Hidden Lineage Complexity of Glycan-Dependent HIV-1 Broadly Neutralizing Antibodies Uncovered by Digital Panning and Native-Like gp140 Trimer.
Hidden Lineage Complexity of Glycan-Dependent HIV-1 Broadly Neutralizing Antibodies Uncovered by Digital Panning and Native-Like gp140 Trimer.
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基团依赖性HIV-1的隐藏谱系复杂性广泛中和抗体，被数字平鸟和类似天然的GP140夹子发现。
DOI：
10.3389/fimmu.2017.01025
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发表时间：
2017
影响因子：
7.3
通讯作者：
Zhu J
中科院分区：
文献类型：
--
作者：
He L;Lin X;de Val N;Saye-Francisco KL;Mann CJ;Augst R;Morris CD;Azadnia P;Zhou B;Sok D;Ozorowski G;Ward AB;Burton DR;Zhu J
广谱中和抗体(BNAbs)的种系前体和中间体对于理解对HIV-1感染的体液反应和B细胞系疫苗的设计是必不可少的。使用一个天然的gp140三聚体探针，我们检查了从供体-17构建的抗体库，供体-17是识别HIV-1包膜糖蛋白上的N332超级位点的糖依赖的PGT121类bNAbs的来源。为了便于这一分析，设计了一种数字淘选方法，该方法结合了噬菌体展示抗体库的生物扫描、900 bp的长读下一代测序以及重/轻(H/L)成对的抗体组学。除了与野生型bNAbs相似的单链可变片段外，数字平移还发现了PGT124(PGT121类成员)的变异体，在重链互补决定区1中有一个独特的插入，以及PGT124的中间体，显示出与天然三聚体和广泛的HIV-1中和显著的亲和力。在竞争分析中，这些bNAb中间体可以有效地与支架BG505 gp140.681三聚体诱导的小鼠血清竞争N332超位点。因此，我们的研究揭示了以前未知的PGT121类bNAbs的谱系复杂性，并提供了一系列文库衍生的bNAb中间体，用于评估包含N332超位点的免疫原。数字平移可能被证明是未来研究bNAb多样性和谱系发展的一个有价值的工具。
Germline precursors and intermediates of broadly neutralizing antibodies (bNAbs) are essential to the understanding of humoral response to HIV-1 infection and B-cell lineage vaccine design. Using a native-like gp140 trimer probe, we examined antibody libraries constructed from donor-17, the source of glycan-dependent PGT121-class bNAbs recognizing the N332 supersite on the HIV-1 envelope glycoprotein. To facilitate this analysis, a digital panning method was devised that combines biopanning of phage-displayed antibody libraries, 900 bp long-read next-generation sequencing, and heavy/light (H/L)-paired antibodyomics. In addition to single-chain variable fragments resembling the wild-type bNAbs, digital panning identified variants of PGT124 (a member of the PGT121 class) with a unique insertion in the heavy chain complementarity-determining region 1, as well as intermediates of PGT124 exhibiting notable affinity for the native-like trimer and broad HIV-1 neutralization. In a competition assay, these bNAb intermediates could effectively compete with mouse sera induced by a scaffolded BG505 gp140.681 trimer for the N332 supersite. Our study thus reveals previously unrecognized lineage complexity of the PGT121-class bNAbs and provides an array of library-derived bNAb intermediates for evaluation of immunogens containing the N332 supersite. Digital panning may prove to be a valuable tool in future studies of bNAb diversity and lineage development.
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影响因子：
64.5
作者：
Briney, Bryan;Sok, Devin;Jardine, Joseph G.;Kulp, Daniel W.;Skog, Patrick;Menis, Sergey;Jacak, Ronald;Kalyuzhniy, Oleksandr;de Val, Natalia;Sesterhenn, Fabian;Le, Khoa M.;Ramos, Alejandra;Jones, Meaghan;Saye-Francisco, Karen L.;Blane, Tanya R.;Spencer, Skye;Georgeson, Erik;Hu, Xiaozhen;Ozorowski, Gabriel;Adachi, Yumiko;Kubitz, Michael;Sarkar, Anita;Wilson, Ian A.;Ward, Andrew B.;Nemazee, David;Burton, Dennis R.;Schief, William R.
通讯作者：
Schief, William R.
影响因子：
6.7
作者：
Derking R;Ozorowski G;Sliepen K;Yasmeen A;Cupo A;Torres JL;Julien JP;Lee JH;van Montfort T;de Taeye SW;Connors M;Burton DR;Wilson IA;Klasse PJ;Ward AB;Moore JP;Sanders RW
通讯作者：
Sanders RW
影响因子：
32.4
作者：
Falkowska, Emilia;Le, Khoa M.;Ramos, Alejandra;Doores, Katie J.;Lee, Jeong Hyun;Blattner, Claudia;Ramirez, Alejandro;Derking, Ronald;van Gils, Marit J.;Liang, Chi-Hui;Mcbride, Ryan;von Bredow, Benjamin;Shivatare, Sachin S.;Wu, Chung-Yi;Chan-Hui, Po-Ying;Liu, Yan;Feizi, Ten;Zwick, Michael B.;Koff, Wayne C.;Seaman, Michael S.;Swiderek, Kristine;Moore, John P.;Evans, David;Paulson, James C.;Wong, Chi-Huey;Ward, Andrew B.;Wilson, Ian A.;Sanders, Rogier W.;Poignard, Pascal;Burton, Dennis R.
通讯作者：
Burton, Dennis R.
影响因子：
56.9
作者：
BURTON, DR;PYATI, J;BARBAS, CF
通讯作者：
BARBAS, CF
影响因子：
64.5
作者：
Garces F;Sok D;Kong L;McBride R;Kim HJ;Saye-Francisco KF;Julien JP;Hua Y;Cupo A;Moore JP;Paulson JC;Ward AB;Burton DR;Wilson IA
通讯作者：
Wilson IA