Hierarchical sequence-affinity landscapes shape the evolution of breadth in an anti-influenza receptor binding site antibody.
Hierarchical sequence-affinity landscapes shape the evolution of breadth in an anti-influenza receptor binding site antibody.
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DOI：
10.7554/elife.83628
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发表时间：
2023-01-10
期刊：
影响因子：
7.7
通讯作者：
Desai, Michael M.
中科院分区：
文献类型：
--
作者：
Phillips, Angela M.;Maurer, Daniel P.;Brooks, Caelan;Dupic, Thomas;Schmidt, Aaron G.;Desai, Michael M.
广泛中和抗体（bnAbs）可以中和一种特定病毒的多种变体，具有相当大的治疗意义。最近的进展使我们能够分离和设计这些抗体作为治疗药物，但通过疫苗接种诱导它们仍然具有挑战性，部分原因是我们对抗体如何进化广度的理解有限。在这里，我们分析了抗流感受体结合位点（RBS） bnAb CH65进化出对多种H1流感毒株的广泛亲和力的景观。我们通过生成未突变共同祖先（UCA）和亲和成熟的CH65抗体之间所有可能的进化中间体的抗体库来做到这一点，并测量每个中间体对三种不同H1抗原的亲和性。我们发现对每个抗原的亲和力需要一组特定的突变-分布在可变的轻链和重链上-非加性相互作用（即，epistatically）。这些突变在抗原上形成了一种等级模式，除了需要结合较少分化抗原的突变外，越来越分化的抗原还需要额外的上位性突变。我们研究了这些分层突变集的潜在生化和结构基础，发现重链突变和VH-VL界面轻链突变之间的上位性对于结合发散H1至关重要。总的来说，这是第一次全面描述重链和轻链突变之间的上位性，并表明这种相互作用既强又广泛。结合我们之前对另一类抗流感抗体的分析，我们的结果表明，上位性是抗体序列亲和力景观的一个普遍特征，可以增强和限制广度的进化。
Broadly neutralizing antibodies (bnAbs) that neutralize diverse variants of a particular virus are of considerable therapeutic interest. Recent advances have enabled us to isolate and engineer these antibodies as therapeutics, but eliciting them through vaccination remains challenging, in part due to our limited understanding of how antibodies evolve breadth. Here, we analyze the landscape by which an anti-influenza receptor binding site (RBS) bnAb, CH65, evolved broad affinity to diverse H1 influenza strains. We do this by generating an antibody library of all possible evolutionary intermediates between the unmutated common ancestor (UCA) and the affinity-matured CH65 antibody and measure the affinity of each intermediate to three distinct H1 antigens. We find that affinity to each antigen requires a specific set of mutations – distributed across the variable light and heavy chains – that interact non-additively (i.e., epistatically). These sets of mutations form a hierarchical pattern across the antigens, with increasingly divergent antigens requiring additional epistatic mutations beyond those required to bind less divergent antigens. We investigate the underlying biochemical and structural basis for these hierarchical sets of epistatic mutations and find that epistasis between heavy chain mutations and a mutation in the light chain at the VH-VL interface is essential for binding a divergent H1. Collectively, this is the first work to comprehensively characterize epistasis between heavy and light chain mutations and shows that such interactions are both strong and widespread. Together with our previous study analyzing a different class of anti-influenza antibodies, our results implicate epistasis as a general feature of antibody sequence-affinity landscapes that can potentiate and constrain the evolution of breadth.
影响因子：
2.9
作者：
Xu, Huafeng;Schmidt, Aaron G.;O'Donnell, Timothy;Therkelsen, Matthew D.;Kepler, Thomas B.;Moody, M. Anthony;Haynes, Barton F.;Liao, Hua-Xin;Harrison, Stephen C.;Shaw, David E.
通讯作者：
Shaw, David E.