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Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env.

ABSTRACT: As the sole viral antigen on the HIV-1-virion surface, trimeric Env is a focus of vaccine efforts. Here we present the structure of the ligand-free HIV-1-Env trimer, fix its conformation and determine its receptor interactions. Epitope analyses revealed trimeric ligand-free Env to be structurally compatible with broadly neutralizing antibodies but not poorly neutralizing ones. We coupled these compatibility considerations with binding antigenicity to engineer conformationally fixed Envs, including a 201C 433C (DS) variant specifically recognized by broadly neutralizing antibodies. DS-Env retained nanomolar affinity for the CD4 receptor, with which it formed an asymmetric intermediate: a closed trimer bound by a single CD4 without the typical antigenic hallmarks of CD4 induction. Antigenicity-guided structural design can thus be used both to delineate mechanism and to fix conformation, with DS-Env trimers in virus-like-particle and soluble formats providing a new generation of vaccine antigens.

SUBMITTER: Kwon YD

PROVIDER: S-EPMC4706170 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env.

Kwon Young Do YD Pancera Marie M Acharya Priyamvada P Georgiev Ivelin S IS Crooks Emma T ET Gorman Jason J Joyce M Gordon MG Guttman Miklos M Ma Xiaochu X Narpala Sandeep S Soto Cinque C Terry Daniel S DS Yang Yongping Y Zhou Tongqing T Ahlsen Goran G Bailer Robert T RT Chambers Michael M Chuang Gwo-Yu GY Doria-Rose Nicole A NA Druz Aliaksandr A Hallen Mark A MA Harned Adam A Kirys Tatsiana T Louder Mark K MK O'Dell Sijy S Ofek Gilad G Osawa Keiko K Prabhakaran Madhu M Sastry Mallika M Stewart-Jones Guillaume B E GB Stuckey Jonathan J Thomas Paul V PV Tittley Tishina T Williams Constance C Zhang Baoshan B Zhao Hong H Zhou Zhou Z Donald Bruce R BR Lee Lawrence K LK Zolla-Pazner Susan S Baxa Ulrich U Schön Arne A Freire Ernesto E Shapiro Lawrence L Lee Kelly K KK Arthos James J Munro James B JB Blanchard Scott C SC Mothes Walther W Binley James M JM McDermott Adrian B AB Mascola John R JR Kwong Peter D PD

Nature structural & molecular biology 20150622 7

As the sole viral antigen on the HIV-1-virion surface, trimeric Env is a focus of vaccine efforts. Here we present the structure of the ligand-free HIV-1-Env trimer, fix its conformation and determine its receptor interactions. Epitope analyses revealed trimeric ligand-free Env to be structurally compatible with broadly neutralizing antibodies but not poorly neutralizing ones. We coupled these compatibility considerations with binding antigenicity to engineer conformationally fixed Envs, includi ...[more]

PMID: 26098315

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Project description:BackgroundWe previously developed drug-like peptide triazoles (PTs) that target HIV-1 Envelope (Env) gp120, potently inhibit viral entry, and irreversibly inactivate virions. Here, we investigated potential mechanisms of viral escape from this promising class of HIV-1 entry inhibitors.ResultsHIV-1 resistance to cyclic (AAR029b) and linear (KR13) PTs was obtained by dose escalation in viral passaging experiments. High-level resistance for both inhibitors developed slowly (relative to escape from gp41-targeted C-peptide inhibitor C37) by acquiring mutations in gp120 both within (Val255) and distant to (Ser143) the putative PT binding site. The similarity in the resistance profiles for AAR029b and KR13 suggests that the shared IXW pharmacophore provided the primary pressure for HIV-1 escape. In single-round infectivity studies employing recombinant virus, V255I/S143N double escape mutants reduced PT antiviral potency by 150- to 3900-fold. Curiously, the combined mutations had a much smaller impact on PT binding affinity for monomeric gp120 (four to ninefold). This binding disruption was entirely due to the V255I mutation, which generated few steric clashes with PT in molecular docking. However, this minor effect on PT affinity belied large, offsetting changes to association enthalpy and entropy. The escape mutations had negligible effect on CD4 binding and utilization during entry, but significantly altered both binding thermodynamics and inhibitory potency of the conformationally-specific, anti-CD4i antibody 17b. Moreover, the escape mutations substantially decreased gp120 shedding induced by either soluble CD4 or AAR029b.ConclusionsTogether, the data suggest that the escape mutations significantly modified the energetic landscape of Env's prefusogenic state, altering conformational dynamics to hinder PT-induced irreversible inactivation of Env. This work therein reveals a unique mode of virus escape for HIV-1, namely, resistance by altering the intrinsic conformational dynamics of the Env trimer.

Dataset Information

Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env.

Publications

Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env.

Similar Datasets

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