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Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations

Journal Article · · Nature Communications
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  1. Duke Univ. School of Medicine, Durham, NC (United States)
  2. Boston Children's Hospital and Harvard Medical School, Boston, MA (United States)
  3. Jinan Univ., Guangzhou (China); Duke Univ. School of Medicine, Durham, NC (United States)
  4. Boston Univ. School of Medicine, MA (United States)
  5. National Inst. of Health (NIH), Bethesda, MD (United States)
  6. Duke Univ. School of Medicine, Durham, NC (United States); Wake Forest School of Medicine, Winston-Salem, NC (United States)
  7. Duke Univ., Durham, NC (United States)
  8. Duke Univ. School of Medicine, Durham, NC (United States); Duke Univ., Durham, NC (United States)
  9. Infectious Disease Research Inst., Seattle, WA (United States)
  10. GSK Vaccines, Rixensart (Belgium)
+ Show Author Affiliations
A strategy for HIV-1 vaccine development is to define envelope (Env) evolution of broadly neutralizing antibodies (bnAbs) in infection and to recreate those events by vaccination. Here, we report host tolerance mechanisms that limit the development of CD4-binding site (CD4bs), HCDR3-binder bnAbs via sequential HIV-1 Env vaccination. Vaccine-induced macaque CD4bs antibodies neutralize 7% of HIV-1 strains, recognize open Env trimers, and accumulate relatively modest somatic mutations. In naive CD4bs, unmutated common ancestor knock-in mice Env+B cell clones develop anergy and partial deletion at the transitional to mature B cell stage, but become Env¯ upon receptor editing. In comparison with repetitive Env immunizations, sequential Env administration rescue anergic Env+ (non-edited) precursor B cells. Thus, stepwise immunization initiates CD4bs-bnAb responses, but immune tolerance mechanisms restrict their development, suggesting that sequential immunogen-based vaccine regimens will likely need to incorporate strategies to expand bnAb precursor pools.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
NIH; National Inst. of Allergy and Infectious Diseases; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Grant/Contract Number:
W-31109-ENG-38
OSTI ID:
1462570
Journal Information:
Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 8; ISSN 2041-1723
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (91)

A Novel AICDA Splice-Site Mutation in Two Siblings with HIGM2 Permits Somatic Hypermutation but Abrogates Mutational Targeting journal March 2022
Mutational Impact on “in-Between-Ring” (IBR) Domain of PARKIN on Protein Stability and Function journal January 2021
Cooperation of B Cell Lineages in Induction of HIV-1-Broadly Neutralizing Antibodies journal July 2014
Immunization for HIV-1 Broadly Neutralizing Antibodies in Human Ig Knockin Mice journal June 2015
Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody journal April 2016
Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires journal September 2016
Sequential Immunization Elicits Broadly Neutralizing Anti-HIV-1 Antibodies in Ig Knockin Mice journal September 2016
HIV-Host Interactions: Implications for Vaccine Design journal March 2016
Vaccine Induction of Antibodies against a Structurally Heterogeneous Site of Immune Pressure within HIV-1 Envelope Protein Variable Regions 1 and 2 journal January 2013
Cloning and expression of murine Ig genes from single B cells journal October 2009
High-throughput isolation of immunoglobulin genes from single human B cells and expression as monoclonal antibodies journal June 2009
HIV/SIV DNA vaccine combined with protein in a co-immunization protocol elicits highest humoral responses to envelope in mice and macaques journal August 2013
Differential immune responses to HIV-1 envelope protein induced by liposomal adjuvant formulations containing monophosphoryl lipid A with or without QS21 journal October 2015
A group M consensus envelope glycoprotein induces antibodies that neutralize subsets of subtype B and C HIV-1 primary viruses journal September 2006
Structures of HIV-1 gp120 Envelope Glycoproteins from Laboratory-Adapted and Primary Isolates journal February 2001
Very Efficient Template/Primer-Independent DNA Synthesis by Thermophilic DNA Polymerase in the Presence of a Thermophilic Restriction Endonuclease journal October 2004
Structural definition of a conserved neutralization epitope on HIV-1 gp120 journal February 2007
Molecular architecture of native HIV-1 gp120 trimers journal July 2008
Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus journal April 2013
Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies journal March 2014
Pentavalent HIV-1 vaccine protects against simian-human immunodeficiency virus challenge journal June 2017
