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

Title: Initiation of immune tolerance–controlled HIV gp41 neutralizing B cell lineages

Journal Article · · Science Translational Medicine

Development of an HIV vaccine is a global priority. A major roadblock to a vaccine is an inability to induce protective broadly neutralizing antibodies (bnAbs). HIV gp41 bnAbs have characteristics that predispose them to be controlled by tolerance. We used gp41 2F5 bnAb germline knock-in mice and macaques vaccinated with immunogens reactive with germline precursors to activate neutralizing antibodies. In germline knock-in mice, bnAb precursors were deleted, with remaining anergic B cells capable of being activated by germline-binding immunogens to make gp41-reactive immunoglobulin M (IgM). Immunized macaques made B cell clonal lineages targeted to the 2F5 bnAb epitope, but 2F5-like antibodies were either deleted or did not attain sufficient affinity for gp41-lipid complexes to achieve the neutralization potency of 2F5. Structural analysis of members of a vaccine-induced antibody lineage revealed that heavy chain complementarity-determining region 3 (HCDR3) hydrophobicity was important for neutralization. Furthermore, gp41 bnAbs are controlled by immune tolerance, requiring vaccination strategies to transiently circumvent tolerance controls.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery; National Institutes of Health (NIH); National Inst. of Allergy and Infectious Diseases
Grant/Contract Number:
W-31-109-Eng-38; CHAVI-ID; UMI-AI100645
OSTI ID:
1257467
Journal Information:
Science Translational Medicine, Vol. 8, Issue 336; ISSN 1946-6234
Publisher:
AAASCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 52 works
Citation information provided by
Web of Science

References (70)

