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

Title: Diverse specificity and effector function among human antibodies to HIV-1 envelope glycoprotein epitopes exposed by CD4 binding

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [3];  [4];  [1];  [1];  [1]
  1. Univ. of Maryland School of Medicine, Baltimore, MD (United States)
  2. Tulane Univ., New Orleans, LA (United States)
  3. Harvard Medical School, Boston, MA (United States)
  4. Profectus Biosciences, Inc., Baltimore, MD (United States)
+ Show Author Affiliations

The HIV-1 envelope glycoprotein (Env) undergoes conformational transitions consequent to CD4 binding and coreceptor engagement during viral entry. The physical steps in this process are becoming defined, but less is known about their significance as targets of antibodies potentially protective against HIV-1 infection. Here we probe the functional significance of transitional epitope exposure by characterizing 41 human mAbs specific for epitopes exposed on trimeric Env after CD4 engagement. These mAbs recognize three epitope clusters: cluster A, the gp120 face occluded by gp41 in trimeric Env; cluster B, a region proximal to the coreceptor-binding site (CoRBS) and involving the V1/V2 domain; and cluster C, the coreceptor-binding site. The mAbs were evaluated functionally by antibody-dependent, cell-mediated cytotoxicity (ADCC) and for neutralization of Tiers 1 and 2 pseudoviruses. All three clusters included mAbs mediating ADCC. However, there was a strong potency bias for cluster A, which harbors at least three potent ADCC epitopes whose cognate mAbs have electropositive paratopes. Cluster A epitopes are functional ADCC targets during viral entry in an assay format using virion-sensitized target cells. In contrast, only cluster C contained epitopes that were recognized by neutralizing mAbs. There was significant diversity in breadth and potency that correlated with epitope fine specificity. In contrast, ADCC potency had no relationship with neutralization potency or breadth for any epitope cluster. In conclusion, Fc-mediated effector function and neutralization coselect with specificity in anti-Env antibody responses, but the nature of selection is distinct for these two antiviral activities.

Research Organization:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC)
Grant/Contract Number:
AC02-76SF00515
OSTI ID:
1136677
Report Number(s):
SLAC-REPRINT-2014-212
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, Issue 1; ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)Copyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 127 works
Citation information provided by
Web of Science

References (91)

