skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Antibody Lineages with Vaccine-Induced Antigen-Binding Hotspots Develop Broad HIV Neutralization

Journal Article · · Cell
 [1];  [1];  [2];  [1];  [3];  [1];  [1];  [4];  [5];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1] more »;  [1];  [1];  [1];  [6];  [1];  [7];  [8];  [1];  [1];  [2];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [9];  [1];  [1];  [7];  [1];  [1];  [1];  [1];  [6];  [1];  [10];  [11];  [7];  [7];  [12];  [12];  [1] « less
  1. National Institutes of Health (NIH), Bethesda, MD (United States)
  2. Columbia Univ., New York, NY (United States)
  3. National Institutes of Health (NIH), Bethesda, MD (United States); New York Structural Biology Center, New York, NY (United States); Duke Univ. School of Medicine, Durham, NC (United States)
  4. Fred Hutchinson Cancer Research Center, Seattle, WA (United States); Univ. of Washington, Seattle, WA (United States)
  5. National Institutes of Health (NIH), Bethesda, MD (United States); New York Structural Biology Center, New York, NY (United States)
  6. Karolinska Inst., Stockholm (Sweden)
  7. New York Structural Biology Center, New York, NY (United States)
  8. New York Structural Biology Center, New York, NY (United States)
  9. Johns Hopkins Univ., Baltimore, MD (United States)
  10. Univ. of Washington, Seattle, WA (United States)
  11. Fred Hutchinson Cancer Research Center, Seattle, WA (United States); Howard Hughes Medical Inst., Seattle, WA (United States)
  12. National Institutes of Health (NIH), Bethesda, MD (United States); Columbia Univ., New York, NY (United States)

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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); Bill and Melinda Gates Foundation; National Science Foundation (NSF); Swedish Research Council (SRC); International AIDS Vaccine Initiative; Simons Foundation; NYSTAR; Agouron Inst.
Contributing Organization:
NISC Comparative Sequencing Program
Grant/Contract Number:
W-31-109-Eng-38; OPP1162123; R21-1R21AI138024-01A1; R01AI140891; DA039543; R01AI120961; DGE-1256082; SF349247; GM103310; F00316; OD019994
OSTI ID:
1557322
Journal Information:
Cell, Vol. 178, Issue 3; ISSN 0092-8674
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 63 works
Citation information provided by
Web of Science

References (94)

Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env journal June 2015
MOLPROBITY: structure validation and all-atom contact analysis for nucleic acids and their complexes journal July 2004
Immunization for HIV-1 Broadly Neutralizing Antibodies in Human Ig Knockin Mice journal June 2015
Comprehensive Mapping of HIV-1 Escape from a Broadly Neutralizing Antibody journal June 2017
Gene-Specific Substitution Profiles Describe the Types and Frequencies of Amino Acid Changes during Antibody Somatic Hypermutation journal May 2017
Recent progress in broadly neutralizing antibodies to HIV journal October 2018
Principles of Broad and Potent Antiviral Human Antibodies: Insights for Vaccine Design journal August 2017
Mutations in HIV-1 Envelope That Enhance Entry with the Macaque CD4 Receptor Alter Antibody Recognition by Disrupting Quaternary Interactions within the Trimer journal January 2015
An Antigenic Atlas of HIV-1 Escape from Broadly Neutralizing Antibodies Distinguishes Functional and Structural Epitopes journal February 2019
Structural Delineation of a Quaternary, Cleavage-Dependent Epitope at the gp41-gp120 Interface on Intact HIV-1 Env Trimers journal May 2014
Elicitation of structure-specific antibodies by epitope scaffolds journal September 2010
Tailored Immunogens Direct Affinity Maturation toward HIV Neutralizing Antibodies journal September 2016
Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody journal June 1998
Broadly Neutralizing HIV Antibodies Define a Glycan-Dependent Epitope on the Prefusion Conformation of gp41 on Cleaved Envelope Trimers journal May 2014
Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1 journal June 2018
A Next-Generation Cleaved, Soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but Not Non-Neutralizing Antibodies journal September 2013
Mapping mutational effects along the evolutionary landscape of HIV envelope journal March 2018
Structural Survey of Broadly Neutralizing Antibodies Targeting the HIV-1 Env Trimer Delineates Epitope Categories and Characteristics of Recognition journal January 2019
Optimizing “self-wicking” nanowire grids journal May 2018
Spotiton: New features and applications journal May 2018
Frequent microsatellite instability and BAX mutations in T cell acute lymphoblastic leukemia cell lines journal March 2000
Inference of Macromolecular Assemblies from Crystalline State journal September 2007
Human monoclonal antibody 2G12 defines a distinctive neutralization epitope on the gp120 glycoprotein of human immunodeficiency virus type 1. journal January 1996
UCSF Chimera?A visualization system for exploratory research and analysis journal January 2004
Vaccine Induction of Heterologous Tier 2 HIV-1 Neutralizing Antibodies in Animal Models journal December 2017
An HIV-1 antibody from an elite neutralizer implicates the fusion peptide as a site of vulnerability journal November 2016
Transplanting Supersites of HIV-1 Vulnerability journal July 2014
Gctf: Real-time CTF determination and correction journal January 2016
Optimization and validation of the TZM-bl assay for standardized assessments of neutralizing antibodies against HIV-1 journal July 2014
Error filtering, pair assembly and error correction for next-generation sequencing reads journal July 2015
Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires journal September 2016
Consistent elicitation of cross-clade HIV-neutralizing responses achieved in guinea pigs after fusion peptide priming by repetitive envelope trimer boosting journal April 2019
Experimental Estimation of the Effects of All Amino-Acid Mutations to HIV’s Envelope Protein on Viral Replication in Cell Culture journal December 2016
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Sequential Immunization Elicits Broadly Neutralizing Anti-HIV-1 Antibodies in Ig Knockin Mice journal September 2016
Targeted Isolation of Antibodies Directed against Major Sites of SIV Env Vulnerability journal April 2016
B-cell–lineage immunogen design in vaccine development with HIV-1 as a case study journal May 2012
Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors journal June 2015
Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies journal March 2014
Isolation of antibody V(D)J sequences from single cell sorted rhesus macaque B cells journal December 2012
Complete functional mapping of infection- and vaccine-elicited antibodies against the fusion peptide of HIV journal July 2018
High throughput HIV-1 microneutralization assay journal September 2013
cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination journal February 2017
A new method for vitrifying samples for cryoEM journal August 2016
[20] Processing of X-ray diffraction data collected in oscillation mode book January 1997
IgBLAST: an immunoglobulin variable domain sequence analysis tool journal May 2013
Neutralization of diverse human immunodeficiency virus type 1 variants by an anti-V3 human monoclonal antibody. journal January 1992
Vaccine-Induced Antibodies that Neutralize Group 1 and Group 2 Influenza A Viruses journal July 2016
Structure and immune recognition of trimeric pre-fusion HIV-1 Env journal October 2014
Immunization-Elicited Broadly Protective Antibody Reveals Ebolavirus Fusion Loop as a Site of Vulnerability journal May 2017
Antibodies from a Human Survivor Define Sites of Vulnerability for Broad Protection against Ebolaviruses journal May 2017
Broad neutralization coverage of HIV by multiple highly potent antibodies journal September 2011
DoG Picker and TiltPicker: Software tools to facilitate particle selection in single particle electron microscopy journal May 2009
Computation-Guided Backbone Grafting of a Discontinuous Motif onto a Protein Scaffold journal October 2011
HIV-1 neutralizing antibodies: understanding nature's pathways journal June 2013
Vaccine-Induced Protection from Homologous Tier 2 SHIV Challenge in Nonhuman Primates Depends on Serum-Neutralizing Antibody Titers journal January 2019
Delineating Antibody Recognition in Polyclonal Sera from Patterns of HIV-1 Isolate Neutralization journal May 2013
PIGS: automatic prediction of antibody structures journal July 2008
Use of broadly neutralizing antibodies for HIV-1 prevention journal January 2017
Production of individualized V gene databases reveals high levels of immunoglobulin genetic diversity journal December 2016
A hot spot of binding energy in a hormone-receptor interface journal January 1995
Appion: An integrated, database-driven pipeline to facilitate EM image processing journal April 2009
Automated molecular microscopy: The new Leginon system journal July 2005
Surface-Matrix Screening Identifies Semi-specific Interactions that Improve Potency of a Near Pan-reactive HIV-1-Neutralizing Antibody journal February 2018
CTFFIND4: Fast and accurate defocus estimation from electron micrographs journal November 2015
Rational HIV Immunogen Design to Target Specific Germline B Cell Receptors journal March 2013
SONAR: A High-Throughput Pipeline for Inferring Antibody Ontogenies from Longitudinal Sequencing of B Cell Transcripts journal September 2016
Proof of principle for epitope-focused vaccine design journal February 2014
Recent developments in the PHENIX software for automated crystallographic structure determination journal November 2003
Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1 journal July 2010
MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy journal February 2017
Maturation and Diversity of the VRC01-Antibody Lineage over 15 Years of Chronic HIV-1 Infection journal April 2015
Epitopes Involved in Antibody-Mediated Protection from Ebola Virus journal March 2000
WebLogo: A Sequence Logo Generator journal May 2004
Single-Chain Soluble BG505.SOSIP gp140 Trimers as Structural and Antigenic Mimics of Mature Closed HIV-1 Env journal March 2015
HIV-1 neutralizing antibodies induced by native-like envelope trimers journal June 2015
The HIV-1 envelope glycoprotein structure: nailing down a moving target journal January 2017
HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen journal March 2016
ggseqlogo: a versatile R package for drawing sequence logos journal July 2017
Structure and Diversity of the Rhesus Macaque Immunoglobulin Loci through Multiple De Novo Genome Assemblies journal October 2017
Soluble Prefusion Closed DS-SOSIP.664-Env Trimers of Diverse HIV-1 Strains journal December 2017
RELION: Implementation of a Bayesian approach to cryo-EM structure determination journal December 2012
Dendroscope 3: An Interactive Tool for Rooted Phylogenetic Trees and Networks journal September 2012
EMRinger: side chain–directed model and map validation for 3D cryo-electron microscopy journal August 2015
HIV-1 Vaccines Based on Antibody Identification, B Cell Ontogeny, and Epitope Structure journal May 2018
Broadly Neutralizing Antiviral Antibodies journal March 2013
Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody journal May 2016
Fast, scalable generation of high‐quality protein multiple sequence alignments using Clustal Omega journal January 2011
Match criteria for human cell line authentication: Where do we draw the line? journal November 2012
Complete mapping of viral escape from neutralizing antibodies journal March 2017
Influenza vaccine: The challenge of antigenic drift journal September 2007
MEGA6: Molecular Evolutionary Genetics Analysis Version 6.0 journal October 2013
Mimicry of an HIV broadly neutralizing antibody epitope with a synthetic glycopeptide journal March 2017
Software for the analysis and visualization of deep mutational scanning data journal May 2015

Cited By (6)