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 ρ = -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 ρ = -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.

开发可诱导广泛中和抗体（broadly neutralizing antibodies，bnAbs）的HIV-1疫苗是当前研究的核心要务，因bnAbs被视为诱导保护性免疫应答的关键要素。为探究中和抗体（neutralizing antibody，nAb）的广谱性是否取决于其表位在循环流行毒株中的保守性，我们对抗体-包膜（Antibody:Envelope，Ab:Env）相互作用及全球包膜蛋白（Env）多样性展开了分析。研究发现，对应bnAbs表位的位点，其变异程度与其他可及的非高变包膜蛋白位点无显著差异（曼-惠特尼U检验，p=0.50），且表位保守性与中和抗体广谱性之间未存在显著关联（斯皮尔曼秩相关系数ρ=-0.44，校正后P值=0.079）。不过，当纳入抗体-包膜相互作用的关键位点进行分析时，我们证实广谱性最强的bnAbs所靶向的表位保守性更高（斯皮尔曼秩相关系数ρ=-0.70，校正后P值=5.0e-5）。中和抗体的广谱性并非源自抗体表位的整体保守性，而是取决于抗体-包膜相互作用的关键位点保守性，这一机制可为疫苗设计提供理论指导。