | |
| Linear Sequence | AVGIGAVF | |
| Source Molecule Name | Envelope glycoprotein gp160 | |
| Source Organism | Human immunodeficiency virus 1 (human immunodeficiency virus 1 HIV-1) | |
| Starting Position | 509 | |
| Ending Position | 516 | |
| Epitope Reference Details | ||
|---|---|---|
| Epitope Structure Defines | Exact Epitope | |
| Epitope Name | HIV-1 Env Fusion peptide (FP8) | |
| Reference Starting Position | 512 | |
| Reference Ending Position | 519 | |
| Location of Data in Reference | Method details | |
| Immunization | ||
|---|---|---|
| Host Organism | Macaca mulatta (rhesus macaque) | |
| 1st In Vivo Process | ||
|---|---|---|
| In Vivo Process Type | Administration in vivo | |
| 1st In Vivo Process Administration Details | ||
|---|---|---|
| Adjuvants | Other; | VO:0000580 |
| Route | subcutaneous | |
| Dose Schedule | 2 doses of 100 µg FP-KLH at 4-week intervals | |
| 1st Immunogen | ||
|---|---|---|
| Epitope Relation | Epitope | |
| Chemical Type | Linear peptide | |
| Linear Sequence | AVGIGAVF | |
| Source Molecule Name | Envelope glycoprotein gp160 | |
| Source Organism | Human immunodeficiency virus 1 (human immunodeficiency virus 1 HIV-1) | |
| Starting Position | 509 | |
| Ending Position | 516 | |
| Immunogen Details | ||
|---|---|---|
| Immunogen Reference Name | FP-KLH | |
| 2nd In Vivo Process | ||
|---|---|---|
| In Vivo Process Type | Administration in vivo | |
| 2nd In Vivo Process Administration Details | ||
|---|---|---|
| Dose Schedule | 3 doses | |
| 2nd Immunogen | ||
|---|---|---|
| Epitope Relation | Source Antigen | |
| Chemical Type | Protein | |
| Molecule Name | Envelope glycoprotein gp160 | |
| Organism | Human immunodeficiency virus 1 (human immunodeficiency virus 1 HIV-1) | |
| Immunogen Details | ||
|---|---|---|
| Immunogen Evidence Code | Representative selection | |
| Immunization Comments | ||
|---|---|---|
| Immunization Comments | Rhesus macaques were immunized with 2 doses of 100 µg FP8 (AVGIGAVFC)-KLH mixed with Adjuplex, at 4-week intervals. The peptide was synthesized with an extra cysteine residue at the C-terminus for coupling to KLH. Animals were boosted with 3 doses HIV-1 Env BG505 DS-SOSIP trimer at 4-week intervals. B cells were sorted from PBMCs using both FP and Env trimer probes. Antibodies were sequenced and expressed. | |
| B Cell Assay | ||
|---|---|---|
| Qualitative Measurement | Positive | |
| Method/Technique | electron microscopy | |
| Measurement of | 3D structure | |
| Assayed Antibody | ||
|---|---|---|
| Assayed Antibody Source Material | Purified Immunoglobulin | |
| Assayed Antibody Immunoglobulin Domain | Fab | |
| Assayed Antibody Purification Status | Monoclonal | |
| Assayed Antibody Name | DFPH-a.15 | |
| Assayed Antibody Heavy Chain Type | IgG | |
| Assayed Antibody Light Chain Type | Kappa | |
| Assayed Antibody Object | ||
|---|---|---|
| Chemical Type | Multi-Chain protein | |
| Chain 1 Accession Name | Chain H, DFPH-a.15 heavy chain | |
| Source Organism | Macaca mulatta (rhesus macaque) | |
| Molecule Name | DFPH.a15 | |
| Chain 2 Name | Chain L, DFPH-a.15 Light chain | |
| Source Organism | Macaca mulatta (rhesus macaque) | |
| Antigen | ||
|---|---|---|
| Epitope Relation | Source Antigen | |
| Chemical Type | Protein | |
| Molecule Name | Envelope glycoprotein gp160 | |
| Organism | Human immunodeficiency virus 1 (human immunodeficiency virus 1 HIV-1) | |
| 3D Structure of Complex | ||
|---|---|---|
| Complex PDB ID | 6N1W | |
| Antibody Chain 1 PDB Chain | H | |
| Antibody Chain 2 PDB Chain | L | |
| Antigen PDB Chain | D | |
| Calculated Contacts | ||
|---|---|---|
| Epitope Residues | D: A512, V513, G514, I515, G516, A517, V518, F519, L520, V539, R542 | |
| Antibody Residues Interacting with Antigen | H: T29, F31B, D31A, R31, F32, R95, A96, K97, I98, Y99, R100H, Y100, S100A; L: D32, D91, F92, S93, F94 | |
| Contact Area for Antibody | 749 | |
| View 3D Structure | ||
| Assay Reference Details | ||
|---|---|---|
| Assay Comments by IEDB Curator | The epitope of DFPH-a.15 Fab on HIV-1 Env trimer was determined from the cryo-EM reconstruction, to a resolution of 3.8 Å, of a quaternary complex of Fabs DFPH-a.15, PGT122 and VRC03 bound to Env construct BG505-DS-SOSIP. Fabs PGT122 and VRC03 were added to increase the size of the complex and to provide fiducial markers allowing better particle visualization and alignment. | |
| Location of Assay Data in Reference | Figures 2, S4, Table S4 and PDB 6N1W | |
| Receptor(s) |
|---|
1 receptor (Click to view) |