U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States of America.
Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States of America.
PLoS Comput Biol. 2019 Jun 6;15(6):e1007056. doi: 10.1371/journal.pcbi.1007056. eCollection 2019 Jun.
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.
开发能够引发广泛中和抗体 (bnAbs) 的 HIV-1 疫苗是当务之急，因为 bnAbs 被认为是引发保护性免疫反应的关键。为了研究中和抗体 (nAb) 的广谱性是否取决于其表位在循环病毒中的保守性，我们研究了抗体:包膜 (Ab:Env) 相互作用和全球Env 多样性。我们发现，与其他可及的、非超变 Env 位点相比，对应 bnAb 表位的位点具有相同的变异性（p = 0.50，Mann-Whitney U 检验），表位保守性与中和广度之间没有显著关系（Spearman's ρ = -0.44，调整后 p = 0.079）。然而，当考虑到 Ab:Env 相互作用中的关键位点时，我们表明最广泛的 bnAbs 针对更保守的表位（Spearman's ρ = -0.70，调整后 p = 5.0e-5）。中和广度并非源于 Ab 表位的整体保守性，而是取决于 Ab:Env 相互作用的关键位点的保守性，这揭示了中和广度的机制基础，可以被用于疫苗设计。
