Back to Search
Start Over
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
- Source :
- Journal of Virology, Journal of Virology, 2013, 87 (18), pp.10173-10181. ⟨10.1128/JVI.01332-13⟩, Journal of Virology, American Society for Microbiology, 2013, 87 (18), pp.10173-10181. ⟨10.1128/JVI.01332-13⟩, Journal of Virology; Vol 87
- Publication Year :
- 2013
- Publisher :
- HAL CCSD, 2013.
-
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. 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.
- Subjects :
- Immunology
[CHIM.THER]Chemical Sciences/Medicinal Chemistry
V3 loop
HIV Antibodies
HIV Envelope Protein gp120
Crystallography, X-Ray
Microbiology
Epitope
Neutralization
03 medical and health sciences
0302 clinical medicine
Neutralization Tests
Virology
Vaccines and Antiviral Agents
[CHIM.CRIS]Chemical Sciences/Cristallography
Animals
Surface plasmon resonance
Binding site
[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM]
ComputingMilieux_MISCELLANEOUS
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
Heavy chain
Binding Sites
biology
[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM]
virus diseases
[SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy
Surface Plasmon Resonance
Antibodies, Neutralizing
3. Good health
chemistry
030220 oncology & carcinogenesis
Insect Science
Immunoglobulin G
biology.protein
HIV-1
Antibody
Glycoprotein
Camelids, New World
Subjects
Details
- Language :
- English
- ISSN :
- 0022538X and 10985514
- Database :
- OpenAIRE
- Journal :
- Journal of Virology, Journal of Virology, 2013, 87 (18), pp.10173-10181. ⟨10.1128/JVI.01332-13⟩, Journal of Virology, American Society for Microbiology, 2013, 87 (18), pp.10173-10181. ⟨10.1128/JVI.01332-13⟩, Journal of Virology; Vol 87
- Accession number :
- edsair.doi.dedup.....cb09af1587995e280fc87ad45656b495