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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.

Publication ,  Journal Article
Acharya, P; Luongo, TS; Georgiev, IS; Matz, J; Schmidt, SD; Louder, MK; Kessler, P; Yang, Y; McKee, K; O'Dell, S; Chen, L; Baty, D; Chames, P ...
Published in: J Virol
September 2013

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.

Duke Scholars

Published In

J Virol

DOI

EISSN

1098-5514

Publication Date

September 2013

Volume

87

Issue

18

Start / End Page

10173 / 10181

Location

United States

Related Subject Headings

  • Virology
  • Surface Plasmon Resonance
  • Neutralization Tests
  • Immunoglobulin G
  • HIV-1
  • HIV Envelope Protein gp120
  • HIV Antibodies
  • Crystallography, X-Ray
  • Camelids, New World
  • Binding Sites
 

Citation

APA
Chicago
ICMJE
MLA
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Acharya, P., Luongo, T. S., Georgiev, I. S., Matz, J., Schmidt, S. D., Louder, M. K., … Kwong, P. 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. J Virol, 87(18), 10173–10181. https://doi.org/10.1128/JVI.01332-13
Acharya, Priyamvada, Timothy S. Luongo, Ivelin S. Georgiev, Julie Matz, Stephen D. Schmidt, Mark K. Louder, Pascal Kessler, et al. “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.J Virol 87, no. 18 (September 2013): 10173–81. https://doi.org/10.1128/JVI.01332-13.
Acharya, Priyamvada, et al. “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.J Virol, vol. 87, no. 18, Sept. 2013, pp. 10173–81. Pubmed, doi:10.1128/JVI.01332-13.
Acharya P, Luongo TS, Georgiev IS, Matz J, Schmidt SD, Louder MK, Kessler P, Yang Y, McKee K, O’Dell S, Chen L, Baty D, Chames P, Martin L, Mascola JR, Kwong PD. 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. J Virol. 2013 Sep;87(18):10173–10181.

Published In

J Virol

DOI

EISSN

1098-5514

Publication Date

September 2013

Volume

87

Issue

18

Start / End Page

10173 / 10181

Location

United States

Related Subject Headings

  • Virology
  • Surface Plasmon Resonance
  • Neutralization Tests
  • Immunoglobulin G
  • HIV-1
  • HIV Envelope Protein gp120
  • HIV Antibodies
  • Crystallography, X-Ray
  • Camelids, New World
  • Binding Sites