Analysis of antibodies from HCV elite neutralizers identifies genetic determinants of broad neutralization.
Analysis of antibodies from HCV elite neutralizers identifies genetic determinants of broad neutralization.
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DOI：
10.1016/j.immuni.2021.12.003
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发表时间：
2022-02-08
期刊：
影响因子：
32.4
通讯作者：
Klein, Florian
中科院分区：
文献类型：
--
作者：
Weber, Timm;Potthoff, Julian;Bizu, Sven;Labuhn, Maurice;Dold, Leona;Schoofs, Till;Horning, Marcel;Ercanoglu, Meryem S.;Kreer, Christoph;Gieselmann, Lutz;Vanshylla, Kanika;Langhans, Bettina;Janicki, Hanna;Stroeh, Luisa J.;Knops, Elena;Nierhoff, Dirk;Spengler, Ulrich;Kaiser, Rolf;Bjorkman, Pamela J.;Krey, Thomas;Bankwitz, Dorothea;Pfeifer, Nico;Pietschmann, Thomas;Flyak, Andrew, I;Klein, Florian
丙型肝炎病毒（HCV）的高度遗传多样性使有效疫苗的开发变得复杂。我们对435名HCV感染者进行了筛查，发现2%-5%的人表现出出色的HCV中和活性。从其中4名患者中，我们分离出310种HCV抗体，包括具有特殊广度和效力的中和抗体。通过使用VH 1 -69重链基因区段、CDRH 1内的体细胞突变和CDRH 2疏水性实现了高中和活性。结构和突变分析揭示了在位置30和31处替换丝氨酸的突变的重要作用，以及在CDRH 3的尖端处存在中性和疏水残基。基于这些特征，我们通过计算创建了具有完全合成的VH 1 -69重链的从头抗体，其有效地中和多种HCV基因型。我们的研究结果提供了对广泛HCV中和抗体产生的深入理解，这些抗体可以指导有效候选疫苗的设计。广泛中和抗体（bNAb）可以保护免受HCV感染，但对其发展和具体特征知之甚少。Weber、Potthoff等人从具有异常HCV抗体应答的个体中分离出有效的HCV bNAb，并确定了高中和活性的遗传要求。基于这些数据，他们通过计算设计了一种从头抗体，可以有效地中和多种HCV基因型。
The high genetic diversity of hepatitis C virus (HCV) complicates effective vaccine development. We screened a cohort of 435 HCV-infected individuals and found that 2%–5% demonstrated outstanding HCV-neutralizing activity. From four of these patients, we isolated 310 HCV antibodies, including neutralizing antibodies with exceptional breadth and potency. High neutralizing activity was enabled by the use of the VH1-69 heavy-chain gene segment, somatic mutations within CDRH1, and CDRH2 hydrophobicity. Structural and mutational analyses revealed an important role for mutations replacing the serines at positions 30 and 31, as well as the presence of neutral and hydrophobic residues at the tip of the CDRH3. Based on these characteristics, we computationally created a de novo antibody with a fully synthetic VH1-69 heavy chain that efficiently neutralized multiple HCV genotypes. Our findings provide a deep understanding of the generation of broadly HCV-neutralizing antibodies that can guide the design of effective vaccine candidates. Broadly neutralizing antibodies (bNAbs) can protect from HCV infection, but little is known about their development and specific characteristics. Weber, Potthoff et al. isolated potent HCV bNAbs from individuals with exceptional HCV antibody responses and determined the genetic requirements for high neutralizing activity. Based on these data, they computationally designed a de novo antibody that efficiently neutralized multiple HCV genotypes.
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影响因子：
7.7
作者：
Flyak, Andrew, I;Ruiz, Stormy E.;Bjorkman, Pamela J.
通讯作者：
Bjorkman, Pamela J.
影响因子：
32.4
作者：
Chen F;Tzarum N;Lin X;Giang E;Velázquez-Moctezuma R;Augestad EH;Nagy K;He L;Hernandez M;Fouch ME;Grinyó A;Chavez D;Doranz BJ;Prentoe J;Stanfield RL;Lanford R;Bukh J;Wilson IA;Zhu J;Law M
通讯作者：
Law M
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
56.9
作者：
Haynes, BF;Fleming, J;Alam, SM
通讯作者：
Alam, SM
影响因子：
8
作者：
Bailey, Justin R.;Flyak, Andrew I.;Crowe, James E., Jr.
通讯作者：
Crowe, James E., Jr.