Epidemiologic Characteristics and Natural History of HIV-1 Natural Viral Suppressors journal January 2009
Activation of NK Cells by ADCC Antibodies and HIV Disease Progression journal January 2011
Solving structures of protein complexes by molecular replacement with Phaser journal December 2006
Refinement of Macromolecular Structures by the Maximum-Likelihood Method journal May 1997
Antibody Protects Macaques against Vaginal Challenge with a Pathogenic R5 Simian/Human Immunodeficiency Virus at Serum Levels Giving Complete Neutralization In Vitro journal September 2001
Recombinant gp120 Vaccine-Induced Antibodies Inhibit Clinical Strains of HIV-1 in the Presence of Fc Receptor-Bearing Effector Cells and Correlate Inversely with HIV Infection Rate journal May 2007
Broad neutralization by a combination of antibodies recognizing the CD4 binding site and a new conformational epitope on the HIV-1 envelope protein journal July 2012
Effective, low-titer antibody protection against low-dose repeated mucosal SHIV challenge in macaques journal June 2009
CD4-Induced Epitopes in the HIV Envelope Glycoprotein, Gp120 journal November 2007
Immune-Correlates Analysis of an HIV-1 Vaccine Efficacy Trial journal April 2012
Structures of the CCR5 N Terminus and of a Tyrosine-Sulfated Antibody with HIV-1 gp120 and CD4 journal September 2007
Antibody-Dependent Cell-Mediated Cytotoxicity in Simian Immunodeficiency Virus-Infected Rhesus Monkeys journal May 2011
Structure of a V3-Containing HIV-1 gp120 Core journal November 2005
Discordant memory B cell and circulating anti-Env antibody responses in HIV-1 infection journal February 2009
Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody journal June 1998
Genetic Signatures in the Envelope Glycoproteins of HIV-1 that Associate with Broadly Neutralizing Antibodies journal October 2010
Correlation Between Circulating HIV-1 RNA and Broad HIV-1 Neutralizing Antibody Activity journal January 2011
MrBUMP : an automated pipeline for molecular replacement journal December 2007
Immune escape from HIV-specific antibody-dependent cellular cytotoxicity (ADCC) pressure journal April 2011
Activation of NK Cells by ADCC Responses During Early HIV Infection journal April 2011
Antibody-dependent cell-mediated cytotoxicity directed by a human monoclonal antibody reactive with gp120 of HIV-1 journal January 1991
Improved Breadth and Potency of an HIV-1-Neutralizing Human Single-chain Antibody by Random Mutagenesis and Sequential Antigen Panning journal January 2004
Access of Antibody Molecules to the Conserved Coreceptor Binding Site on Glycoprotein gp120 Is Sterically Restricted on Primary Human Immunodeficiency Virus Type 1 journal September 2003
FcγRIIa Genotype Predicts Progression of HIV Infection journal November 2007
Antibodies to CD4-induced sites in HIV gp120 correlate with the control of SHIV challenge in macaques vaccinated with subunit immunogens journal October 2007
Canonical structures for the hypervariable regions of immunoglobulins journal August 1987
Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility journal December 2009
Human monoclonal antibody that recognizes the V3 region of human immunodeficiency virus gp120 and neutralizes the human T-lymphotropic virus type IIIMN strain. journal November 1990
The CCP4 suite programs for protein crystallography journal September 1994
Identification and Characterization of an Immunogenic Hybrid Epitope Formed by both HIV gp120 and Human CD4 Proteins journal October 2011
Rational antibody-based HIV-1 vaccine design: current approaches and future directions journal June 2010
In vitro reduction of virus infectivity by antibody-dependent cell-mediated immunity journal November 1998
Contribution of Nonneutralizing Vaccine-Elicited Antibody Activities to Improved Protective Efficacy in Rhesus Macaques Immunized with Tat/Env Compared with Multigenic Vaccines journal March 2009
Sustained Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) in SIV-Infected Macaques Correlates with Delayed Progression to AIDS journal November 2002
