VRC34-Antibody Lineage Development Reveals How a Required Rare Mutation Shapes the Maturation of a Broad HIV-Neutralizing
VRC34-Antibody Lineage Development Reveals How a Required Rare Mutation Shapes the Maturation of a Broad HIV-Neutralizing
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DOI：
10.1016/j.chom.2020.01.027
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发表时间：
2020-04-08
影响因子：
30.3
通讯作者：
Kwong, Peter D.
中科院分区：
文献类型：
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作者：
Shen, Chen-Hsiang;DeKosky, Brandon J.;Kwong, Peter D.
一些罕见的突变被认为可以限制广泛中和的抗HIV-1抗体的发展，但这还没有得到明确的证明。我们假设这种罕见的突变可以通过比较广泛中和和非广泛中和的抗体发育树分支来识别。由于从靶向VRC34抗体谱系的融合肽（FP）中分离的抗体序列表明它可能适合这种罕见的突变分析，我们对来自VRC34谱系来源的供体N123的B细胞转录本进行了下一代测序（NGS），并对沿广泛中和和低中和发育分支推断的中间产物进行了功能和结构表征。广泛中和的VRC34.01分支需要罕见的重链突变Y33P来结合FP，而早期分叉的VRC34.05分支不需要这种罕见的突变，进化的宽度更小。我们的研究结果证明了一个必要的罕见突变如何限制发育和塑造广泛的hiv -1中和抗体谱系的成熟。
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.