Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form

Cleavage strongly influences whether soluble HIV-1 envelope glycoprotein trimers adopt a native-like conformation

Academic Article
uri icon
  • Overview
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

related to degree

  • Lee, Jeong Hyun, Ph.D. in Chemical Biology, Scripps Research 2011 - 2016

authors

  • Ringe, R. P.
  • Sanders, R. W.
  • Yasmeen, A.
  • Kim, H. J.
  • Lee, Jeong Hyun
  • Cupo, A.
  • Korzun, J.
  • Derking, R.
  • van Montfort, T.
  • Julien, J. P.
  • Wilson, Ian
  • Klasse, P. J.
  • Ward, Andrew
  • Moore, J. P.

publication date

  • November 2013

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • We compare the antigenicity and conformation of soluble, cleaved vs. uncleaved envelope glycoprotein (Env gp)140 trimers from the subtype A HIV type 1 (HIV-1) strain BG505. The impact of gp120-gp41 cleavage on trimer structure, in the presence or absence of trimer-stabilizing modifications (i.e., a gp120-gp41 disulfide bond and an I559P gp41 change, together designated SOSIP), was assessed. Without SOSIP changes, cleaved trimers disintegrate into their gp120 and gp41-ectodomain (gp41ECTO) components; when only the disulfide bond is present, they dissociate into gp140 monomers. Uncleaved gp140s remain trimeric whether SOSIP substitutions are present or not. However, negative-stain electron microscopy reveals that only cleaved trimers form homogeneous structures resembling native Env spikes on virus particles. In contrast, uncleaved trimers are highly heterogeneous, adopting a variety of irregular shapes, many of which appear to be gp120 subunits dangling from a central core that is presumably a trimeric form of gp41ECTO. Antigenicity studies with neutralizing and nonneutralizing antibodies are consistent with the EM images; cleaved, SOSIP-stabilized trimers express quaternary structure-dependent epitopes, whereas uncleaved trimers expose nonneutralizing gp120 and gp41ECTO epitopes that are occluded on cleaved trimers. These findings have adverse implications for using soluble, uncleaved trimers for structural studies, and the rationale for testing uncleaved trimers as vaccine candidates also needs to be reevaluated.

subject areas

  • AIDS Vaccines
  • Antibodies, Monoclonal
  • Electrophoresis, Polyacrylamide Gel
  • HIV-1
  • Microscopy, Electron
  • Mutation, Missense
  • Protein Conformation
  • Protein Engineering
  • Protein Multimerization
  • Protein Subunits
  • Rosaniline Dyes
  • env Gene Products, Human Immunodeficiency Virus
scroll to property group menus

Identity

PubMed Central ID

  • PMC3831437

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1314351110

PubMed ID

  • 24145402
scroll to property group menus

Additional Document Info

start page

  • 18256

end page

  • 18261

volume

  • 110

issue

  • 45

©2021 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support