Effective, low-titer antibody protection against low-dose repeated mucosal SHIV challenge in macaques text January 2009
Expression and Characterization of a Single-Chain Polypeptide Analogue of the Human Immunodeficiency Virus Type 1 gp120-CD4 Receptor Complex journal December 2000
MolProbity : all-atom structure validation for macromolecular crystallography journal December 2009
Coot model-building tools for molecular graphics journal November 2004
Antigenic Properties of the Human Immunodeficiency Virus Transmembrane Glycoprotein during Cell-Cell Fusion journal December 2002
Vaccine-Elicited Antibodies Mediate Antibody-Dependent Cellular Cytotoxicity Correlated with Significantly Reduced Acute Viremia in Rhesus Macaques Challenged with SIV mac251 journal February 2005
Structural evidence for substrate strain in antibody catalysis journal January 2003
Protection of Macaques against Pathogenic Simian/Human Immunodeficiency Virus 89.6PD by Passive Transfer of Neutralizing Antibodies journal January 1999
Fc receptor but not complement binding is important in antibody protection against HIV journal September 2007
Purified, Proteolytically Mature HIV Type 1 SOSIP gp140 Envelope Trimers journal June 2007
Human Immunodeficiency Virus Type 1 Spinoculation Enhances Infection through Virus Binding journal November 2000
Antigenic conservation and immunogenicity of the HIV coreceptor binding site journal May 2005
Determination of a Statistically Valid Neutralization Titer in Plasma That Confers Protection against Simian-Human Immunodeficiency Virus Challenge following Passive Transfer of High-Titered Neutralizing Antibodies journal March 2002
Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian–human immunodeficiency virus infection journal February 2000
The antigenic structure of the HIV gp120 envelope glycoprotein journal June 1998
HIV-Specific Antibodies Capable of ADCC Are Common in Breastmilk and Are Associated with Reduced Risk of Transmission in Women with High Viral Loads journal June 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
Dependence of the chemical nature of antibodies on the net electrical charge of antigens. journal February 1966
Broadly cross-reactive HIV neutralizing human monoclonal antibody Fab selected by sequential antigen panning of a phage display library journal December 2003
Characterization of CD4-Induced Epitopes on the HIV Type 1 gp120 Envelope Glycoprotein Recognized by Neutralizing Human Monoclonal Antibodies journal November 2002
A simplified method for the rapid fluorometric assessment of antibody-dependent cell-mediated cytotoxicity journal January 2006
Envelope Glycoprotein Incorporation, Not Shedding of Surface Envelope Glycoprotein (gp120/SU), Is the Primary Determinant of SU Content of Purified Human Immunodeficiency Virus Type 1 and Simian Immunodeficiency Virus journal June 2002
Exploring the gas access routes in a [NiFeSe] hydrogenase using crystals pressurized with krypton and oxygen journal August 2020
Involvement of the V1/V2 variable loop structure in the exposure of human immunodeficiency virus type 1 gp120 epitopes induced by receptor binding. journal January 1995
Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals journal March 2009
Stabilization of the Soluble, Cleaved, Trimeric Form of the Envelope Glycoprotein Complex of Human Immunodeficiency Virus Type 1 journal September 2002
Antibodies Mediating Cellular Cytotoxicity and Neutralization Correlate with a Better Clinical Stage in Children Born to Human Immunodeficiency Virus-Infected Mothers journal February 1990
Tiered Categorization of a Diverse Panel of HIV-1 Env Pseudoviruses for Assessment of Neutralizing Antibodies journal November 2009
Joint X-ray and neutron refinement with phenix.refine journal October 2010
Long-term Nonprogressive Disease Among Individuals With Untreated HIV Infection journal October 2010
