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

Nicely, Nathan I.; Wiehe, Kevin; Kepler, Thomas B.; Jaeger, Frederick H.; Dennison, S. Moses; Rerks-Ngarm, Supachai; Nitayaphan, Sorachai; Pitisuttithum, Punnee; Kaewkungwal, Jaranit; Robb, Merlin L.; O'Connell, Robert J.; Michael, Nelson L.; Kim, Jerome H.; Liao, Hua-Xin; Munir Alam, S.; Hwang, Kwan-Ki; Bonsignori, Mattia; Haynes, Barton F.

doi:10.1016/j.ebiom.2015.06.016

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

Journal Article · Wed Jul 01 00:00:00 EDT 2015 · EBioMedicine

DOI:https://doi.org/10.1016/j.ebiom.2015.06.016· OSTI ID:1238694

Nicely, Nathan I.; Wiehe, Kevin; Kepler, Thomas B.; Jaeger, Frederick H.; Dennison, S. Moses; Rerks-Ngarm, Supachai; Nitayaphan, Sorachai; Pitisuttithum, Punnee; Kaewkungwal, Jaranit; Robb, Merlin L.; O'Connell, Robert J.; Michael, Nelson L.; Kim, Jerome H.; Liao, Hua-Xin; Munir Alam, S.; Hwang, Kwan-Ki; Bonsignori, Mattia; Haynes, Barton F.

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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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: W-31-109-Eng-38

OSTI ID:: 1238694

Alternate ID(s):: OSTI ID: 1251225

Journal Information:: EBioMedicine, Journal Name: EBioMedicine Vol. 2 Journal Issue: 7; ISSN 2352-3964

Publisher:: ElsevierCopyright Statement

Country of Publication:: Netherlands

Language:: English

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Cited by: 13 works

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59 BASIC BIOLOGICAL SCIENCES
HIV-1
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V2
RV-144
antibody maturation
germline
unmutated ancestor

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

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