乙肝表面抗原关键免疫逃逸的遗传因子关联与HBV-激活免疫抑

StephenW

HBsAg genetic elements critical for immune escape correlate with HBV-reactivation upon immunosuppression

    Romina Salpini1,
    Luna Colagrossi1,
    Maria Concetta Bellocchi1,
    Matteo Surdo1,
    Christina Becker2,
    Claudia Alteri1,
    Marianna Aragri1,
    Alessandra Ricciardi3,
    Daniele Armenia1,
    Michela Pollicita1,
    Fabiola Di Santo1,
    Luca Carioti1,
    Yoram Louzoun4,
    Claudio Maria Mastroianni5,
    Miriam Lichtner5,
    Maurizio Paoloni6,
    Mariarosaria Esposito7,
    Chiara D'Amore8,
    Aldo Marrone8,
    Massimo Marignani9,
    Cesare Sarrecchia3,
    Loredana Sarmati3,
    Massimo Andreoni3,
    Mario Angelico10,
    Jens Verhejen11,
    Carlo-Federico Perno1,* and
    Valentina Svicher1,*

DOI: 10.1002/hep.27604

Copyright © 2014 by the American Association for the Study of Liver Diseases

Issue
Cover image for Vol. 60 Issue 6
Hepatology

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

    1    University of Rome Tor Vergata, Department of Experimental Medicine and Surgery, Rome, Italy
    2    Institute of Virology, University of Cologne, Germany
    3    Tor Vergata University Hospital, Infectious Diseases Unit, Rome, Italy
    4    Department of Mathematics and Gonda Brain Research Center, Bar-Ilan University, Ramat Gan, Israel
    5    Sapienza University, Polo Pontino, Latina, Italy
    6    S.S. Filippo e Nicola” Hospital, Infectious Disease Unit, Avezzano, Italy
    7    Hematology Unit, San Gennaro Hospital of Naples, Italy
    8    Second University of Naples, Internal Medicine and Hepatology Unit, Naples, Italy
    9    S., Andrea” Hospital, Rome, Italy
    10    Tor Vergata University Hospital, Hepatology Unit, Rome, Italy
    11    Institute of Virology, University of Essen, Germany

*Joint Corresponding Authors: Carlo Federico Perno, Valentina Svicher, University of Rome Tor Vergata, Department of Experimental Medicine and Surgery, Via Montpellier 1, 00133 Rome, e-mail: [email protected]; [email protected], phone: 0039 06 72596566, 0039 06 72596564

Abstract

HBV-reactivation during immunosuppression can lead to severe acute hepatitis, fulminant liver failure, and death. Here, we investigated HBsAg genetic-features underlying this phenomenon by analyzing 93 patients: 29 developing HBV-reactivation, and 64 consecutive patients with chronic HBV-infection (as control). HBsAg genetic-diversity was analyzed by population-based and ultra-deep sequencing (UDS). Before HBV-reactivation, 51.7% of patients were isolated anti-HBc positive, 31.0% inactive carriers, 6.9% anti-HBc/anti-HBs positive, 6.9% isolated anti-HBs positive, and 3.4% had an overt HBV-infection. 51.7% of HBV-reactivated patients were treated with rituximab, 34.5% with different chemotherapeutics, and 13.8% with corticosteroids only for inflammatory-diseases.

75.9% of HBV-reactivated patients (versus 3.1% of control-patients, P<0.001) carried HBsAg-mutations localized in immune-active HBsAg regions. Of the 13 HBsAg-mutations found in these patients, 8/13 (M103I-L109I-T118K-P120A-Y134H-S143L-D144E-S171F) reside in major hydrophilic-loop (target of neutralizing-antibodies); some of them are already known to hamper HBsAg-recognition by humoral-response. The remaining 5 (C48G-V96A-L175S-G185E-V190A) are localized in Class-I/II-restricted T-cell epitopes, suggesting a role in HBV-escape from T-cell mediated responses. By UDS, these mutations occurred in HBV-reactivated patients with a median intra-patient prevalence of 73.3%(27.6%-100%) supporting their fixation in viral-population as predominant species. In control-patients carrying such mutations, their median intra-patient prevalence was 4.6%(2.5%-11.3%) (P<0.001).

Finally, additional N-linked glycosylation-sites within major hydrophilic-loop were found in 24.1% of HBV-reactivated patients (versus 0% of chronic-patients, P<0.001); 5/7 patients carrying these sites remained HBsAg-negative despite HBV-reactivation. N-linked glycosylation can mask immunogenic-epitopes, abrogating HBsAg-recognition by antibodies.

In conclusion, HBV-reactivation occurs in a wide variety of clinical-settings requiring immune-suppressive therapy, and correlates with HBsAg-mutations endowed with enhanced-capability to evade immune-response. This highlights the need of a careful patient's monitoring in all immunosuppressive-settings at reactivation-risk, and of establishing a prompt therapy to prevent HBV-related clinical complications. This article is protected by copyright. All rights reserved.

StephenW

乙肝表面抗原的免疫逃逸的关键遗传因子关联与HBV-激活免疫后，

    罗米纳Salpini1，
    月神Colagrossi1，
    玛丽亚康斯塔Bellocchi1，
    利玛窦Surdo1，
    克里斯蒂娜Becker2，
    克劳迪娅Alteri1，
    玛丽安娜Aragri1，
    亚历山德拉Ricciardi3，
    丹尼尔Armenia1，
    MICHELA Pollicita1，
    法比奥拉迪Santo1，
    卢卡Carioti1，
    约拉姆Louzoun4，
    克劳迪奥·玛丽亚Mastroianni5，
    仪Lichtner5，
    莫里吉奥Paoloni6，
    Mariarosaria Esposito7，
    基娅拉D'Amore8，
    阿尔Marrone8，
    马西莫Marignani9，
    切萨雷Sarrecchia3，
    LOREDANA Sarmati3，
    马西莫Andreoni3，
    马里奥Angelico10，
    延Verhejen11，
    卡罗 - 费德里科Perno1，*和
    瓦伦蒂娜Svicher1，*

DOI：10.1002/ hep.27604

版权所有©2014年由美国协会肝病研究

问题
封面图片的卷。 60第6期
肝病

接受第（接受，未经编辑的文章在网上和引述的公布，最终编辑和记录排版本将出现在未来。）

    罗马在Tor Vergata，实验医学科和外科，意大利罗马第一大学
    病毒学德国科隆大学2研究所，
    3在Tor Vergata大学医院，传染病股，罗马，意大利
    数学巴伊兰大学4系和贡达脑研究中心，拉马特甘，以色列
    5 Sapienza大学，马球Pontino，拉丁，意大利
    6 SS菲利波·ê尼古拉“医院，传染病单位，阿韦扎诺，意大利
    7血液单位，那不勒斯，意大利圣真纳罗医院
    那不勒斯，内科及肝病单位，那不勒斯，意大利8第二大学
    9 S.，安德烈“医院，罗马，意大利
    10的Tor Vergata大学医院，肝病单元，罗马，意大利
    病毒学德国埃森大学11研究所，

*联合通讯作者：卡罗费德里科的Perno，瓦伦蒂娜Svicher，罗马在Tor Vergata大学实验医学和外科学系，通过蒙彼利埃1，00133罗马，电子邮件：[email protected]; [email protected]，电话：00390672596566，00390672596564

抽象

免疫抑制期间HBV-活化可导致严重的急性肝炎，暴发性肝衰竭和死亡。在这里，我们调查HBsAg的遗传特性这一现象，通过分析93例基本：29发展中HBV-激活，并连续64例慢性HBV感染（如控制）。 HBsAg的遗传多样性进行了以人群为基础和超深度测序（UDS）分析。 HBV-激活之前，患者的51.7％是孤立的抗-HBc阳性，31.0％，非活动性携带者，6.9％，抗-HBc/抗-HBs阳性，6.9％的分离抗-HBs阳性，3.4％有明显的HBV感染。 HBV-激活患者51.7％的利妥昔单抗治疗，34.5％有不同的化疗药物，和13.8％，只有对炎性疾病的糖皮质激素。

HBV-激活患者的75.9％（相对于控制患者的3.1％，P <0.001），携带乙肝表面抗原，基因突变的局部免疫活性HBsAg的地区。在这些患者中发现13例HBsAg突变，8/13（M103I-L109I-T118K-P120A-Y134H-S143L-D144E-S171F）位于主要的亲水环（目标中和抗体的）;他们中的一些是已知的阻碍乙肝表面抗原识别通过体液反应。剩余的5（C48G-V96A-L175S-G185E-V190A）局部存在于类I / II限制性T细胞表位，这表明从T细胞介导的反应中的HBV-逃逸的作用。由UDS，这些突变发生于HBV-激活患者的73.3％（27.6％-100％）支持他们固定在病毒群作为主要种类的中值内患者患病。在携带这种突变控制的患者，他们的中位内病人患病率为4.6％（2.5％-11.3％）（P <0.001）。

最后，内主要亲水环的额外的N-连接的糖基化位点被发现在HBV-激活患者的24.1％（相对于慢性患者的0％，P<0.001）; 5/7的患者携带这些网站仍尽管HBV-激活HBsAg阴性。 N-连接的糖基化可以掩盖免疫原性表位，废除的HBsAg识别由抗体。

总之，HBV-激活发生在各种临床设置需要免疫抑制疗法，并且与例HBsAg突变赋予了增强型能力，以逃避免疫应答。这突出了在所有免疫-设置在活化风险，并建立一个提示疗法预防HBV相关的临床并发症的患者仔细的监测的需要。这篇文章是受版权保护的。版权所有。