Multiple Vaccine-Elicited Nonneutralizing Antienvelope Antibody Activities Contribute to Protective Efficacy by Reducing both Acute and Chronic Viremia following Simian/Human Immunodeficiency Virus SHIV89.6P Challenge in Rhesus Macaques journal May 2010
Epitope mapping and characterization of a novel CD4-induced human monoclonal antibody capable of neutralizing primary HIV-1 strains journal October 2003
Broad and Potent Neutralizing Antibodies from an African Donor Reveal a New HIV-1 Vaccine Target journal September 2009
Topological Layers in the HIV-1 gp120 Inner Domain Regulate gp41 Interaction and CD4-Triggered Conformational Transitions journal March 2010
Antigenic Properties of the Human Immunodeficiency Virus Envelope during Cell-Cell Fusion journal November 2001
Synergistic Neutralization of a Chimeric SIV/HIV Type 1 Virus with Combinations of Human Anti-HIV Type 1 Envelope Monoclonal Antibodies or Hyperimmune Globulins journal May 1997
Crystal Structure of the Broadly Cross-Reactive HIV-1-Neutralizing Fab X5 and Fine Mapping of Its Epitope † , ‡ journal February 2004
Transfer of neutralizing IgG to macaques 6 h but not 24 h after SHIV infection confers sterilizing protection: Implications for HIV-1 vaccine development journal November 2003
Structure-Based Stabilization of HIV-1 gp120 Enhances Humoral Immune Responses to the Induced Co-Receptor Binding Site journal May 2009
Challenges of antibody-mediated protection against HIV-1 journal July 2010
Broadly Neutralizing Antibodies Present New Prospects to Counter Highly Antigenically Diverse Viruses journal July 2012
Antibody‐Dependent Cellular Cytotoxicity Independently Predicts Survival in Severely Immunocompromised Human Immunodeficiency Virus–Infected Patients journal October 1999
Broadly cross-reactive HIV-1-neutralizing human monoclonal Fab selected for binding to gp120-CD4-CCR5 complexes journal May 2002
Correlation of Vaccine-Elicited Systemic and Mucosal Nonneutralizing Antibody Activities with Reduced Acute Viremia following Intrarectal Simian Immunodeficiency Virus SIVmac251 Challenge of Rhesus Macaques journal October 2008
An enzyme-linked immunosorbent assay for antibodies to the envelope glycoproteins of divergent strains of HIV-1 journal January 1989
Potent and synergistic neutralization of human immunodeficiency virus (HIV) type 1 primary isolates by hyperimmune anti-HIV immunoglobulin combined with monoclonal antibodies 2F5 and 2G12. journal January 1997
Characterization of conserved human immunodeficiency virus type 1 gp120 neutralization epitopes exposed upon gp120-CD4 binding. journal January 1993
Exploration of antigenic variation in gp120 from clades A through F of human immunodeficiency virus type 1 by using monoclonal antibodies. journal January 1994
Immunological evidence for interactions between the first, second, and fifth conserved domains of the gp120 surface glycoprotein of human immunodeficiency virus type 1. journal January 1994
Antibody cross-competition analysis of the human immunodeficiency virus type 1 gp120 exterior envelope glycoprotein. journal January 1996
Analysis of the interaction of the human immunodeficiency virus type 1 gp120 envelope glycoprotein with the gp41 transmembrane glycoprotein. journal January 1997
Antibody-Dependent Cellular Cytotoxicity-Mediating Antibodies from an HIV-1 Vaccine Efficacy Trial Target Multiple Epitopes and Preferentially Use the VH1 Gene Family journal August 2012
HIV-1 natural viral suppressors: control of viral replication in the absence of therapy journal January 2007
Recognition properties of a panel of human recombinant Fab fragments to the CD4 binding site of gp120 that show differing abilities to neutralize human immunodeficiency virus type 1. journal January 1994
[20] Processing of X-ray diffraction data collected in oscillation mode book January 1997
Genetic Signatures in the Envelope Glycoproteins of HIV-1 that Associate with Broadly Neutralizing Antibodies text January 2010
Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection text January 2000

