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

TitleStructure of a cleavage-independent HIV Env recapitulates the glycoprotein architecture of the native cleaved trimer.
Publication TypeJournal Article
Year of Publication2018
AuthorsSarkar A, Bale S, Behrens A-J, Kumar S, Sharma SKumar, de Val N, Pallesen J, Irimia A, Diwanji DC, Stanfield RL, Ward AB, Crispin M, Wyatt RT, Wilson IA
JournalNat Commun
Volume9
Issue1
Pagination1956
Date Published05/16/2018
ISSN2041-1723
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.

DOI10.1038/s41467-018-04272-y
Alternate JournalNat Commun
PubMed ID29769533
PubMed Central IDPMC5955915
Grant ListP01 AI104722 / AI / NIAID NIH HHS / United States
R01 AI084817 / AI / NIAID NIH HHS / United States
R56 AI084817 / AI / NIAID NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
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