Division of Infectious diseases, Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
Yerkes National Primate Research Center, Emory Vaccine Center, Atlanta, Georgia, USA.
J Clin Invest. 2021 Jan 19;131(2). doi: 10.1172/JCI140590.
Early appearance of neutralizing antibodies during acute hepatitis C virus (HCV) infection is associated with spontaneous viral clearance. However, the longitudinal changes in antigen-specific memory B cell (MBCs) associated with divergent HCV infection outcomes remain undefined. We characterized longitudinal changes in E2 glycoprotein-specific MBCs from subjects who either spontaneously resolved acute HCV infection or progressed to chronic infection, using single-cell RNA-seq and functional assays. HCV-specific antibodies in plasma from chronically infected subjects recognized multiple E2 genotypes, while those from spontaneous resolvers exhibited variable cross-reactivity to heterotypic E2. E2-specific MBCs from spontaneous resolvers peaked early after infection (4-6 months), following expansion of activated circulating T follicular helper cells (cTfh) expressing interleukin 21. In contrast, E2-specific MBCs from chronically infected subjects, enriched in VH1-69, expanded during persistent infection (> 1 year), in the absence of significantly activated cTfh expansion. Early E2-specific MBCs from spontaneous resolvers produced monoclonal antibodies (mAbs) with fewer somatic hypermutations and lower E2 binding but similar neutralization as mAbs from late E2-specific MBCs of chronically infected subjects. These findings indicate that early cTfh activity accelerates expansion of E2-specific MBCs during acute infection, which might contribute to spontaneous clearance of HCV.
急性丙型肝炎病毒 (HCV) 感染期间中和抗体的早期出现与自发病毒清除有关。然而，与不同 HCV 感染结局相关的抗原特异性记忆 B 细胞 (MBC) 的纵向变化仍未定义。我们使用单细胞 RNA-seq 和功能测定法，从自发清除急性 HCV 感染或进展为慢性感染的受试者中，对 E2 糖蛋白特异性 MBC 的纵向变化进行了描述。慢性感染受试者血浆中的 HCV 特异性抗体可识别多种 E2 基因型，而自发缓解者的抗体则对异型 E2 表现出可变的交叉反应性。自发缓解者的 E2 特异性 MBC 在感染后早期（4-6 个月）达到峰值，随后表达白细胞介素 21 的循环滤泡辅助 T 细胞 (cTfh) 扩增。相比之下，慢性感染受试者的 E2 特异性 MBC 富含 VH1-69，在无明显激活的 cTfh 扩增的情况下，在持续感染期间（>1 年）扩增。自发缓解者早期的 E2 特异性 MBC 产生的单克隆抗体 (mAb) 具有较少的体细胞超突变和较低的 E2 结合能力，但与慢性感染受试者晚期的 E2 特异性 MBC 产生的 mAb 具有相似的中和活性。这些发现表明，早期的 cTfh 活性加速了急性感染期间 E2 特异性 MBC 的扩增，这可能有助于 HCV 的自发清除。
