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One-step sequence and structure-guided optimization of HIV-1 envelope gp140

Authors :
Adi Goldenzweig
Ishika Pramanick
Raghavan Varadarajan
Sarel J. Fleishman
Somnath Dutta
Malavika Abhineshababu Sridevi
Sameer Kumar Malladi
David Schreiber
Source :
Current Research in Structural Biology, Vol 2, Iss, Pp 45-55 (2020), Current research in structural biology
Publication Year :
2020
Publisher :
Elsevier, 2020.

Abstract

Stabilization of the metastable envelope glycoprotein (Env) of HIV-1 is hypothesized to improve induction of broadly neutralizing antibodies. We improved the expression yield and stability of the HIV-1 envelope glycoprotein BG505SOSIP.664 gp140 by means of a previously described automated sequence and structure-guided computational thermostabilization approach, PROSS. This combines sequence conservation information with computational assessment of mutant stabilization, thus taking advantage of the extensive natural sequence variation present in HIV-1 Env. PROSS is used to design three gp140 variants with 17-45 mutations relative to the parental construct. One of the designs is experimentally observed to have a fourfold improvement in yield and a 4 °C increment in thermostability. In addition, the designed immunogens have similar antigenicity profiles to the native flexible linker version of wild type, BG505SOSIP.664 gp140 (NFL Wt) to major epitopes targeted by broadly neutralizing antibodies. PROSS eliminates the laborious process of screening many variants for stability and functionality, providing a proof of principle of the method for stabilization and improvement of yield without compromising antigenicity for next generation complex, highly glycosylated vaccine candidates.

Details

Language :
English
Volume :
2
Database :
OpenAIRE
Journal :
Current Research in Structural Biology
Accession number :
edsair.doi.dedup.....a9cd16cab2d906892caa98e05e769a7a