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

Area of Science:

• Immunology and Virology
• Vaccine Design and Development
• Computational Biology

Background:

• Rapidly evolving pathogens like HIV-1 necessitate vaccines that elicit broadly neutralizing antibodies (bnAbs).
• Current methods for identifying immunogen modifications to select for specific bnAb mutations are imprecise.
• Achieving conserved paratopes and specific Ig-heavy chain mutations is crucial for bnAb induction.

Purpose of the Study:

• To precisely engineer bnAb-boosting immunogens for HIV-1 vaccine development.
• To identify specific mutations in the HIV-1 Envelope (Env) that select for desired antibody mutations.
• To demonstrate the feasibility of residue-level precision in designing sequential bnAb-inducing vaccines.

Main Methods:

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

Main Results:

• Identified Env mutations that confer antibody affinity gains.
• Demonstrated in vivo selection of desired antibody mutations through engineered Env immunogens.
• Env mutations were predicted to select for specific antibody mutations at residue-level precision.

Conclusions:

• Env immunogens can be precisely designed to directly select for specific antibody mutations via vaccination.
• This approach provides a proof-of-concept for sequential bnAb-inducing HIV-1 vaccine design.
• Molecular dynamics simulations offer a precise method for engineering bnAb-boosting immunogens.