The breadth of HIV-1 neutralizing antibodies depends on the conservation of key sites in their epitopes

Developing HIV-1 vaccines that trigger broadly neutralizing antibodies (bnAbs) is a priority as bnAbs are considered key to elicitation of a protective immune response. To investigate whether the breadth of a neutralizing antibody (nAb) depended on the conservation of its epitope among circulating viruses, we examined Antibody:Envelope (Ab:Env) interactions and worldwide Env diversity. We found that sites corresponding to bnAb epitopes were as variable as other accessible, non-hypervariable Env sites (p = 0.50, Mann-Whitney U-test) with no significant relationship between epitope conservation and neutralization breadth (Spearman's rho = -0.44, adjusted p = 0.079). However, when accounting for key sites in the Ab:Env interaction, we showed that the broadest bnAbs targeted more conserved epitopes (Spearman's rho = -0.70, adjusted p = 5.0e-5). Neutralization breadth did not stem from the overall conservation of Ab epitopes but depended instead on the conservation of key sites of the Ab:Env interaction, revealing a mechanistic basis for neutralization breadth that could be exploited for vaccine design. Author summary So far, no HIV-1 vaccine has elicited broadly neutralizing antibodies (bnAbs) in humans. HIV-1, one of the most rapidly evolving pathogens, is remarkable for its high variability across individuals and adaptability within hosts. We tested the relationship between HIV-1 diversity and neutralization breadth. While bnAbs did not specifically target more conserved regions of HIV-1 Env, we found that the broadest bnAbs relied forcibly more on structural interactions at key sites of the Ab:Env interaction than other Abs. Understanding mechanisms underlying neutralization breadth provides guidelines to design more efficacious vaccines and antibody-based therapeutics.