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Structural analysis of the unmutated ancestor of the HIV-1 envelope V2 region antibody CH58 isolated from an RV144 vaccine efficacy trial vaccinee.

Publication ,  Journal Article
Nicely, NI; Wiehe, K; Kepler, TB; Jaeger, FH; Dennison, SM; Rerks-Ngarm, S; Nitayaphan, S; Pitisuttithum, P; Kaewkungwal, J; Robb, ML; Kim, JH ...
Published in: EBioMedicine
July 2015

Human monoclonal antibody CH58 isolated from an RV144 vaccinee binds at Lys169 of the HIV-1 Env gp120 V2 region, a site of vaccine-induced immune pressure. CH58 neutralizes HIV-1 CRF_01 AE strain 92TH023 and mediates ADCC against CD4 + T cell targets infected with CRF_01 AE tier 2 virus. CH58 and other antibodies that bind to a gp120 V2 epitope have a second light chain complementarity determining region (LCDR2) bearing a glutamic acid, aspartic acid (ED) motif involved in forming salt bridges with polar, basic side amino acid side chains in V2. In an effort to learn how V2 responses develop, we determined the crystal structures of the CH58-UA antibody unliganded and bound to V2 peptide. The structures showed an LCDR2 structurally pre-conformed from germline to interact with V2 residue Lys169. LCDR3 was subject to conformational selection through the affinity maturation process. Kinetic analyses demonstrate that only a few contacts were responsible for a 2000-fold increase in KD through maturation, and this effect was predominantly due to an improvement in off-rate. This study shows that preconformation and preconfiguration can work in concert to produce antibodies with desired immunogenic properties.

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Published In

EBioMedicine

DOI

ISSN

2352-3964

Publication Date

July 2015

Volume

2

Issue

7

Start / End Page

713 / 722

Location

Netherlands

Related Subject Headings

  • Treatment Outcome
  • Protein Conformation
  • Peptides
  • Mutation
  • Molecular Sequence Data
  • Humans
  • HIV-1
  • HIV Envelope Protein gp120
  • HIV Antigens
  • HIV Antibodies
 

Citation

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Nicely, N. I., Wiehe, K., Kepler, T. B., Jaeger, F. H., Dennison, S. M., Rerks-Ngarm, S., … Haynes, B. F. (2015). Structural analysis of the unmutated ancestor of the HIV-1 envelope V2 region antibody CH58 isolated from an RV144 vaccine efficacy trial vaccinee. EBioMedicine, 2(7), 713–722. https://doi.org/10.1016/j.ebiom.2015.06.016
Nicely, Nathan I., Kevin Wiehe, Thomas B. Kepler, Frederick H. Jaeger, S Moses Dennison, Supachai Rerks-Ngarm, Sorachai Nitayaphan, et al. “Structural analysis of the unmutated ancestor of the HIV-1 envelope V2 region antibody CH58 isolated from an RV144 vaccine efficacy trial vaccinee.EBioMedicine 2, no. 7 (July 2015): 713–22. https://doi.org/10.1016/j.ebiom.2015.06.016.
Nicely NI, Wiehe K, Kepler TB, Jaeger FH, Dennison SM, Rerks-Ngarm S, et al. Structural analysis of the unmutated ancestor of the HIV-1 envelope V2 region antibody CH58 isolated from an RV144 vaccine efficacy trial vaccinee. EBioMedicine. 2015 Jul;2(7):713–22.
Nicely, Nathan I., et al. “Structural analysis of the unmutated ancestor of the HIV-1 envelope V2 region antibody CH58 isolated from an RV144 vaccine efficacy trial vaccinee.EBioMedicine, vol. 2, no. 7, July 2015, pp. 713–22. Pubmed, doi:10.1016/j.ebiom.2015.06.016.
Nicely NI, Wiehe K, Kepler TB, Jaeger FH, Dennison SM, Rerks-Ngarm S, Nitayaphan S, Pitisuttithum P, Kaewkungwal J, Robb ML, O’Connell RJ, Michael NL, Kim JH, Liao H-X, Munir Alam S, Hwang K-K, Bonsignori M, Haynes BF. Structural analysis of the unmutated ancestor of the HIV-1 envelope V2 region antibody CH58 isolated from an RV144 vaccine efficacy trial vaccinee. EBioMedicine. 2015 Jul;2(7):713–722.
Journal cover image

Published In

EBioMedicine

DOI

ISSN

2352-3964

Publication Date

July 2015

Volume

2

Issue

7

Start / End Page

713 / 722

Location

Netherlands

Related Subject Headings

  • Treatment Outcome
  • Protein Conformation
  • Peptides
  • Mutation
  • Molecular Sequence Data
  • Humans
  • HIV-1
  • HIV Envelope Protein gp120
  • HIV Antigens
  • HIV Antibodies