Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Department of Chemical & Petroleum Engineering and Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS 66045, USA.
Cell Host Microbe. 2020 Apr 8;27(4):531-543.e6. doi: 10.1016/j.chom.2020.01.027. Epub 2020 Mar 3.
Rare mutations have been proposed to restrict the development of broadly neutralizing antibodies against HIV-1, but this has not been explicitly demonstrated. We hypothesized that such rare mutations might be identified by comparing broadly neutralizing and non-broadly neutralizing branches of an antibody-developmental tree. Because sequences of antibodies isolated from the fusion peptide (FP)-targeting VRC34-antibody lineage suggested it might be suitable for such rare mutation analysis, we carried out next-generation sequencing (NGS) on B cell transcripts from donor N123, the source of the VRC34 lineage, and functionally and structurally characterized inferred intermediates along broadly neutralizing and poorly neutralizing developmental branches. The broadly neutralizing VRC34.01 branch required the rare heavy-chain mutation Y33P to bind FP, whereas the early bifurcated VRC34.05 branch did not require this rare mutation and evolved less breadth. Our results demonstrate how a required rare mutation can restrict development and shape the maturation of a broad HIV-1-neutralizing antibody lineage.
已经有人提出稀有突变可以限制针对 HIV-1 的广谱中和抗体的产生，但这一点尚未得到明确证明。我们假设，通过比较抗体发育树的广谱中和分支和非广谱中和分支，可能会发现此类稀有突变。由于从融合肽（FP）靶向 VRC34 抗体谱系中分离出的抗体的序列表明，它可能适合进行此类稀有突变分析，因此我们对供体 N123（VRC34 谱系的来源）的 B 细胞转录本进行了下一代测序（NGS），并对广谱中和和中和能力差的发育分支上的推断中间体进行了功能和结构表征。广谱中和的 VRC34.01 分支需要稀有重链突变 Y33P 来结合 FP，而早期分叉的 VRC34.05 分支则不需要这种稀有突变，并且进化的广度较小。我们的研究结果表明，必需的稀有突变如何限制发展并塑造广谱 HIV-1 中和抗体谱系的成熟。