Cited By (48)

Boosting with AIDSVAX B/E Enhances Env Constant Region 1 and 2 Antibody-Dependent Cellular Cytotoxicity Breadth and Potency journal November 2019
Impaired Downregulation of NKG2D Ligands by Nef Proteins from Elite Controllers Sensitizes HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity journal August 2017
Boosting with ALVAC-HIV and AIDSVAX B/E enhances Env constant region 1 and 2 antibody-dependent cellular cytotoxicity posted_content May 2019
Preparation and Evaluation of the Fully Humanized Monoclonal Antibody GD-mAb Against Respiratory Syncytial Virus journal July 2019
Dual-Affinity Re-Targeting proteins direct T cell–mediated cytolysis of latently HIV-infected cells text January 2015
Remodeling of the Host Cell Plasma Membrane by HIV-1 Nef and Vpu: A Strategy to Ensure Viral Fitness and Persistence journal March 2016
Bridging Vaccine-Induced HIV-1 Neutralizing and Effector Antibody Responses in Rabbit and Rhesus Macaque Animal Models journal March 2019
CD4- and Time-Dependent Susceptibility of HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity journal March 2019
Structure and immune recognition of trimeric pre-fusion HIV-1 Env text January 2014
Uninfected Bystander Cells Impact the Measurement of HIV-Specific Antibody-Dependent Cellular Cytotoxicity Responses journal March 2018
Quantifying Anti-HIV Envelope-Specific Antibodies in Plasma from HIV Infected Individuals journal May 2019
Boosting of ALVAC-SIV Vaccine-Primed Macaques with the CD4-SIVgp120 Fusion Protein Elicits Antibodies to V2 Associated with a Decreased Risk of SIV mac251 Acquisition journal September 2016
Quantifying Anti-HIV Envelope-Specific Antibodies in Plasma from HIV Infected Individuals text January 2019
Systems serology: profiling vaccine induced humoral immunity against HIV journal December 2017
Incomplete Downregulation of CD4 Expression Affects HIV-1 Env Conformation and Antibody-Dependent Cellular Cytotoxicity Responses journal April 2018
Adaption of human antibody λ and κ light chain architectures to CDR repertoires journal March 2019
Two Families of Env Antibodies Efficiently Engage Fc-Gamma Receptors and Eliminate HIV-1-Infected Cells journal November 2018
Structural basis for the recognition of complex-type N-glycans by Endoglycosidase S journal May 2018
Lack of ADCC Breadth of Human Nonneutralizing Anti-HIV-1 Antibodies journal April 2017
Concurrent Exposure of Neutralizing and Non-neutralizing Epitopes on a Single HIV-1 Envelope Structure journal July 2019
Increasing the Clinical Potential and Applications of Anti-HIV Antibodies journal November 2017
HIV Nef and Vpu protect HIV-infected CD4+ T cells from antibody-mediated cell lysis through down-modulation of CD4 and BST2 journal January 2014
Stabilizing Exposure of Conserved Epitopes by Structure Guided Insertion of Disulfide Bond in HIV-1 Envelope Glycoprotein journal October 2013
HIV / AIDS Vaccines: 2018 journal October 2018
The Antibodiome—Mapping the Humoral Immune Response to HIV journal March 2019
HIV-specific CD4-induced Antibodies Mediate Broad and Potent Antibody-dependent Cellular Cytotoxicity Activity and are Commonly Detected in Plasma from HIV-infected Humans journal October 2015
Antibody-dependent cellular cytotoxicity targeting CD4-inducible epitopes predicts mortality in HIV-infected infants journal September 2019
A stamp on the envelope journal October 2014
Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations journal November 2017
Structural basis of mammalian high-mannose N-glycan processing by human gut Bacteroides journal February 2020
Molecular basis for epitope recognition by non-neutralizing anti-gp41 antibody F240 journal November 2016
Antibody-Dependent Cellular Cytotoxicity-Competent Antibodies against HIV-1-Infected Cells in Plasma from HIV-Infected Subjects journal December 2019
Development of prophylactic vaccines against HIV-1 journal January 2013
Highlights from the 2014 International Symposium on HIV & Emerging Infectious Diseases (ISHEID): from cART management to the end of the HIV pandemic journal January 2014
Herpes Simplex Virus 2 (HSV-2) Infected Cell Proteins Are among the Most Dominant Antigens of a Live-Attenuated HSV-2 Vaccine journal February 2015
Potent Functional Antibody Responses Elicited by HIV-I DNA Priming and Boosting with Heterologous HIV-1 Recombinant MVA in Healthy Tanzanian Adults journal April 2015
Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques journal August 2015
Epitope Specificity of Human Immunodeficiency Virus-1 Antibody Dependent Cellular Cytotoxicity [ADCC] Responses journal November 2013
Antibody Functional Assays as Measures of Fc Receptor-Mediated Immunity to HIV - New Technologies and their Impact on the HIV Vaccine Field journal July 2017
A New Scientific Paradigm may be Needed to Finally Develop an HIV Vaccine journal March 2015
Natural Killer (NK) Cell Education Differentially Influences HIV Antibody-Dependent NK Cell Activation and Antibody-Dependent Cellular Cytotoxicity journal August 2017
The Early Antibody-Dependent Cell-Mediated Cytotoxicity Response Is Associated With Lower Viral Set Point in Individuals With Primary HIV Infection journal October 2018
Induction of Fc-Mediated Effector Functions Against a Stabilized Inner Domain of HIV-1 gp120 Designed to Selectively Harbor the A32 Epitope Region journal April 2019
Knowns and Unknowns of Assaying Antibody-Dependent Cell-Mediated Cytotoxicity Against HIV-1 journal May 2019
A Sample-Sparing Multiplexed ADCP Assay journal August 2019
Antibody-Dependent Cellular Cytotoxicity (ADCC)-Mediating Antibodies Constrain Neutralizing Antibody Escape Pathway journal December 2019
Structural Basis for Epitopes in the gp120 Cluster A Region that Invokes Potent Effector Cell Activity journal January 2019
Conformational Masking and Receptor-Dependent Unmasking of Highly Conserved Env Epitopes Recognized by Non-Neutralizing Antibodies That Mediate Potent ADCC against HIV-1 journal September 2015

Similar Records

Fusion proteins of HIV-1 envelope glycoprotein gp120 with CD4-induced antibodies showed enhanced binding to CD4 and CD4 binding site antibodies
Journal Article · Fri Sep 07 00:00:00 EDT 2012 · Biochemical and Biophysical Research Communications · OSTI ID:1136677
+2 more
Optimal combinations of broadly neutralizing antibodies for prevention and treatments of HIV-1 clade C infection
Journal Article · Wed Mar 30 00:00:00 EDT 2016 · PLoS Pathogens · OSTI ID:1136677
+20 more
Structure and Recognition of a Novel HIV-1 gp120-gp41 Interface Antibody that Caused MPER Exposure through Viral Escape
Journal Article · Wed Jan 11 00:00:00 EST 2017 · PLoS Pathogens · OSTI ID:1136677
+20 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES