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Heavy Chain-Only IgG2b Llama Antibody Effects Near-Pan HIV-1 Neutralization by Recognizing a CD4-Induced Epitope That Includes Elements of Coreceptor- and CD4-Binding Sites

Journal Article · · Journal of Virology
DOI:https://doi.org/10.1128/JVI.01332-13· OSTI ID:1258683
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  1. National Inst. of Health (NIH), Bethesda, MD (United States)
  2. INSERM, Marseille (France)
  3. Service d'Ingénierie Moléculaire des Protéines, Gif-sur-Yvette (France)
+ Show Author Affiliations
The conserved HIV-1 site of coreceptor binding is protected from antibody-directed neutralization by conformational and steric restrictions. While inaccessible to most human antibodies, the coreceptor site has been shown to be accessed by antibody fragments. In this study, we used X-ray crystallography, surface plasmon resonance, and pseudovirus neutralization to characterize the gp120-envelope glycoprotein recognition and HIV-1 neutralization of a heavy chain-only llama antibody, named JM4. We describe full-length IgG2b and IgG3 versions of JM4 that target the coreceptor-binding site and potently neutralize over 95% of circulating HIV-1 isolates. Contrary to established trends that show improved access to the coreceptor-binding region by smaller antibody fragments, the single-domain (VHH) version of JM4 neutralized less well than the full-length IgG2b version of JM4. The crystal structure at 2.1-Å resolution of VHH JM4 bound to HIV-1 YU2 gp120 stabilized in the CD4-bound state by the CD4-mimetic miniprotein, M48U1, revealed a JM4 epitope that combined regions of coreceptor recognition (including the gp120 bridging sheet, V3 loop, and β19 strand) with gp120 structural elements involved in recognition of CD4 such as the CD4-binding loop. The structure of JM4 with gp120 thus defines a novel CD4-induced site of vulnerability involving elements of both coreceptor- and CD4-binding sites. Here, the potently neutralizing JM4 IgG2b antibody that targets this newly defined site of vulnerability adds to the expanding repertoire of broadly neutralizing antibodies that effectively neutralize HIV-1 and thereby potentially provides a new template for vaccine development and target for HIV-1 therapy.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
NIH; National Institute 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:
1258683
Journal Information:
Journal of Virology, Journal Name: Journal of Virology Journal Issue: 18 Vol. 87; ISSN 0022-538X
Publisher:
American Society for MicrobiologyCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (47)

