Immune and Viral Profile from Tolerance to Hepatitis B Surface Antigen Clearance

StephenW

<http://jvi.asm.org/cgi/content/abstract/85/5/2416>

Journal of Virology, March 2011, p. 2416-2428, Vol. 85, No. 5
0022-538X/11/$012.00+0     doi:10.1128/JVI.01449-10
Copyright © 2011, American Society for Microbiology. All Rights Reserved.

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
Ivana Carey,1 Lorenzo D'Antiga,1 Sanjay Bansal,1 Maria Serena Longhi,1 Yun Ma,1
Irene Rebollo Mesa,2 Giorgina Mieli-Vergani,1 and Diego Vergani1*

Institute of Liver Studies and Paediatric Liver Centre, King's College London
School of Medicine at King's College Hospital, Denmark Hill, London SE5 9RS,
United Kingdom,1 MRC Centre for Transplantation, King's College London School of
Medicine at Guy's Hospital, St. Thomas Street, London, SE1 9RT, United Kingdom2

Received 12 July 2010/ Accepted 2 December 2010

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-) 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 core18-27 pentamer
staining and CD8+ IFN- 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.

菀凯里，一德Antiga洛伦佐，1邦萨尔桑杰，1玛丽亚小威隆吉，1恽码，1
艾琳Rebollo梅萨，2 Giorgina Mieli - Vergani，1和迭戈Vergani1 *

研究所的研究和儿科肝肝中心，伦敦大学国王学院
学校在国王学院医院，丹麦Hill，伦敦SE5 9RS医药，
英国，1个移植，伦敦大学国王学院医学研究委员会中心学校
医学盖伊医院，圣托马斯街，伦敦，SE1 9RT，美国Kingdom2

收到2010年7月12日/ 2010年12月2日接受

这项研究的目的是探讨B型肝炎病毒纵向
（HBV）的特异性T细胞反应和病毒的行为与治疗反应
在联合抗病毒治疗宽容孩子。二十三名儿童
婴儿获得性乙型肝炎（HBeAg阳性+）属于公布的初步研究
1年与拉米夫定/阿尔法干扰素治疗（干扰素-）进行了调查。五
血清学转化到抗- HBs（反应）。九为HLA - A2号+（4和5反应
无反应）。在乙肝病毒核心基因突变，测定了基线
在肝脏和直接测序的序列在基线血清样品;在
治疗第2周（TW2），TW9，TW28和TW52和后，后续24周（FUW24）
和FUW52。 HBV特异性反应进行了评价T细胞的增殖与16
乙肝病毒核心20个碱基重叠肽的HLA - A2限制性core18 - 27五聚体
染色和CD8 +干扰素酶联免疫斑点（ELISPOT法）检测。乙肝病毒
核心特异性T细胞增殖和CD8反应更具活力，
中比之间在更广泛的TW28和TW52无反应反应，而
突变的数量在乙型肝炎病毒核心抗原基因免疫较低，
TW28和呈负HBV特异性T细胞增殖相关
在这两个时间点的反应。乙型肝炎病毒DNA病毒载量呈负相关
乙肝病毒特异性T细胞增殖反应和治疗过程中CD8，
特别是在TW28。治疗引起的乙型肝炎病毒免疫耐受过渡到
免疫控制的特点是高效率的病毒特异性的出现
抑制突变能力，防止病毒逃避免疫反应。





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