Antibody Lineages with Vaccine-Induced Antigen-Binding Hotspots Develop Broad HIV Neutralization.

Area of Science:

• Immunology
• Virology
• Vaccine Development

Background:

• Eliciting broadly neutralizing antibodies (bNAbs) against diverse HIV-1 strains via vaccination remains a significant challenge.
• Understanding the mechanisms for inducing bNAbs is crucial for effective HIV vaccine design.

Purpose of the Study:

• To identify, characterize, and track antibody lineages targeting the HIV-1 fusion peptide (FP) in vaccinated macaques.
• To determine if priming with FP can induce broadly neutralizing antibodies (bNAbs).

Main Methods:

• Vaccination of macaques with FP-carrier constructs and envelope (Env)-trimer boosts.
• Genetic and structural analyses of antibody lineages.
• B cell analysis to track antibody initiation and expansion.
• Assessment of antibody neutralization breadth against diverse HIV-1 strains.

Main Results:

• Five neutralizing antibody (Ab) lineages targeting the FP were identified and tracked.
• Two lineages demonstrated reproducible broad neutralization, effective against 59% of 208 diverse HIV-1 strains.
• FP-carrier priming initiated and expanded all five lineages, with Env-trimer boosts inducing cross-reactive neutralization.
• Abs elicited by FP-priming showed binding-energy hotspots focused on FP, unlike Abs from Env-trimer-only immunization.

Conclusions:

• Priming with conserved subregions like the HIV-1 FP can induce antibodies with binding-energy hotspots at the target site.
• This priming strategy leads to antibodies capable of broad neutralization against diverse HIV-1 strains.
• FP-directed bNAbs represent a promising avenue for HIV vaccine development.