Structural Analysis of Human and Macaque mAbs 2909 and 2.5B: Implications for the Configuration of the Quaternary Neutralizing Epitope of HIV-1 gp120 journal May 2011
Structure and Mechanistic Analysis of the Anti-Human Immunodeficiency Virus Type 1 Antibody 2F5 in Complex with Its gp41 Epitope journal September 2004
Immunization for HIV-1 Broadly Neutralizing Antibodies in Human Ig Knockin Mice journal June 2015
Utilization of Immunoglobulin G Fc Receptors by Human Immunodeficiency Virus Type 1: a Specific Role for Antibodies against the Membrane-Proximal External Region of gp41 journal May 2009
Distinct conformational states of HIV-1 gp41 are recognized by neutralizing and non-neutralizing antibodies journal November 2010
T Follicular Helper Cell Differentiation, Function, and Roles in Disease journal October 2014
Deficiency in CD22, a B Cell–specific Inhibitory Receptor, Is Sufficient to Predispose to Development of High Affinity Autoantibodies journal April 1999
Stapled HIV-1 peptides recapitulate antigenic structures and engage broadly neutralizing antibodies journal November 2014
Functional, Non-Clonal IgMa-Restricted B Cell Receptor Interactions with the HIV-1 Envelope gp41 Membrane Proximal External Region journal October 2009
Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding journal November 2007
HIV-1 Broadly Neutralizing Antibody Extracts Its Epitope from a Kinked gp41 Ectodomain Region on the Viral Membrane journal January 2008
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
High-throughput isolation of immunoglobulin genes from single human B cells and expression as monoclonal antibodies journal June 2009
Redemption of autoreactive B cells journal June 2014
Structure-guided Alterations of the gp41-directed HIV-1 Broadly Neutralizing Antibody 2F5 Reveal New Properties Regarding its Neutralizing Function journal July 2012
Isolation of a Human Anti-HIV gp41 Membrane Proximal Region Neutralizing Antibody by Antigen-Specific Single B Cell Sorting journal September 2011
Antibody responses to envelope glycoproteins in HIV-1 infection journal May 2015
Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity journal May 2014
The Role of Antibody Polyspecificity and Lipid Reactivity in Binding of Broadly Neutralizing Anti-HIV-1 Envelope Human Monoclonal Antibodies 2F5 and 4E10 to Glycoprotein 41 Membrane Proximal Envelope Epitopes journal March 2007
Cardiolipin Polyspecific Autoreactivity in Two Broadly Neutralizing HIV-1 Antibodies journal June 2005
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Initial B-Cell Responses to Transmitted Human Immunodeficiency Virus Type 1: Virion-Binding Immunoglobulin M (IgM) and IgG Antibodies Followed by Plasma Anti-gp41 Antibodies with Ineffective Control of Initial Viremia journal October 2008
Kinetic and affinity limits on antibodies produced during immune responses. journal February 1995
NMRPipe: A multidimensional spectral processing system based on UNIX pipes journal November 1995
Early high-affinity neutralizing anti-viral IgG responses without further overall improvements of affinity. journal February 1995
Reconstructing a B-cell clonal lineage. I. Statistical inference of unobserved ancestors journal January 2013
Human Circulating PD-1+CXCR3−CXCR5+ Memory Tfh Cells Are Highly Functional and Correlate with Broadly Neutralizing HIV Antibody Responses journal October 2013
Immunoglobulin heavy chain expression shapes the B cell receptor repertoire in human B cell development journal September 2001
Differential Reactivity of Germ Line Allelic Variants of a Broadly Neutralizing HIV-1 Antibody to a gp41 Fusion Intermediate Conformation journal September 2011
Polyreactivity and Autoreactivity among HIV-1 Antibodies journal October 2014
Structural Basis for HIV-1 Neutralization by 2F5-Like Antibodies m66 and m66.6 journal December 2013
Exposure of the Membrane-Proximal External Region of HIV-1 gp41 in the Course of HIV-1 Envelope Glycoprotein-Mediated Fusion journal February 2007
Prolonged exposure of the HIV-1 gp41 membrane proximal region with L669S substitution journal March 2010
Induction of self-tolerance in mature peripheral B lymphocytes journal November 1989
Iterative model building, structure refinement and density modification with the PHENIX AutoBuild wizard journal December 2007
Induction of Antibodies in Rhesus Macaques That Recognize a Fusion-Intermediate Conformation of HIV-1 gp41 journal November 2011
HIV-1 neutralizing antibodies: understanding nature's pathways journal June 2013
Mosaic vaccines elicit CD8+ T lymphocyte responses that confer enhanced immune coverage of diverse HIV strains in monkeys journal February 2010
Mechanism of HIV-1 Neutralization by Antibodies Targeting a Membrane-Proximal Region of gp41 journal November 2013
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
Nonneutralizing HIV-1 gp41 Envelope Cluster II Human Monoclonal Antibodies Show Polyreactivity for Binding to Phospholipids and Protein Autoantigens journal November 2010
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
Kinetics of protein-protein association explained by Brownian dynamics computer simulation. journal April 1992
Antibody Light-Chain-Restricted Recognition of the Site of Immune Pressure in the RV144 HIV-1 Vaccine Trial Is Phylogenetically Conserved journal December 2014
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
Modulation of Nonneutralizing HIV-1 gp41 Responses by an MHC-Restricted T H Epitope Overlapping Those of Membrane Proximal External Region Broadly Neutralizing Antibodies journal January 2014
Envelope Deglycosylation Enhances Antigenicity of HIV-1 gp41 Epitopes for Both Broad Neutralizing Antibodies and Their Unmutated Ancestor Antibodies journal September 2011
Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus journal April 2013
Human Immunodeficiency Virus Type 1 env Clones from Acute and Early Subtype B Infections for Standardized Assessments of Vaccine-Elicited Neutralizing Antibodies journal July 2005
HIV-1 gp41 envelope IgA is frequently elicited after transmission but has an initial short response half-life journal January 2013
HIV-1 neutralizing antibodies induced by native-like envelope trimers journal June 2015
Sequestering of the Prehairpin Intermediate of gp41 by Peptide N36Mut(e,g) Potentiates the Human Immunodeficiency Virus Type 1 Neutralizing Activity of Monoclonal Antibodies Directed against the N-Terminal Helical Repeat of gp41 journal July 2008
Features and development of Coot journal March 2010
Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies journal March 2013
Identification of autoantigens recognized by the 2F5 and 4E10 broadly neutralizing HIV-1 antibodies journal January 2013
Protein Design of an HIV-1 Entry Inhibitor journal January 2001
Role of HIV membrane in neutralization by two broadly neutralizing antibodies journal November 2009
Structure validation by Cα geometry: ϕ,ψ and Cβ deviation journal January 2003
Solvent content of protein crystals journal April 1968
Stable Docking of Neutralizing Human Immunodeficiency Virus Type 1 gp41 Membrane-Proximal External Region Monoclonal Antibodies 2F5 and 4E10 Is Dependent on the Membrane Immersion Depth of Their Epitope Regions journal July 2009
Reconstructing a B-Cell Clonal Lineage. II. Mutation, Selection, and Affinity Maturation journal April 2014
Diversion of HIV-1 vaccine-induced immunity by gp41-microbiota cross-reactive antibodies journal July 2015
MPEx: A tool for exploring membrane proteins journal December 2009
Antibody mechanics on a membrane-bound HIV segment essential for GP41-targeted viral neutralization journal October 2011
CD4 Ligation on Human Blood Monocytes Triggers Macrophage Differentiation and Enhances HIV Infection journal June 2014
Autoreactivity in an HIV-1 broadly reactive neutralizing antibody variable region heavy chain induces immunologic tolerance journal December 2009
Experimentally determined hydrophobicity scale for proteins at membrane interfaces journal October 1996
HIV-1 gp120 Vaccine Induces Affinity Maturation in both New and Persistent Antibody Clonal Lineages journal May 2012
Priming a broadly neutralizing antibody response to HIV-1 using a germline-targeting immunogen journal June 2015
[20] Processing of X-ray diffraction data collected in oscillation mode book January 1997

