Hepatitis B virus-specific T cells associate with viral control upon nucleos(t)ide-analogue therapy discontinuation
Hepatitis B virus-specific T cells associate with viral control upon nucleos(t)ide-analogue therapy discontinuation
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DOI：
10.1172/jci92812
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发表时间：
2018-02-01
影响因子：
15.9
通讯作者：
Bertoletti, Antonio
中科院分区：
文献类型：
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作者：
Rivino, Laura;Le Bert, Nina;Bertoletti, Antonio
背景慢性B型肝炎病毒（HBV）患者的临床管理完全基于病毒学参数，这些参数不能独立确定哪些患者可以安全地停止核苷（酸）类似物（NUC）治疗。NUC有效抑制病毒复制，但不能消除HBV。因此，治疗中断可能与病毒学和生化复发有关，因此，大多数治疗是终身的。由于抗病毒免疫是HBV控制的关键，我们研究了慢性HBV患者免疫特征中安全停用NUC的潜在生物标志物，方法是利用传统免疫学检测（ELISPOT，流式细胞术）结合全球非抗原特异性免疫群体（NanoString和CyTOF）分析。分别对19例和27例慢性HBV患者的两个不同队列在2种不同NUC治疗策略停药前后进行纵向分析。在NUC病毒抑制期间，NUC治疗停止后肝耀斑的消失与离体PD-1（+）人群中包含的HBV核心和聚合酶特异性T细胞的存在相关。这项研究确定了功能性HBV特异性T细胞的存在作为慢性HBV患者安全停药的候选免疫学生物标志物。此外，PD-1（+）HBV特异性T细胞的持久和功能性抗病毒活性突出了T细胞耗竭标志物表达在人类慢性病毒感染期间的潜在有益作用。
BACKGROUND. The clinical management of chronic hepatitis B virus (HBV) patients is based exclusively on virological parameters that cannot independently determine in which patients nucleos(t)ide-analogue (NUC) therapy can be safely discontinued. NUCs efficiently suppress viral replication, but do not eliminate HBV. Thus, therapy discontinuation can be associated with virological and biochemical relapse and, consequently, therapy in the majority is life-long.METHODS. Since antiviral immunity is pivotal for HBV control, we investigated potential biomarkers for the safe discontinuation of NUCs within immune profiles of chronic HBV patients by utilizing traditional immunological assays (ELISPOT, flow cytometry) in conjunction with analyses of global non-antigen-specific immune populations (NanoString and CyTOF). Two distinct cohorts of 19 and 27 chronic HBV patients, respectively, were analyzed longitudinally prior to and after discontinuation of 2 different NUC therapy strategies.RESULTS. Absence of hepatic flares following discontinuation of NUC treatment correlated with the presence, during NUC viral suppression, of HBV core and polymerase-specific T cells that were contained within the ex vivo PD-1(+) population.CONCLUSIONS. This study identifies the presence of functional HBV-specific T cells as a candidate immunological biomarker for safe therapy discontinuation in chronic HBV patients. Furthermore, the persistent and functional antiviral activity of PD-1(+) HBV-specific T cells highlights the potential beneficial role of the expression of T cell exhaustion markers during human chronic viral infection.