Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom.
CEINGE-Advanced Biotechnologies, Naples, Italy.
Hepatology. 2020 Nov;72(5):1541-1555. doi: 10.1002/hep.31160.
Induction of functional helper CD4 T cells is the hallmark of a protective immune response against hepatitis C virus (HCV), associated with spontaneous viral clearance. Heterologous prime/boost viral vectored vaccination has demonstrated induction of broad and polyfunctional HCV-specific CD8 T cells in healthy volunteers; however, much less is known about CD4 T-cell subsets following vaccination.
We analyzed HCV-specific CD4 T-cell populations using major histocompatibility complex class II tetramers in volunteers undergoing HCV vaccination with recombinant HCV adenoviral/modified vaccinia Ankara viral vectors. Peptide-specific T-cell responses were tracked over time, and functional (proliferation and cytokine secretion) and phenotypic (cell surface and intranuclear) markers were assessed using flow cytometry. These were compared to CD4 responses in 10 human leukocyte antigen-matched persons with HCV spontaneous resolution and 21 chronically infected patients treated with directly acting antiviral (DAA) therapy. Vaccination induced tetramer-positive CD4 T cells that were highest 1-4 weeks after boosting (mean, 0.06%). Similar frequencies were obtained for those tracked following spontaneous resolution of disease (mean, 0.04%). In addition, the cell-surface phenotype (CD28, CD127) memory subset markers and intranuclear transcription factors, as well as functional capacity of peptide-specific CD4 T-cell responses characterized after vaccination, are comparable to those following spontaneous viral resolution. In contrast, helper responses in chronic infection were infrequently detected and poorly functional and did not consistently recover following HCV cure.
Helper CD4 T-cell phenotype and function following HCV viral vectored vaccination resembles "protective memory" that is observed following spontaneous clearance of HCV. DAA cure does not promote resurrection of exhausted CD4 T-cell memory in chronic infection.
诱导功能性辅助性 CD4 T 细胞是针对丙型肝炎病毒（HCV）产生保护性免疫反应的标志，与自发性病毒清除有关。异源初免/加强病毒载体疫苗接种已证明可在健康志愿者中诱导广泛的、多功能的 HCV 特异性 CD8 T 细胞；然而，对于接种疫苗后 CD4 T 细胞亚群的了解要少得多。
我们使用主要组织相容性复合物 II 四聚体分析了接受 HCV 重组腺病毒/改良安卡拉痘苗病毒载体疫苗接种的志愿者中的 HCV 特异性 CD4 T 细胞群体。随着时间的推移跟踪肽特异性 T 细胞反应，并使用流式细胞术评估功能（增殖和细胞因子分泌）和表型（细胞表面和核内）标志物。将这些与 10 名具有 HLA 匹配的 HCV 自发性缓解者和 21 名接受直接作用抗病毒（DAA）治疗的慢性感染患者的 CD4 反应进行比较。疫苗接种诱导的四聚体阳性 CD4 T 细胞在加强后 1-4 周最高（平均 0.06%）。对于跟踪疾病自发性缓解的细胞（平均 0.04%），也获得了相似的频率。此外，在接种疫苗后，CD4 特异性 T 细胞反应的细胞表面表型（CD28、CD127）记忆亚群标志物和核内转录因子以及功能能力与自发性病毒清除后相似。相比之下，慢性感染中的辅助反应很少被检测到，且功能较差，并且在 HCV 治愈后并未持续恢复。
HCV 病毒载体疫苗接种后的辅助性 CD4 T 细胞表型和功能类似于 HCV 自发性清除后观察到的“保护性记忆”。DAA 治愈不会促进慢性感染中耗尽的 CD4 T 细胞记忆的复活。
