5KZC

Crystal structure of an HIV-1 gp120 engineered outer domain with a Man9 glycan at position N276, in complex with broadly neutralizing antibody VRC01

Summary for 5KZC

• Entry DOI: 10.2210/pdb5kzc/pdb
• Related: 4JPJ 4JPK 5D9Q
• Descriptor: VRC01 Fab heavy chain, Engineered outer domain of gp120, VRC01 Fab light chain, ... (6 entities in total)
• Functional Keywords: hiv, env, gp120, neutralizing antibody, n-linked glycan, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 9
• Total formula weight: 206912.06

Authors

Julien, J.-P.,Jardine, J.G.,Diwanji, D.,Schief, W.R.,Wilson, I.A. (deposition date: 2016-07-24, release date: 2016-08-10, Last modification date: 2024-10-16)

Primary citation

Jardine, J.G.,Sok, D.,Julien, J.P.,Briney, B.,Sarkar, A.,Liang, C.H.,Scherer, E.A.,Henry Dunand, C.J.,Adachi, Y.,Diwanji, D.,Hsueh, J.,Jones, M.,Kalyuzhniy, O.,Kubitz, M.,Spencer, S.,Pauthner, M.,Saye-Francisco, K.L.,Sesterhenn, F.,Wilson, P.C.,Galloway, D.M.,Stanfield, R.L.,Wilson, I.A.,Burton, D.R.,Schief, W.R.
Minimally Mutated HIV-1 Broadly Neutralizing Antibodies to Guide Reductionist Vaccine Design.
Plos Pathog., 12:e1005815-e1005815, 2016

PubMed Abstract: An optimal HIV vaccine should induce broadly neutralizing antibodies (bnAbs) that neutralize diverse viral strains and subtypes. However, potent bnAbs develop in only a small fraction of HIV-infected individuals, all contain rare features such as extensive mutation, insertions, deletions, and/or long complementarity-determining regions, and some are polyreactive, casting doubt on whether bnAbs to HIV can be reliably induced by vaccination. We engineered two potent VRC01-class bnAbs that minimized rare features. According to a quantitative features frequency analysis, the set of features for one of these minimally mutated bnAbs compared favorably with all 68 HIV bnAbs analyzed and was similar to antibodies elicited by common vaccines. This same minimally mutated bnAb lacked polyreactivity in four different assays. We then divided the minimal mutations into spatial clusters and dissected the epitope components interacting with those clusters, by mutational and crystallographic analyses coupled with neutralization assays. Finally, by synthesizing available data, we developed a working-concept boosting strategy to select the mutation clusters in a logical order following a germline-targeting prime. We have thus developed potent HIV bnAbs that may be more tractable vaccine goals compared to existing bnAbs, and we have proposed a strategy to elicit them. This reductionist approach to vaccine design, guided by antibody and antigen structure, could be applied to design candidate vaccines for other HIV bnAbs or protective Abs against other pathogens.

PubMed: 27560183
DOI: 10.1371/journal.ppat.1005815

Experimental method

X-RAY DIFFRACTION (3.25 Å)