Divalent HIV-1 gp120 Immunogen Exhibits Selective Avidity for Broadly Neutralizing Antibody VRC01 Precursors

Area of Science:

• Immunology and Vaccine Development
• Structural Biology
• Virology

Background:

• Eliciting broadly neutralizing antibodies (bnAbs) is crucial for vaccines against diverse pathogens like HIV.
• The HIV spike protein's CD4 binding site (CD4bs) is a key target for bnAbs, including VRC01.
• Antigenic diversity in pathogens poses challenges for vaccine design.

Purpose of the Study:

• To design a rigid divalent immunogen for enhanced binding to VRC01-class bnAbs.
• To investigate the concept of 'selective avidity' for targeted antibody engagement.
• To lay the groundwork for future in vivo vaccination studies.

Main Methods:

• Covalently linked two HIV-1 gp120 antigens to a complementary antibody.
• Crosslinked the light chains of the antibody to create a rigid structure.
• Assessed binding affinity and specificity of the divalent immunogen to antibodies.

Main Results:

• The rigid divalent immunogen demonstrated higher affinity for VRC01-class antibodies compared to controls.
• The immunogen exhibited selective avidity: divalent binding to VRC01 and monovalent binding to a non-CD4bs antibody (A32).
• Antigen pre-organization likely reduced the entropic penalty for divalent binding.

Conclusions:

• The designed rigid divalent immunogen effectively enhances binding to specific bnAbs.
• The 'selective avidity' characteristic offers a promising strategy for immune focusing.
• This approach holds potential for broad application in future vaccine design.