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

Area of Science:

• Immunology
• Virology
• Computational Biology

Background:

• The metastable nature of HIV-1 envelope glycoprotein (Env) presents challenges for vaccine development.
• Stabilizing Env is hypothesized to improve the induction of broadly neutralizing antibodies (bNAbs).

Purpose of the Study:

• To enhance the expression yield and stability of the HIV-1 envelope glycoprotein BG505SOSIP.664 gp140.
• To validate a computational thermostabilization approach (PROSS) for improving immunogen design.

Main Methods:

• Utilized PROSS, an automated sequence and structure-guided computational method.
• PROSS integrates sequence conservation and computational stability assessments.
• Designed three gp140 variants with 17-45 mutations.

Main Results:

• One designed variant showed a fourfold increase in expression yield and a 4 °C rise in thermostability.
• Designed immunogens maintained similar antigenicity to the wild-type, targeting key bNAb epitopes.
• PROSS streamlined the design process, eliminating laborious screening.

Conclusions:

• PROSS effectively stabilizes HIV-1 Env glycoproteins and improves expression yield without compromising antigenicity.
• This computational approach offers a promising strategy for next-generation complex vaccine candidates.
• The method demonstrates proof of principle for stabilizing and enhancing immunogen design for HIV-1 vaccine development.