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Title: 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

Abstract

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.more » 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.« less

Authors:
 [1];  [1];  [1];  [2];  [1];  [1];  [3];  [1];  [1];  [1];  [1];  [2];  [2];  [3];  [1];  [1]
  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)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH)
OSTI Identifier:
1258683
Grant/Contract Number:  
W-31-109-Eng-38
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Virology
Additional Journal Information:
Journal Volume: 87; Journal Issue: 18; Journal ID: ISSN 0022-538X
Publisher:
American Society for Microbiology
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Acharya, Priyamvada, Luongo, Timothy S., Georgiev, Ivelin S., Matz, Julie, Schmidt, Stephen D., Louder, Mark K., Kessler, Pascal, Yang, Yongping, McKee, Krisha, O'Dell, Sijy, Chen, Lei, Baty, Daniel, Chames, Patrick, Martin, Loic, Mascola, John R., and Kwong, Peter D. 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. United States: N. p., 2013. Web. doi:10.1128/JVI.01332-13.
Acharya, Priyamvada, Luongo, Timothy S., Georgiev, Ivelin S., Matz, Julie, Schmidt, Stephen D., Louder, Mark K., Kessler, Pascal, Yang, Yongping, McKee, Krisha, O'Dell, Sijy, Chen, Lei, Baty, Daniel, Chames, Patrick, Martin, Loic, Mascola, John R., & Kwong, Peter D. 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. United States. https://doi.org/10.1128/JVI.01332-13
Acharya, Priyamvada, Luongo, Timothy S., Georgiev, Ivelin S., Matz, Julie, Schmidt, Stephen D., Louder, Mark K., Kessler, Pascal, Yang, Yongping, McKee, Krisha, O'Dell, Sijy, Chen, Lei, Baty, Daniel, Chames, Patrick, Martin, Loic, Mascola, John R., and Kwong, Peter D. 2013. "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". United States. https://doi.org/10.1128/JVI.01332-13. https://www.osti.gov/servlets/purl/1258683.
@article{osti_1258683,
title = {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},
author = {Acharya, Priyamvada and Luongo, Timothy S. and Georgiev, Ivelin S. and Matz, Julie and Schmidt, Stephen D. and Louder, Mark K. and Kessler, Pascal and Yang, Yongping and McKee, Krisha and O'Dell, Sijy and Chen, Lei and Baty, Daniel and Chames, Patrick and Martin, Loic and Mascola, John R. and Kwong, Peter D.},
abstractNote = {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.},
doi = {10.1128/JVI.01332-13},
url = {https://www.osti.gov/biblio/1258683}, journal = {Journal of Virology},
issn = {0022-538X},
number = 18,
volume = 87,
place = {United States},
year = {Thu Aug 22 00:00:00 EDT 2013},
month = {Thu Aug 22 00:00:00 EDT 2013}
}

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Cited by: 21 works
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Works referenced in this record:

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


Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01
journal, July 2010


HIV therapy by a combination of broadly neutralizing antibodies in humanized mice
journal, October 2012


Broad and potent neutralization of HIV-1 by a gp41-specific human antibody
journal, September 2012


Overview of the CCP 4 suite and current developments
journal, March 2011


Potent and broad neutralization of HIV-1 by a llama antibody elicited by immunization
journal, May 2012


Human domain antibodies to conserved sterically restricted regions on gp120 as exceptionally potent cross-reactive HIV-1 neutralizers
journal, October 2008


MolProbity : all-atom structure validation for macromolecular crystallography
journal, December 2009


Broad and Potent Neutralizing Antibodies from an African Donor Reveal a New HIV-1 Vaccine Target
journal, September 2009


Structure-Based Identification and Neutralization Mechanism of Tyrosine Sulfate Mimetics That Inhibit HIV-1 Entry
journal, August 2011


Features and development of Coot
journal, March 2010


Delineating Antibody Recognition in Polyclonal Sera from Patterns of HIV-1 Isolate Neutralization
journal, May 2013


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


Sequence and Structural Convergence of Broad and Potent HIV Antibodies That Mimic CD4 Binding
journal, July 2011


Structures of the CCR5 N Terminus and of a Tyrosine-Sulfated Antibody with HIV-1 gp120 and CD4
journal, September 2007


Comparison of llama VH sequences from conventional and heavy chain antibodies
journal, November 1997


Structure of a V3-Containing HIV-1 gp120 Core
journal, November 2005


Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody
journal, June 1998


PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010


Unliganded HIV-1 gp120 core structures assume the CD4-bound conformation with regulation by quaternary interactions and variable loops
journal, March 2012


CD4 mimetic miniproteins: potent anti-HIV compounds with promising activity as microbicides
journal, February 2008


Antibody neutralization and escape by HIV-1
journal, March 2003


A Potent and Broad Neutralizing Antibody Recognizes and Penetrates the HIV Glycan Shield
journal, October 2011


Antigenic conservation and immunogenicity of the HIV coreceptor binding site
journal, May 2005


Tiered Categorization of a Diverse Panel of HIV-1 Env Pseudoviruses for Assessment of Neutralizing Antibodies
journal, November 2009


Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility
journal, December 2009


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


The Development of CD4 Binding Site Antibodies during HIV-1 Infection
journal, May 2012


[20] Processing of X-ray diffraction data collected in oscillation mode
book, January 1997


Neutralizing Antibodies Have Limited Effects on the Control of Established HIV-1 Infection In Vivo
journal, April 1999


Structural definition of a conserved neutralization epitope on HIV-1 gp120
journal, February 2007


Structures of HIV-1 gp120 Envelope Glycoproteins from Laboratory-Adapted and Primary Isolates
journal, December 2000


HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites
journal, December 2002


Structural Basis of Immune Evasion at the Site of CD4 Attachment on HIV-1 gp120
journal, November 2009


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Intracellular Neutralization of Ricin Toxin by Single Domain Antibodies Targeting the Active Site Pocket
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Single-Domain Antibodies As Therapeutics against Human Viral Diseases
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IgM Antibodies Can Access Cryptic Antigens Denied to IgG: Hypothesis on Novel Binding Mechanism
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