Structure of a cleavage-independent HIV Env recapitulates the glycoprotein architecture of the native cleaved trimer.
Anita SarkarShridhar BaleAnna-Janina BehrensSonu KumarShailendra Kumar SharmaNatalia de ValJesper PallesenAdriana IrimiaDevan C DiwanjiRobyn L StanfieldAndrew B WardMax CrispinRichard T WyattIan A WilsonPublished in: Nature communications (2018)
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.
Keyphrases
- antiretroviral therapy
- dna binding
- hiv positive
- hiv infected
- human immunodeficiency virus
- hepatitis c virus
- hiv testing
- sars cov
- cell surface
- single cell
- men who have sex with men
- gene expression
- hydrogen peroxide
- molecular dynamics simulations
- transcription factor
- mesenchymal stem cells
- small molecule
- amino acid
- climate change
- anti inflammatory