Structure of a cleavage-independent HIV Env recapitulates the glycoprotein architecture of the native cleaved trimer

Nature Communications
Anita SarkarIan A Wilson

Abstract

Furin cleavage of the HIV envelope glycoprotein is an essential step for cell entry that enables formation of well-folded, native-like glycosylated trimers, releases constraints on the fusion peptide, and limits enzymatic processing of the N-glycan shield. Here, we show that a cleavage-independent, stabilized, soluble Env trimer mimic (BG505 NFL.664) exhibits a "closed-form", native-like, prefusion conformation akin to furin-cleaved Env trimers. The crystal structure of BG505 NFL.664 at 3.39 Å resolution with two potent bNAbs also identifies the full epitopes of PGV19 and PGT122 that target the receptor binding site and N332 supersite, respectively. Quantitative site-specific analysis of the glycan shield reveals that native-like glycan processing is maintained despite furin-independent maturation in the secretory pathway. Thus, cleavage-independent NFL Env trimers exhibit quaternary protein and carbohydrate structures similar to the native viral spike that further validate their potential as vaccine immunogen candidates.

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Citations

Jan 10, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Yoann AldonPaul F McKay
Dec 21, 2019·Frontiers of Medicine·Qian Wang, Linqi Zhang
Dec 14, 2019·Annals of Biomedical Engineering·Shuai ShaoJonathan F Lovell
Nov 28, 2019·Nature Communications·Lei ZhangMichael B Zwick
Apr 4, 2020·Emerging Microbes & Infections·Qian WangLinqi Zhang
Jan 26, 2020·Nature Communications·Rory HendersonS Munir Alam
Dec 4, 2019·Expert Review of Vaccines·Iván Del Moral-Sánchez, Kwinten Sliepen
Oct 27, 2020·Therapeutic Advances in Vaccines and Immunotherapy·Supratik DasSweety Samal
Sep 20, 2020·Biochimica Et Biophysica Acta. General Subjects·Shubbir AhmedSweety Samal
Jun 3, 2021·Viruses·Ashley Lauren Bennett, Rory Henderson
Jul 18, 2021·Seminars in Immunology·Jeong Hyun Lee, Shane Crotty

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Methods Mentioned

BETA
glycosylation
electron microscopy
protein folding
size exclusion chromatography
PCR
biosensors

Software Mentioned

AmberTools12
Appion
Privateer
Byologic
MolProbity
Glycam
Phenix
Origin
AMBER
CTFFind3

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