Improving the Immunogenicity of Native-like HIV-1 Envelope Trimers by Hyperstabilization

Area of Science:

• Structural biology
• Immunology
• Virology

Background:

• Recombinant HIV-1 envelope glycoprotein (Env) trimers are crucial for vaccine development but suffer from instability and flexibility.
• The BG505 SOSIP.664 trimer is an engineered model mimicking native Env structure and antigenicity.

Purpose of the Study:

• To enhance the stability and antigenicity of SOSIP trimers by introducing new disulfide bonds.
• To assess the immunogenicity of these stabilized trimers in inducing neutralizing antibody (NAb) responses.

Main Methods:

• Introduction of novel disulfide bonds between gp120 and gp41 subunits in BG505 and other HIV-1 genotype SOSIP trimers.
• Evaluation of trimer stability, conformational flexibility, and antigenicity.
• Assessment of autologous and heterologous neutralizing antibody (NAb) responses in rabbits.

Main Results:

• New disulfide bonds significantly improved trimer stability and antigenicity, reducing conformational flexibility.
• The next-generation SOSIP.v5 trimers induced potent autologous tier-2 NAb responses.
• BG505 SOSIP.v6 trimers elicited weak heterologous NAb responses against specific tier-2 viruses.

Conclusions:

• Stabilization of SOSIP trimers via disulfide bonds is a viable strategy to improve immunogenicity.
• These methods can be applied across multiple HIV-1 genotypes for developing multivalent vaccines.
• The stabilized trimers represent a promising platform for inducing broadly neutralizing antibodies (bNAbs).