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 »
- Authors:
-
- National Inst. of Health (NIH), Bethesda, MD (United States)
- INSERM, Marseille (France)
- 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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