Engineering immunogens that select for specific mutations in HIV broadly neutralizing antibodies.

Area of Science:

• Immunology
• Virology
• Computational Biology

Background:

• Developing effective vaccines against rapidly evolving viruses like HIV-1 necessitates inducing broadly neutralizing antibodies (bnAbs).
• Current methods for identifying immunogen modifications that promote specific bnAb mutations are imprecise and rely on trial-and-error.
• Achieving conserved paratopes and specific mutations in bnAbs, including shared Ig-heavy chains, is crucial for broad neutralization.

Approach:

• Utilized molecular dynamics simulations to analyze antibody-HIV-1 Envelope (Env) encounter states.
• Mapped how bnAbs navigate encounter states to reach their bound states.
• Identified specific Env mutations predicted to select for desired antibody mutations in two HIV-1 bnAb B cell lineages.

Key Points:

• Env mutations were identified that precisely target specific antibody mutations.
• These mutations enhanced antibody affinity and successfully selected for desired antibody mutations in vivo.
• Demonstrated residue-level precision in designing immunogens to direct antibody mutation selection.

Conclusions:

• Proof-of-concept achieved for designing Env immunogens to directly select specific antibody mutations via vaccination.
• Establishes the feasibility of a sequential design approach for bnAb-inducing HIV-1 vaccines.
• Advances the precise engineering of immunogens for targeted antibody responses.