Department of Medical Microbiology and Infection Prevention, Laboratory of Experimental Virology, Amsterdam UMC, University of Amsterdam, 1105, AZ, Amsterdam, Netherlands.
Amsterdam Institute for Infection and Immunity, Infectious Diseases, 1105, AZ, Amsterdam, Netherlands.
Nat Commun. 2023 Jul 7;14(1):4036. doi: 10.1038/s41467-023-39690-0.
An effective preventive vaccine for hepatitis C virus (HCV) remains a major unmet need. Antigenic region 3 (AR3) on the E1E2 envelope glycoprotein complex overlaps with the CD81 receptor binding site and represents an important epitope for broadly neutralizing antibodies (bNAbs) and is therefore important for HCV vaccine design. Most AR3 bNAbs utilize the V1-69 gene and share structural features that define the AR3C-class of HCV bNAbs. In this work, we identify recombinant HCV glycoproteins based on a permuted E2E1 trimer design that bind to the inferred V1-69 germline precursors of AR3C-class bNAbs. When presented on nanoparticles, these recombinant E2E1 glycoproteins efficiently activate B cells expressing inferred germline AR3C-class bNAb precursors as B cell receptors. Furthermore, we identify critical signatures in three AR3C-class bNAbs that represent two subclasses of AR3C-class bNAbs that will allow refined protein design. These results provide a framework for germline-targeting vaccine design strategies against HCV.
一种有效的丙型肝炎病毒 (HCV) 预防性疫苗仍然是一个主要的未满足需求。E1E2 包膜糖蛋白复合物上的抗原区 3 (AR3) 与 CD81 受体结合位点重叠，是广泛中和抗体 (bNAb) 的重要表位，因此对 HCV 疫苗设计很重要。大多数 AR3 bNAb 利用 V1-69 基因，并具有定义 AR3C 类 HCV bNAb 的结构特征。在这项工作中，我们基于改组的 E2E1 三聚体设计鉴定了结合 AR3C 类 bNAb 假定 V1-69 种系前体的重组 HCV 糖蛋白。当在纳米颗粒上呈现时，这些重组 E2E1 糖蛋白能够有效地激活表达推断的 AR3C 类 bNAb 前体作为 B 细胞受体的 B 细胞。此外，我们鉴定了三种 AR3C 类 bNAb 中的关键特征，这些特征代表了 AR3C 类 bNAb 的两个亚类，这将允许对蛋白质进行精细设计。这些结果为针对 HCV 的种系靶向疫苗设计策略提供了框架。
