多HBV准种和免疫逃逸突变是乙肝病毒存在表面抗原和急性乙

StephenW

Multiple HBV Quasispecies and Immune-Escape Mutations Are Present in HBV Surface Antigen and Reverse Transcriptase of Patients with Acute Hepatitis B

    Marianna Aragri1,*, Claudia Alteri1,*, Arianna Battisti1, Domenico Di Carlo1, Carmine Minichini2, Caterina Sagnelli3, Maria Concetta Bellocchi1, Maria Antonietta Pisaturo2, Mario Starace2, Daniele Armenia1, Luca Carioti1, Michela Pollicita1, Romina Salpini1, Evangelista Sagnelli2, Carlo Federico Perno1, Nicola Coppola2,§ and Valentina Svicher1,§

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Author Affiliations

    1Department of Experimental Medicine and Surgery, University of Rome “Tor Vergata”, Italy
    2Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, ITALY
    3Department of Clinical and Experimental Medicine and Surgery, Second University of Naples, Naples, Italy

    Correspondence: 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

    ↵* Marianna Aragri and Claudia Alteri equally contributed to this study

    ↵§ Joint last authorship

Abstract

Background. To characterize HBV RT and HBsAg quasispecies heterogeneity in acute HBV-infected (AHB) patients and to define their clinical value.

Methods. 62 patients with AHB (44 genotype-D and 18 genotype-A) were enrolled from 2000 to 2010. Plasma-samples obtained at first observation were analyzed by Ultra-deep-pyrosequencing (UDPS). Extent of HBsAg amino acid variability was measured by Shannon-Entropy.

Results. Median (IQR) ALT and serum HBV-DNA were 2,544(1,938-3,078)U/L and 5.88(4.47-7.37)log10IU/ml, respectively. Although most patients serologically resolved AHB, only 54.1% developed anti-HBs.

A viral-population with >1 immune-escape mutation was found in 53.2% of patients (intra-patient prevalence range:0.16%-100%). Notably, by Shannon-Entropy, an higher genetic-variability at HBsAg amino acid positions 130, 133, and 157 significantly correlated with no anti-HBs production in genotype-D (P<0.05).

Stop-codons were detected in 19.3% of patients (intra-patient prevalence range:1.6%-47.5%). They occurred at 11 HBsAg-positions including 172 and 182, known to increase HBV oncogenic-potential.

Finally, >1 drug-resistance mutation was detected in 8.1% of patients (intra-patient prevalence range: 0.11%-47.5% for primary-mutations, and 10.5%-99.9% for compensatory ones).

Conclusions. AHB is characterized by complex array of viral quasispecies with reduced antigenicity/immunogenicity, and enhanced oncogenic-potential. These viral variants may induce difficult-to-treat HBV forms, favor HBV-reactivation upon iatrogenic-immunosuppression even years after infection, and potentially affect current HBV-vaccination efficacy.

    © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail [email protected].

StephenW

多HBV准种和免疫逃逸突变是乙肝病毒存在表面抗原和急性乙肝玛丽安娜Aragri1患者的逆转录酶，*，克劳迪娅Alteri1，*，阿里安娜Battisti1，多梅尼科·迪Carlo1，胭脂红Minichini2，卡特里纳Sagnelli3，玛丽亚康斯塔贝洛奇奥，玛丽亚安东尼塔Pisaturo2，马里奥Starace2，丹尼尔Armenia1，卢卡Carioti1，MICHELA Pollicita1，罗米纳Salpini1，杰利斯塔Sagnelli2，卡罗费德里科Perno1，尼古拉Coppola2，§和瓦伦蒂娜Svicher 1，§
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那不勒斯第二大学实验医学和外科手术，罗马“在Tor Vergata”大学的作者机构教研室，心理健康与公共医学，传染病科，那不勒斯第二大学，临床意大利3Department和实验医学和外科意大利教研室， ，意大利那不勒斯通讯：卡罗费德里科的Perno，瓦伦蒂娜Svicher，罗马在Tor Vergata，实验医学和外科学系的大学，蒙彼利埃通过1，00133罗马，电子邮件：[email protected]; [email protected]，电话：0039 06 72596566，0039 06 72596564↵*玛丽安娜Aragri和Claudia Alteri同等贡献这项研究↵§去年联合署名权
抽象
背景。为了描述HBV RT与HBsAg准种异质性急性HBV感染（AHB）患者，并定义它们的临床应用价值。
方法。 62例AHB（44基因型-D和18型-A）参加2000年在第一次观测得到的2010年等离子样品用超深焦磷酸测序（UDPS）分析。乙肝表面抗原氨基酸变异的程度被香农熵测量。
结果。中位数（IQR）ALT和血清HBV-DNA是2544（1,938-3,078）U / L和5.88（4.47-7.37）log10IU /毫升。虽然大多数患者的血清学解决AHB，只有54.1％，开发抗-HBs。
（：0.16％-100％内病人患病范围）的病毒，人群> 1免疫逃逸突变的患者53.2％被发现。值得注意的是，通过香农熵，一个更高的遗传变异在HBsAg的氨基酸位置130，133和157与无抗HBs产量基因型-D（P <0.05）显​​著相关。
（：1.6％-47.5％患者内流行范围）的患者19.3％，检测终止密码子。这些发生在11例HBsAg职位，包括172和182，已知增加HBV致癌潜力。
最后，在患者的8.1％，检测> 1耐药突变（帧内患者患病范围：0.11％为初级突变-47.5％，和10.5％补偿性那些-99.9％）。
结论。 AHB的特征在于通过与抗原性/免疫原性降低的病毒准种的复数排列，和增强的致癌潜能。这些病毒变体可以诱发难以治疗HBV的形式，有利于在医源性免疫抑制感染甚至几年之后HBV-激活，并有可能影响当前的HBV疫苗接种功效。 ©的美国传染病学会出版由牛津大学出版社的作者2016年。版权所有。对于权限，电子邮件[email protected]。