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

Area of Science:

• Vaccinology
• Immunology
• Structural Biology

Background:

• Developing vaccines against diverse pathogens requires eliciting broadly neutralizing antibodies (bnAbs).
• HIV's extensive antigenic diversity presents a significant challenge for vaccine design.
• Targeting conserved epitopes, like the CD4 binding site (CD4bs) on the HIV spike protein, is a key strategy.

Purpose of the Study:

• To design a rigid, bivalent immunogen for enhanced binding to bnAbs.
• To investigate the binding kinetics and affinity of the novel immunogen.
• To explore the concept of 'selective avidity' for targeted antibody engagement.

Main Methods:

• Constructed a rigid bivalent immunogen by covalently linking two HIV-1 gp120 antigens.
• Utilized a complementary antibody and crosslinked light chains for immunogen assembly.
• Analyzed binding kinetics using a novel gel shift assay and surface plasmon resonance (SPR).

Main Results:

• The rigid bivalent immunogen demonstrated higher affinity for VRC01-class bnAbs compared to flexible controls.
• Antigen pre-organization in the rigid structure likely reduced the entropic penalty for divalent binding.
• The immunogen showed selective avidity, binding bivalently to VRC01 but monovalently to a non-CD4bs antibody (A32).

Conclusions:

• The designed immunogen exhibits selective avidity, a promising characteristic for vaccine development.
• Future in vivo vaccination studies will assess the immunogen's immune-focusing properties.
• The selective avidity concept may have broad applications in designing immunogens for eliciting specific antibody responses.