Absence of surrogate light chain results in spontaneous autoreactive germinal centres expanding VH81X-expressing B cells journal May 2015
Rapid generation of fully human monoclonal antibodies specific to a vaccinating antigen journal February 2009
B-cell anergy: from transgenic models to naturally occurring anergic B cells? journal July 2007
Crystal structure of a non-neutralizing antibody to the HIV-1 gp41 membrane-proximal external region journal November 2010
Multiplex profiling of serum proteins in solution using barcoded antibody fragments and next generation sequencing journal July 2020
Immune-Correlates Analysis of an HIV-1 Vaccine Efficacy Trial journal April 2012
Structural basis of tyrosine sulfation and VH-gene usage in antibodies that recognize the HIV type 1 coreceptor-binding site on gp120 journal February 2004
Envelope glycans of immunodeficiency virions are almost entirely oligomannose antigens journal July 2010
Diverse specificity and effector function among human antibodies to HIV-1 envelope glycoprotein epitopes exposed by CD4 binding journal December 2012
Receptor editing: an approach by autoreactive B cells to escape tolerance journal April 1993
SoDA: implementation of a 3D alignment algorithm for inference of antigen receptor recombinations journal December 2005
Features and development of Coot journal March 2010
HIV-1 neutralizing antibodies: understanding nature's pathways journal June 2013
Structural Basis of Immune Evasion at the Site of CD4 Attachment on HIV-1 gp120 journal November 2009
Host Controls of HIV Neutralizing Antibodies journal May 2014
Antigen modification regulates competition of broad and narrow neutralizing HIV antibodies journal December 2014
Diversion of HIV-1 vaccine-induced immunity by gp41-microbiota cross-reactive antibodies journal July 2015
Priming a broadly neutralizing antibody response to HIV-1 using a germline-targeting immunogen journal June 2015
Initiation of immune tolerance–controlled HIV gp41 neutralizing B cell lineages journal April 2016
The Development of CD4 Binding Site Antibodies during HIV-1 Infection journal May 2012
Structural Definition of an Antibody-Dependent Cellular Cytotoxicity Response Implicated in Reduced Risk for HIV-1 Infection journal August 2014
Polyreactivity and Autoreactivity among HIV-1 Antibodies journal October 2014
Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus journal November 2005
Crystal Structures of HIV-1 gp120 Envelope Glycoprotein in Complex with NBD Analogues That Target the CD4-Binding Site journal January 2014
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
PHENIX: a comprehensive Python-based system for macromolecular structure solution. text January 2010
Iterative model building, structure refinement and density modification with the PHENIX AutoBuild wizard. journalarticle January 2008
Rescue of HIV-1 Broad Neutralizing Antibody-Expressing B Cells in 2F5 V H × V L Knockin Mice Reveals Multiple Tolerance Controls journal September 2011
Common Tolerance Mechanisms, but Distinct Cross-Reactivities Associated with gp41 and Lipids, Limit Production of HIV-1 Broad Neutralizing Antibodies 2F5 and 4E10 journal July 2013
B Cells from Knock-in Mice Expressing Broadly Neutralizing HIV Antibody b12 Carry an Innocuous B Cell Receptor Responsive to HIV Vaccine Candidates journal August 2013
Immune Tolerance Negatively Regulates B Cells in Knock-In Mice Expressing Broadly Neutralizing HIV Antibody 4E10 journal August 2013
Impaired Intracellular Calcium Mobilization and NFATc1 Availability in Tolerant Anti-Insulin B Cells journal August 2006
Computed Origami Tomography preprint January 2020
UCSF Chimera?A visualization system for exploratory research and analysis journal January 2004
Structure validation by Cα geometry: ϕ,ψ and Cβ deviation journal January 2003
Crystal structure of a fully glycosylated HIV-1 gp120 core reveals a stabilizing role for the glycan at Asn262: Stabilizing Role for the Glycan at Asn262 journal January 2015
Universal PCR amplification of mouse immunoglobulin gene variable regions: the design of degenerate primers and an assessment of the effect of DNA polymerase 3′ to 5′ exonuclease activity journal January 2000
[20] Processing of X-ray diffraction data collected in oscillation mode book January 1997
Structures of HIV-1 gp120 Envelope Glycoproteins from Laboratory-Adapted and Primary Isolates journal December 2000
Trimeric HIV-1-Env Structures Define Glycan Shields from Clades A, B, and G journal May 2016
Tailored Immunogens Direct Affinity Maturation toward HIV Neutralizing Antibodies journal September 2016
Direct Probing of Germinal Center Responses Reveals Immunological Features and Bottlenecks for Neutralizing Antibody Responses to HIV Env Trimer journal November 2016
Quantification of the Impact of the HIV-1-Glycan Shield on Antibody Elicitation journal April 2017
EMAN2: An extensible image processing suite for electron microscopy journal January 2007
Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody journal June 1998
Breakdown of self-tolerance in anergic B lymphocytes journal August 1991
Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice journal February 2016
Immune-Correlates Analysis of an HIV-1 Vaccine Efficacy Trial journal April 2012
Autoreactivity in an HIV-1 broadly reactive neutralizing antibody variable region heavy chain induces immunologic tolerance journal December 2009
Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity journal May 2014
Affinity maturation in an HIV broadly neutralizing B-cell lineage through reorientation of variable domains journal June 2014
Identification of autoantigens recognized by the 2F5 and 4E10 broadly neutralizing HIV-1 antibodies journal January 2013
Magnitude and Breadth of the Neutralizing Antibody Response in the RV144 and Vax003 HIV-1 Vaccine Efficacy Trials journal May 2012
Base-Calling of Automated Sequencer Traces Using Phred.  I. Accuracy Assessment journal March 1998
Iterative model building, structure refinement and density modification with the PHENIX AutoBuild wizard journal December 2007
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Features and development of Coot journal March 2010
Structures of the CCR5 N Terminus and of a Tyrosine-Sulfated Antibody with HIV-1 gp120 and CD4 journal September 2007
HIV-1 neutralizing antibodies induced by native-like envelope trimers journal June 2015
HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen journal March 2016
Antigenicity and Immunogenicity of RV144 Vaccine AIDSVAX Clade E Envelope Immunogen Is Enhanced by a gp120 N-Terminal Deletion journal November 2012
The Development of CD4 Binding Site Antibodies during HIV-1 Infection journal May 2012
Tiered Categorization of a Diverse Panel of HIV-1 Env Pseudoviruses for Assessment of Neutralizing Antibodies journal November 2009
Structural Definition of an Antibody-Dependent Cellular Cytotoxicity Response Implicated in Reduced Risk for HIV-1 Infection journal August 2014
Polyreactivity and Autoreactivity among HIV-1 Antibodies journal October 2014
Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus journal November 2005
Spontaneous formation of germinal centers in autoimmune mice journal October 2001
Reconstructing a B-Cell Clonal Lineage. II. Mutation, Selection, and Affinity Maturation journal April 2014
Direct probing of germinal center responses reveals immunological features and bottlenecks for neutralizing antibody responses to HIV env trimer journal November 2016
Induction of HIV-1 Broad Neutralizing Antibodies in 2F5 Knock-in Mice: Selection against Membrane Proximal External Region–Associated Autoreactivity Limits T-Dependent Responses journal August 2013

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Electroactive Amphiphiles for Addressable Supramolecular Nanostructures journal July 2018
The Chimpanzee SIV Envelope Trimer: Structure and Deployment as an HIV Vaccine Template journal May 2019
Development of broadly neutralizing antibodies in HIV-1 infected elite neutralizers journal September 2018
Adeno-associated virus gene delivery of broadly neutralizing antibodies as prevention and therapy against HIV-1 journal October 2018
HIV-1 immunogens and strategies to drive antibody responses towards neutralization breadth journal November 2018
Robotic selection for the rapid development of stable CHO cell lines for HIV vaccine production journal August 2018
Viral Vectors for the Induction of Broadly Neutralizing Antibodies against HIV journal September 2019
Strategies for inducing effective neutralizing antibody responses against HIV-1 journal November 2019
Anti-idiotypic antibodies elicit anti-HIV-1–specific B cell responses journal July 2019
Robotic selection for the rapid development of stable CHO cell lines for HIV vaccine for production posted_content May 2018
SHIV.CH505-infected infant and adult rhesus macaques exhibit similar HIV Env-specific antibody kinetics, despite distinct T-follicular helper (Tfh) and germinal center B cell landscapes posted_content February 2019
Human adaptive immune receptor repertoire analysis-Past, present, and future journal June 2018
Targeted selection of HIV-specific antibody mutations by engineering B cell maturation journal December 2019
Simian-Human Immunodeficiency Virus SHIV.CH505-Infected Infant and Adult Rhesus Macaques Exhibit Similar Env-Specific Antibody Kinetics, despite Distinct T-Follicular Helper and Germinal Center B Cell Landscapes journal May 2019

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
B-cell receptor
HIV infections
peripheral tolerance
protein vaccines