Glycine Substitution at Helix-to-Coil Transitions Facilitates the Structural Determination of a Stabilized Subtype C HIV Envelope Glycoprotein

Javier Guenaga, Fernando Garces, Natalia de Val, Robyn L. Stanfield, Viktoriya Dubrovskaya, Brett Higgins, Barbara Carrette, Andrew B. Ward, Ian A. Wilson, Richard T. Wyatt

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Advances in HIV-1 envelope glycoprotein (Env) design generate native-like trimers and high-resolution clade A, B, and G structures and elicit neutralizing antibodies. However, a high-resolution clade C structure is critical, as this subtype accounts for the majority of HIV infections worldwide, but well-ordered clade C Env trimers are more challenging to produce due to their instability. Based on targeted glycine substitutions in the Env fusion machinery, we defined a general approach that disfavors helical transitions leading to post-fusion conformations, thereby favoring the pre-fusion state. We generated a stabilized, soluble clade C Env (16055 NFL) and determined its crystal structure at 3.9 Å. Its overall conformation is similar to SOSIP.664 and native Env trimers but includes a covalent linker between gp120 and gp41, an engineered 201-433 disulfide bond, and density corresponding to 22 N-glycans. Env-structure-guided design strategies resulted in multiple homogeneous cross-clade immunogens with the potential to advance HIV vaccine development.

Original languageEnglish (US)
Pages (from-to)792-803.e3
JournalImmunity
Volume46
Issue number5
DOIs
StatePublished - May 16 2017

Keywords

  • Antibody
  • Envelope glycoprotein
  • Glycan shield
  • HIV
  • Immunogen
  • Trimer
  • Vaccine
  • bNAb

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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