Cited By (27)

Targeted selection of HIV-specific antibody mutations by engineering B cell maturation journal December 2019
Detection and activation of HIV broadly neutralizing antibody precursor B cells using anti-idiotypes journal July 2019
Strategies for inducing effective neutralizing antibody responses against HIV-1 journal November 2019
Clonal redemption and clonal anergy as mechanisms to balance B cell tolerance and immunity journal September 2019
Minding the gap: The impact of B‐cell tolerance on the microbial antibody repertoire journal September 2019
Distinct, IgG1-driven antibody response landscapes demarcate individuals with broadly HIV-1 neutralizing activity journal May 2018
Germline-targeting immunogens journal January 2017
Breaching peripheral tolerance promotes the production of HIV-1–neutralizing antibodies journal July 2017
Cross-Reactivity to Kynureninase Tolerizes B Cells That Express the HIV-1 Broadly Neutralizing Antibody 2F5 journal November 2019
Widespread B cell perturbations in HIV-1 infection afflict naive and marginal zone B cells journal June 2019
Optimal Development of Mature B Cells Requires Recognition of Endogenous Antigens journal June 2019
Progress toward active or passive HIV-1 vaccination journal December 2016
The expanding array of HIV broadly neutralizing antibodies journal October 2018
Human Immunodeficiency Virus Proteins Mimic Human T Cell Receptors Inducing Cross-Reactive Antibodies journal October 2017
Potent and broad HIV-neutralizing antibodies in memory B cells and plasma journal January 2017
Distinct, IgG1-driven antibody response landscapes demarcate individuals with broadly HIV-1 neutralizing activity text January 2018
Structure of the membrane proximal external region of HIV-1 envelope glycoprotein journal September 2018
Widespread B cell perturbations in HIV-1 infection afflict naive and marginal zone B cells text January 2019
Distinct, IgG1-driven antibody response landscapes demarcate individuals with broadly HIV-1 neutralizing activity. text January 2018
HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies journal November 2018
Guiding the humoral response against HIV-1 toward a MPER adjacent region by immunization with a VLP-formulated antibody-selected envelope variant journal December 2018
Antibody-virus co-evolution in HIV infection: paths for HIV vaccine development journal January 2017
Host controls of HIV broadly neutralizing antibody development journal January 2017
Clonal anergy of CD117+chB6+ B cell progenitors induced by avian leukosis virus subgroup J is associated with immunological tolerance journal January 2019
Human Ig knockin mice to study the development and regulation of HIV-1 broadly neutralizing antibodies journal January 2017
Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations journal November 2017
Immunologic Insights on the Membrane Proximal External Region: A Major Human Immunodeficiency Virus Type-1 Vaccine Target journal September 2017

Similar Records

Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations
Journal Article · Thu Nov 23 00:00:00 EST 2017 · Nature Communications · OSTI ID:1257467

Potent and broad HIV-neutralizing antibodies in memory B cells and plasma
Journal Article · Fri Jan 27 00:00:00 EST 2017 · Science Immunology · OSTI ID:1257467

HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies
Journal Article · Thu Sep 01 00:00:00 EDT 2016 · Immunity · OSTI ID:1257467

Related Subjects