Epitope mapping and characterization of a novel CD4-induced human monoclonal antibody capable of neutralizing primary HIV-1 strains journal October 2003
[20] Processing of X-ray diffraction data collected in oscillation mode book January 1997
Comparison of llama VH sequences from conventional and heavy chain antibodies journal November 1997
Structures of HIV-1 gp120 Envelope Glycoproteins from Laboratory-Adapted and Primary Isolates journal December 2000
Neutralizing Antibodies Have Limited Effects on the Control of Established HIV-1 Infection In Vivo journal April 1999
Inference of Macromolecular Assemblies from Crystalline State journal September 2007
Scorpion-Toxin Mimics of CD4 in Complex with Human Immunodeficiency Virus gp120 journal May 2005
Structure-Based Identification and Neutralization Mechanism of Tyrosine Sulfate Mimetics That Inhibit HIV-1 Entry journal August 2011
Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody journal June 1998
HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites journal December 2002
Antibody neutralization and escape by HIV-1 journal March 2003
Structural definition of a conserved neutralization epitope on HIV-1 gp120 journal February 2007
Broad and potent neutralization of HIV-1 by a gp41-specific human antibody journal September 2012
HIV therapy by a combination of broadly neutralizing antibodies in humanized mice journal October 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
Human domain antibodies to conserved sterically restricted regions on gp120 as exceptionally potent cross-reactive HIV-1 neutralizers journal October 2008
Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility journal December 2009
Unliganded HIV-1 gp120 core structures assume the CD4-bound conformation with regulation by quaternary interactions and variable loops journal March 2012
Antigenic conservation and immunogenicity of the HIV coreceptor binding site journal May 2005
Potent and broad neutralization of HIV-1 by a llama antibody elicited by immunization journal May 2012
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
CD4 mimetic miniproteins: potent anti-HIV compounds with promising activity as microbicides journal February 2008
MolProbity : all-atom structure validation for macromolecular crystallography journal December 2009
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Features and development of Coot journal March 2010
Overview of the CCP 4 suite and current developments journal March 2011
Structure of a V3-Containing HIV-1 gp120 Core journal November 2005
Structures of the CCR5 N Terminus and of a Tyrosine-Sulfated Antibody with HIV-1 gp120 and CD4 journal September 2007
Structural Basis of Immune Evasion at the Site of CD4 Attachment on HIV-1 gp120 journal November 2009
Broad and Potent Neutralizing Antibodies from an African Donor Reveal a New HIV-1 Vaccine Target journal September 2009
Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1 journal July 2010
Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01 journal July 2010
Sequence and Structural Convergence of Broad and Potent HIV Antibodies That Mimic CD4 Binding journal July 2011
A Potent and Broad Neutralizing Antibody Recognizes and Penetrates the HIV Glycan Shield journal October 2011
Delineating Antibody Recognition in Polyclonal Sera from Patterns of HIV-1 Isolate Neutralization journal May 2013
The HIV-1 Envelope Glycoproteins: Fusogens, Antigens, and Immunogens journal June 1998
A Conserved HIV gp120 Glycoprotein Structure Involved in Chemokine Receptor Binding journal June 1998
Straightforward Selection of Broadly Neutralizing Single-Domain Antibodies Targeting the Conserved CD4 and Coreceptor Binding Sites of HIV-1 gp120 journal November 2012
The Development of CD4 Binding Site Antibodies during HIV-1 Infection journal May 2012
HIV-1 Neutralizing Antibodies Display Dual Recognition of the Primary and Coreceptor Binding Sites and Preferential Binding to Fully Cleaved Envelope Glycoproteins journal August 2012
Tiered Categorization of a Diverse Panel of HIV-1 Env Pseudoviruses for Assessment of Neutralizing Antibodies journal November 2009
Characterization of Human Immunodeficiency Virus Type 1 Monomeric and Trimeric gp120 Glycoproteins Stabilized in the CD4-Bound State: Antigenicity, Biophysics, and Immunogenicity journal March 2007
Two Distinct Broadly Neutralizing Antibody Specificities of Different Clonal Lineages in a Single HIV-1-Infected Donor: Implications for Vaccine Design journal February 2012
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
Neutralization of Human Immunodeficiency Virus Type 1 by sCD4-17b, a Single-Chain Chimeric Protein, Based on Sequential Interaction of gp120 with CD4 and Coreceptor journal March 2003
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
Elicitation of Neutralizing Antibodies Directed against CD4-Induced Epitope(s) Using a CD4 Mimetic Cross-Linked to a HIV-1 Envelope Glycoprotein journal January 2012

Cited By (8)

Role of the non‐hypervariable FR3 D‐E loop in single‐domain antibody recognition of haptens and carbohydrates journal July 2019
Antigen recognition by single-domain antibodies: structural latitudes and constraints journal August 2018
Intracellular Neutralization of Ricin Toxin by Single Domain Antibodies Targeting the Active Site Pocket journal October 2019
The Glycosylphosphatidylinositol-Anchored Variable Region of Llama Heavy Chain-Only Antibody JM4 Efficiently Blocks both Cell-Free and T Cell-T Cell Transmission of Human Immunodeficiency Virus Type 1 journal September 2016
Intracellular Expression of Camelid Single-Domain Antibodies Specific for Influenza Virus Nucleoprotein Uncovers Distinct Features of Its Nuclear Localization journal December 2014
Unique binding modes for the broad neutralizing activity of single-chain variable fragments (scFv) targeting CD4-induced epitopes journal September 2017
Single-Domain Antibodies As Therapeutics against Human Viral Diseases journal December 2017
IgM Antibodies Can Access Cryptic Antigens Denied to IgG: Hypothesis on Novel Binding Mechanism journal August 2019

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