乙肝表面抗原的免疫逃逸的关键遗传因子关联与乙肝病毒激

StephenW

Hepatitis B surface antigen genetic elements critical for immune escape correlate with hepatitis B virus 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 Verheyen11,†,
    Carlo-Federico Perno1,* and
    Valentina Svicher1,*

Article first published online: 28 JAN 2015

DOI: 10.1002/hep.27604

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

Issue
Hepatology

Volume 61, Issue 3, pages 823–833, March 2015



    Potential conflict of interest: Dr. Andreoni consults and received grants from Gilead, Bristol-Myers Squibb, Viiv, Janssen, and Merck. Dr. Angelico consults for, is on the speakers' bureau of, and received grants from Gilead. He is on the speakers' bureau for Roche. He received grants from AbbVie, Bristol-Myers Squibb, and Janssen. Dr. Verhejen is on the speakers' bureau for Siemens and Janssen and received grants from Abbott. Dr. Perno consults for and received grants from Viiv, Bristol-Myers Squibb, Gilead, Janssen, Merck, and AbbVie. Dr. Svicher received grants from Bristol-Myers Squibb, Gilead, and Roche.

    This work was supported by the FIRB project (RBAP11YS7K_001), by the Italian Ministry of Instruction, University and Research (Progetto Bandiera PB05), the Aviralia Foundation, and by financial support from the Bristol-Myers Squibb Partnering for Cure Research Program 2013.

Hepatitis B virus (HBV) reactivation during immunosuppression can lead to severe acute hepatitis, fulminant liver failure, and death. Here, we investigated hepatitis B surface antigen (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 ultradeep sequencing (UDS). Before HBV reactivation, 51.7% of patients were isolated hepatitis B core antibody (anti-HBc) positive, 31.0% inactive carriers, 6.9% anti-HBc/anti-HBs (hepatitis B surface antibody) positive, 6.9% isolated anti-HBs positive, and 3.4% had an overt HBV infection. Of HBV-reactivated patients, 51.7% were treated with rituximab, 34.5% with different chemotherapeutics, and 13.8% with corticosteroids only for inflammatory diseases. In total, 75.9% of HBV-reactivated patients (vs. 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 of 13 (M103I-L109I-T118K-P120A-Y134H-S143L-D144E-S171F) reside in a major hydrophilic loop (target of neutralizing antibodies [Abs]); some of them are already known to hamper HBsAg recognition by humoral response. The remaining five (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 intrapatient prevalence of 73.3% (range, 27.6%-100%) supporting their fixation in the viral population as a predominant species. In control patients carrying such mutations, their median intrapatient prevalence was 4.6% (range, 2.5%-11.3%; P < 0.001). Finally, additional N-linked glycosylation (NLG) sites within the major hydrophilic loop were found in 24.1% of HBV-reactivated patients (vs. 0% of chronic patients; P < 0.001); 5 of 7 patients carrying these sites remained HBsAg negative despite HBV reactivation. NLG can mask immunogenic epitopes, abrogating HBsAg recognition by Abs. 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 for careful patient monitoring in all immunosuppressive settings at reactivation risk and of establishing a prompt therapy to prevent HBV-related clinical complications. (Hepatology 2015;61:823–833)

StephenW

乙肝表面抗原的免疫逃逸的关键遗传因子关联与乙肝病毒激活后，免疫抑制

    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Verheyen11，†，
    卡罗 - 费德里科Perno1，*和
    瓦伦蒂娜Svicher1，*

文章首次在网上公布：2015年1月28日

DOI：10.1002 / hep.27604

©2014年肝病研究的美国协会

问题
肝病

第61卷，第3期，页823-833，2015年3月



    潜在的利益冲突：Andreoni医生咨询，并从Gilead公司，施贵宝，欢跃，扬森和默克公司收到的补助。安吉利科医生咨询的，是对发言者的局，并从Gilead公司收到的补助。他对说话者的罗氏局。他从AbbVie，施贵宝，和扬森获得补助。 Verhejen博士是扬声器的来自雅培局西门子和扬森，并获得资助。作者Perno医生咨询并从欢跃，施贵宝，Gilead公司，西安杨森，默沙东和AbbVie收到的补助。 Svicher博士获得补助施贵宝，Gilead公司和罗氏公司。

    这项工作是由FIRB项目（RBAP11YS7K_001），由大学意大利外交部指示，并研究（波捷特班迪耶拉PB05），该Aviralia基金会，并从施贵宝，携手防治研究项目2013年资金支持的支持。

乙型肝炎病毒（HBV）的免疫抑制期间再活化可能导致严重的急性肝炎，暴发性肝衰竭和死亡。在这里，我们调查乙肝表面抗原（HBsAg）基因的功能这一现象，通过分析93例基本：29开发HBV再激活，并连续64例慢性HBV感染（如控制）。乙肝表面抗原的遗传多样性进行了以人群为基础和超测序（UDS）分析。 HBV再激活前，病人51.7％分离乙型肝炎核心抗体（抗-HBc）阳性，31.0％非活性载体，6.9％抗-HBc /抗HBs（乙肝表面抗体）阳性，6.9％分离的抗HBs抗体阳性和3.4％有明显的HBV感染。 HBV-激活患者中，51.7％的利妥昔单抗治疗，34.5％有不同的化疗药物，和13.8％，只有炎症性疾病皮质类固醇。总共，HBV-激活患者的75.9％（相对于对照患者3.1％，P <0.001）进行局部存在于免疫活性的HBsAg区的HBsAg突变。在这些患者中发现13 HBsAg的突变，13（M103I-L109I-T118K-P120A-Y134H-S143L-D144E-S171F）8居住在一个大的亲水环（目标中和抗体[绝对]的）;他们中的一些是已知的妨碍HBsAg的认可体液反应。剩余的五（C48G-V96A-L175S-G185E-V190A）被定位在类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-重新激活的患者的73.3％的中值intrapatient患病（范围27.6％-100％）支持他们固定在病毒群体作为主要物种。在携带这种突变控制的患者，他们的中位intrapatient患病率为4.6％（范围，2.5％-11.3％; P <0.001）。最后，附加的N联糖基化（NLG）的主要亲水循环内的网站中发现HBV-激活患者（与慢性病患者的0％; P <0.001）的24.1％; 5 7例携带这些网站仍然是HBsAg阴性，尽管HBV再激活。 NLG可以掩盖免疫原性表位，废除乙肝表面抗原认可的腹肌。结论：HBV再激活发生于各种需要免疫抑制疗法的临床设置，并且与赋予增强的能力，以逃避免疫反应的HBsAg突变。这凸显了需要建立一个提示治疗，以预防HBV相关的临床并发症的风险重新仔细病人监护中的所有免疫设置和。 （肝病2015; 61：823-833）