中和抗体利用丙型肝炎病毒（HCV）包膜糖蛋白E2的易损位点进行进化，并介导自发清除感染的病毒，这一成果由美国约翰霍普金斯大学医学院Justin R. Bailey研究小组经过不懈努力而取得。2024年1月2日，《免疫》发表了这一成果。

研究人员利用反复HCV感染康复患者的HCV变体和血浆来揭示包膜糖蛋白E2序列、功能和中和抗体（NAb）抗性的纵向变化。感染清除与早期选择具有NAb抗性替代的病毒有关，这些替代也减少了E2与主要HCV受体CD81的结合。随后，清除期血浆样本恢复了对这些变体的中和能力。

研究发现了广义NAbs（bNAbs）的一个子集，这些适配性缺失替代赋予这些子集对未变异bNAb的抗性，但却增加了对成熟bNAbs的敏感性。这些数据证明了中和抗体有助于重复免疫介导的HCV清除，并揭示特异性bNAbs利用了E2的基本易损性。该研究表明这些特异性的bNAbs具有成为HCV疫苗的潜力。

据悉，80%以上原发性HCV感染康复的患者都能清除随后再次感染的病毒，但不清楚其机制。

附：英文原文

Title: Neutralizing antibodies evolve to exploit vulnerable sites in the HCV envelope glycoprotein E2 and mediate spontaneous clearance of infection

Author: Nicole Frumento, Ariadne Sinnis-Bourozikas, Harry T. Paul, Georgia Stavrakis, Muhammad N. Zahid, Shuyi Wang, Stuart C. Ray, Andrew I. Flyak, George M. Shaw, Andrea L. Cox, Justin R. Bailey

Issue&Volume: 2024-01-02

Abstract: Individuals who clear primary hepatitis C virus (HCV) infections clear subsequent reinfections more than 80% of the time, but the mechanisms are poorly defined. Here, we used HCV variants and plasma from individuals with repeated clearance to characterize longitudinal changes in envelope glycoprotein E2 sequences, function, and neutralizing antibody (NAb) resistance. Clearance of infection was associated with early selection of viruses with NAb resistance substitutions that also reduced E2 binding to CD81, the primary HCV receptor. Later, peri-clearance plasma samples regained neutralizing capacity against these variants. We identified a subset of broadly NAbs (bNAbs) for which these loss-of-fitness substitutions conferred resistance to unmutated bNAb ancestors but increased sensitivity to mature bNAbs. These data demonstrate a mechanism by which neutralizing antibodies contribute to repeated immune-mediated HCV clearance, identifying specific bNAbs that exploit fundamental vulnerabilities in E2. The induction of bNAbs with these specificities should be a goal of HCV vaccine development.

DOI: 10.1016/j.immuni.2023.12.004

Source: https://www.cell.com/immunity/fulltext/S1074-7613(23)00535-6