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Please use this identifier to cite or link to this item: http://repository.li.mahidol.ac.th/dspace/handle/123456789/35430
Title: Structural analysis of the unmutated ancestor of the HIV-1 envelope V2 region antibody CH58 isolated from an RV144 vaccine efficacy trial vaccinee
Authors: Nathan I. Nicely
Kevin Wiehe
Thomas B. Kepler
Frederick H. Jaeger
S. Moses Dennison
Supachai Rerks-Ngarm
Sorachai Nitayaphan
Punnee Pitisuttithum
Jaranit Kaewkungwal
Merlin L. Robb
Robert J. O'Connell
Nelson L. Michael
Jerome H. Kim
Hua Xin Liao
S. Munir Alam
Kwan Ki Hwang
Mattia Bonsignori
Barton F. Haynes
Duke University School of Medicine
Boston University
Thailand Ministry of Public Health
Armed Forces Research Institute of Medical Sciences, Thailand
Mahidol University
Henry Jackson Foundation
Walter Reed Army Institute of Research
Keywords: Biochemistry, Genetics and Molecular Biology
Issue Date: 1-Jul-2015
Citation: EBioMedicine. Vol.2, No.7 (2015), 713-722
Abstract: © 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 KDthrough 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.
URI: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84951574208&origin=inward
http://repository.li.mahidol.ac.th/dspace/handle/123456789/35430
ISSN: 23523964
Appears in Collections:Scopus 2011-2015

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