HCV中和抗体的分析揭示广泛中和的遗传决定因素
2022-01-09   阅读:355   来源:细胞

德国科隆大学Florian Klein研究团队通过分析丙型肝炎病毒(HCV)的中和抗体揭示广泛中和的遗传决定因素。相关论文于2022年1月5日在线发表于国际学术期刊《免疫》。

研究人员对435名丙型肝炎病毒(HCV)感染者的队列进行了筛选,发现2%-5%的人表现出突出的HCV中和活性。从这些患者中的四位,研究人员分离出310个HCV抗体,包括具有特殊广度和效力的中和抗体。高中和活性是通过使用VH1-69重链基因段、CDRH1内的体细胞突变和CDRH2的疏水性实现的。结构和突变分析显示,取代第30和31位丝氨酸的突变具有重要作用,而且CDRH3顶端存在中性和疏水性残基。

基于这些特征,研究人员通过计算创建了一个具有完全合成的VH1-69重链的新抗体,它能有效地中和多种HCV基因型。这些发现使人们对广泛HCV中和抗体的产生有了深入的了解,并可以指导有效候选疫苗的设计。

据悉,HCV的高度遗传多样性使有效的疫苗开发变得复杂。

附:英文原文

Title: Analysis of antibodies from HCV elite neutralizers identifies genetic determinants of broad neutralization

Author: Timm Weber, Julian Potthoff, Sven Bizu, Maurice Labuhn, Leona Dold, Till Schoofs, Marcel Horning, Meryem S. Ercanoglu, Christoph Kreer, Lutz Gieselmann, Kanika Vanshylla, Bettina Langhans, Hanna Janicki, Luisa J. Strh, Elena Knops, Dirk Nierhoff, Ulrich Spengler, Rolf Kaiser, Pamela J. Bjorkman, Thomas Krey, Dorothea Bankwitz, Nico Pfeifer, Thomas Pietschmann, Andrew I. Flyak, Florian Klein

Issue&Volume: 2022-01-05

Abstract: The high genetic diversity of hepatitis C virus (HCV) complicates effective vaccinedevelopment. We screened a cohort of 435 HCV-infected individuals and found that 2%–5%demonstrated outstanding HCV-neutralizing activity. From four of these patients, weisolated 310 HCV antibodies, including neutralizing antibodies with exceptional breadthand 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 replacingthe serines at positions 30 and 31, as well as the presence of neutral and hydrophobicresidues at the tip of the CDRH3. Based on these characteristics, we computationallycreated a de novo antibody with a fully synthetic VH1-69 heavy chain that efficiently neutralized multiple HCV genotypes. Our findings providea deep understanding of the generation of broadly HCV-neutralizing antibodies thatcan guide the design of effective vaccine candidates.

DOI: 10.1016/j.immuni.2021.12.003

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