Immune and Viral Profile from Tolerance to Hepatitis B Surface Antigen Clearance: a Longitudinal Study of Vertically Hepatitis B Virus-Infected Children on Combined Therapy
Immune and Viral Profile from Tolerance to Hepatitis B Surface Antigen Clearance: a Longitudinal Study of Vertically Hepatitis B Virus-Infected Children on Combined Therapy
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DOI：
10.1128/jvi.01449-10
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发表时间：
2011-03-01
影响因子：
5.4
通讯作者：
Vergani, Diego
中科院分区：
文献类型：
--
作者：
Carey, Ivana;D'Antiga, Lorenzo;Vergani, Diego
该研究的目的是纵向调查耐受儿童在联合抗病毒治疗期间乙型肝炎病毒（HBV）特异性t细胞反应性和病毒行为与治疗反应的关系。23名患有婴儿获得性乙型肝炎（HBeAg+）的儿童参加了一项已发表的拉米夫定/ α干扰素（ifn - α）治疗1年的试点研究。5例血清转化为抗hbs（应答者）。9例为HLA-A2(+)（4例有反应，5例无反应）。在基线时通过直接测序在肝脏和系列血清样本中确定HBV核心基因的突变；治疗第2周（TW2）、TW9、TW28、TW52；随访第24周（FUW24）和FUW52周。通过t细胞增殖16个HBV核心20-mer重叠肽，hla - a2限制性核心（18-27）五聚体染色和CD8(+) ifn - γ酶联免疫斑点（ELISPOT）检测来评估HBV特异性反应性。在TW28和TW52时，应答者中HBV核心特异性t细胞增殖和CD8反应比无应答者更强烈和更广泛，而在TW28时，HBV核心基因免疫显性表位的突变数量较低，并且在两个时间点与HBV特异性t细胞增殖反应呈负相关。在治疗期间，HBV DNA病毒载量与HBV特异性t细胞增殖和CD8反应呈负相关，特别是在TW28。治疗诱导的从免疫耐受到HBV免疫控制的转变的特点是出现了有效的病毒特异性免疫反应，能够抑制突变并防止病毒逃逸。
The aim of the study was to investigate longitudinally hepatitis B virus (HBV)-specific T-cell reactivity and viral behavior versus treatment response in tolerant children during combined antiviral therapy. Twenty-three children with infancy-acquired hepatitis B (HBeAg+) belonging to a published pilot study of 1-year treatment with lamivudine/alpha interferon (IFN-alpha) were investigated. Five seroconverted to anti-HBs (responders). Nine were HLA-A2(+) (4 responders and 5 nonresponders). Mutations within the HBV core gene were determined at baseline in liver and in serial serum samples by direct sequencing at baseline; during treatment week 2 (TW2), TW9, TW28, and TW52; and after follow-up week 24 (FUW24) and FUW52. HBV-specific reactivity was evaluated by T-cell proliferation with 16 HBV core 20-mer overlapping peptides and by HLA-A2-restricted core(18-27) pentamer staining and CD8(+) IFN-gamma enzyme-linked immunospot (ELISPOT) assay. HBV core-specific T-cell proliferative and CD8 responses were more vigorous and broader among responders than among nonresponders at TW28 and TW52, while the number of mutations within HBV core gene immunodominant epitopes was lower at TW28 and was negatively associated with HBV-specific T-cell proliferative responses at both time points. The HBV DNA viral load was negatively associated with HBV-specific T-cell proliferative and CD8 responses during treatment, especially at TW28. Treatment-induced transition from immunotolerance to HBV immune control is characterized by the emergence of efficient virus-specific immune responses capable of restraining mutations and preventing viral evasion.