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

Nat Commun. 2018 May 16;9(1):1956. doi: 10.1038/s41467-018-04272-y.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Neutralizing / chemistry
  • Antibodies, Neutralizing / metabolism
  • Binding Sites
  • Crystallography, X-Ray
  • Epitopes / chemistry
  • Glycoproteins / chemistry*
  • Glycoproteins / metabolism
  • Glycosylation
  • HIV Antibodies / chemistry
  • HIV Antibodies / metabolism
  • HIV-1 / immunology
  • HIV-1 / metabolism
  • Humans
  • Models, Molecular
  • Protein Binding
  • Protein Multimerization*
  • Protein Structure, Quaternary*
  • env Gene Products, Human Immunodeficiency Virus / chemistry*
  • env Gene Products, Human Immunodeficiency Virus / immunology
  • env Gene Products, Human Immunodeficiency Virus / metabolism

Substances

  • Antibodies, Neutralizing
  • Epitopes
  • Glycoproteins
  • HIV Antibodies
  • env Gene Products, Human Immunodeficiency Virus