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.

清除原发性丙型肝炎病毒 (HCV) 感染的个体在 80% 以上的情况下可以清除随后的再感染，但其机制尚不清楚。在这里，我们使用来自反复清除的个体的 HCV 变异体和血浆来表征包膜糖蛋白 E2 序列、功能和中和抗体 (NAb) 抗性的纵向变化。感染的清除与早期选择具有 NAb 抗性替代的病毒有关，这种替代也减少了 E2 与 CD81（主要 HCV 受体）的结合。后来，间隙周围血浆样本恢复了针对这些变体的中和能力。我们鉴定了一个广泛的 NAb (bNAb) 子集，这些失去适应性的替代赋予了对未突变的 bNAb 祖先的抗性，但增加了对成熟 bNAb 的敏感性。这些数据证明了中和抗体有助于反复免疫介导的 HCV 清除的机制，从而识别出利用 E2 基本漏洞的特定 bNAb。诱导具有这些特异性的 bNAb 应成为 HCV 疫苗开发的目标。