Structure-guided redesign increases the propensity of HIV Env to generate highly stable soluble trimers

Javier Guenaga, Viktoriya Dubrovskaya, Natalia De Val, Shailendra K. Sharma, Barbara Carrette, Andrew B. Ward, Richard T. Wyatt

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Due to high viral diversity, an effective HIV-1 vaccine will likely require Envs derived from multiple subtypes to generate broadly neutralizing antibodies (bNAbs). Soluble Env mimics, like the native flexibly linked (NFL) and SOSIP trimers, derived from the subtype A BG505 Env, form homogeneous, stable native-like trimers. However, other Env sequences, such as JRFL and 16055 from subtypes B and C, do so to a lesser degree. The high-resolution BG505 SOSIP crystal structures permit the identification and redesign of Env elements involved in trimer stability. Here, we identified structure trimer-derived (TD) residues that increased the propensity of the subtype B JRFL and subtype C 16055 Env sequences to form well-ordered, homogenous, and highly stable soluble trimers. The generation of these spike mimics no longer required antibody-based selection, positive or negative. Using the redesigned subtype B and C trimer representatives as respective foundations, we further stabilized the NFL TD trimers by engineering an intraprotomer disulfide linkage in the prebridging sheet, I201C-A433C (CC), that locks the gp120 in the receptor nontriggered state. We demonstrated that this disulfide pair prevented CD4 induced-conformational rearrangements in NFL trimers derived from the prototypic subtype A, B, and C representatives. Coupling the TD-based design with the engineered disulfide linkage, CC, increased the propensity of Env to form soluble highly stable spike mimics that are resistant to CD4-induced changes. These advances will allow testing of the hypothesis that such stabilized immunogens will more efficiently elicit neutralizing antibodies in small-animal models and primates.

Original languageEnglish (US)
Pages (from-to)2806-2817
Number of pages12
JournalJournal of virology
Volume90
Issue number6
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

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sulfides
Disulfides
HIV
Neutralizing Antibodies
neutralizing antibodies
AIDS Vaccines
crystal structure
Human immunodeficiency virus 1
Primates
HIV-1
engineering
Animal Models
animal models
vaccines
antigens
receptors
antibodies
Antibodies
testing

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Structure-guided redesign increases the propensity of HIV Env to generate highly stable soluble trimers. / Guenaga, Javier; Dubrovskaya, Viktoriya; De Val, Natalia; Sharma, Shailendra K.; Carrette, Barbara; Ward, Andrew B.; Wyatt, Richard T.

In: Journal of virology, Vol. 90, No. 6, 01.01.2016, p. 2806-2817.

Research output: Contribution to journalArticle

Guenaga, Javier ; Dubrovskaya, Viktoriya ; De Val, Natalia ; Sharma, Shailendra K. ; Carrette, Barbara ; Ward, Andrew B. ; Wyatt, Richard T. / Structure-guided redesign increases the propensity of HIV Env to generate highly stable soluble trimers. In: Journal of virology. 2016 ; Vol. 90, No. 6. pp. 2806-2817.
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