Impact of hepatitis B virus (HBV) preS/S genomic variability on HBV surface anti

StephenW

http://onlinelibrary.wiley.com/doi/10.1002/hep.25592/abstract
Impact of hepatitis B virus (HBV) preS/S genomic variability on HBV surface antigen and HBV DNA serum levels
    Teresa Pollicino 1,*,
    Giuliana Amaddeo 1,
    Agnese Restuccia 1,
    Giuseppina Raffa 1,
    Angela Alibrandi 2,
    Giuseppina Cutroneo 3,
    Angelo Favaloro 3,
    Sergio Maimone 1,
    Giovanni Squadrito 1,
    Giovanni Raimondo 1

Article first published online: 13 JUL 2012

DOI: 10.1002/hep.25592

1    Unit of Clinical and Molecular Hepatology, Department of Internal Medicine, University of Messina, Messina, Italy
2    Department of SEFISAST, University of Messina, Messina, Italy
3    Department of Biomorphology and Biotechnology, University of Messina, Messina, Italy

Email: Teresa Pollicino ([email protected])

*Unit of Clinical and Molecular Hepatology, Department of Internal Medicine, University Hospital of Messina, Via Consolare Valeria, 98124 Messina, Italy

†    Potential conflict of interest: Nothing to report.

Abstract

To evaluate whether hepatitis B virus (HBV) preS/S gene variability has any impact on serum hepatitis B surface antigen (HBsAg) levels and to analyze the replication capacity of naturally occurring preS/S variants, sera from 40 untreated patients with HBV-related chronic liver disease (hepatitis B e antigen [HBeAg]-positive, n = 11; HBeAg-negative, n = 29) were virologically characterized. Additionally, phenotypic analysis of three different preS/S variant isolates (carrying a 183-nucleotide deletion within the preS1 region, the deletion of preS2 start codon, and a stop signal at codon 182 within the S gene, respectively) was performed. HBV infecting 14 (35%) patients had single or multiple preS/S genomic mutations (i.e., preS1 and/or preS2 deletions, preS2 start codon mutations, C-terminally truncated and/or “a” determinant mutated S protein). Presence of preS/S variants negatively correlated with HBsAg titers (r = −0.431; P = 0.005) and its prevalence did not significantly differ between HBeAg-positive and HBeAg-negative patients. No correlation was found between HBsAg and HBV DNA levels in patients infected with preS/S mutants, whereas a significant correlation was found between HBsAg and viremia levels (r = 0.607; P = 0.001) in patients infected with wild-type HBV strains. HepG2 cells replicating the above-mentioned three preS/S variants showed significant reduction of HBsAg secretion, retention of envelope proteins in the endoplasmic reticulum, less efficient virion secretion and nuclear accumulation of significantly higher amounts of covalently closed circular DNA compared with wild-type HBV replicating cells. Conclusion: In patients infected with preS/S variants, HBV DNA replication and HBsAg synthesis/secretion appear to be dissociated. Therefore, the use of HBsAg titer as diagnostic/prognostic tool has to take into account the frequent emergence of preS/S variants in chronic HBV infection. (HEPATOLOGY 2012;)

StephenW

影响B型肝炎病毒（HBV）的前S / S基因变异对乙肝病毒表面抗原和血清HBV DNA水平
    邓丽君Pollicino 1，*，
    朱丽安娜Amaddeo 1，
    agnese Restuccia 1，
    giuseppina Raffa 1，
    安吉拉阿里布兰迪2，
    giuseppina Cutroneo 3，
    安杰洛Favaloro 3，
    塞尔吉奥Maimone 1，
    乔瓦尼Squadrito 1，
    乔瓦尼·雷蒙1

条第一网上公布：2012年7月13日

DOI：10.1002/hep.25592

作者信息

    1

    墨西拿，意大利墨西拿大学，内科，肝病的临床和分子，单位
    2

    部，墨西拿，意大利墨西拿大学SEFISAST
    3

    部Biomorphology和生物技术，墨西拿，意大利墨西拿大学

电子邮件：：邓丽君Pollicino（[email protected]）

*单位通过98124 Consolare瓦莱里娅，墨西拿，意大利墨西拿大学医院，内科，肝病的临床和分子，

    †

    潜在的利益冲突：任何报告。

抽象

以评估是否有B型肝炎病毒（HBV）的preS / S基因变异血清乙型肝炎表面抗原（HBsAg）水平造成任何影响，并分析自然发生的preS / S的变种，从40例HBV相关的未经治疗的患者血清复制能力慢性肝病（乙肝e抗原HBeAg的]阳性，11例HBeAg阴性，N = 29）的病毒学特征。此外，三种不同的preS / S变异株（携带内地区的前S1，前S2起始密码子的缺失，在S基因，分别为182位密码子内停止信号具有183个核苷酸缺失）的表型分析。乙肝病毒感染14例（35％）的患者有单个或多个的preS / S基因突变（即，前S1和/或前S2缺失，前S2起始密码子突变，C端截短和/或“的”决定性因素突变S蛋白）。的preS / S的变种存在负相关与HBsAg滴度相关（r = -0.431，P = 0.005），其发病率没有明显差异HBeAg阳性和HBeAg阴性患者。没有被发现之间的preS / S突变株感染的患者中HBsAg和HBV DNA水平相关，与野生型乙型肝炎病毒株感染的患者中发现乙肝表面抗原和病毒血症水平（R = 0.607，P = 0.001）之间，而一个显着的相关性。与野生型HBV相比，HepG2细胞复制上述三个前S / S的变种表明HBsAg的分泌显着减少，内质网滞留在包膜蛋白，低效率的病毒颗粒的分泌量显着较高的共价闭合环状DNA和核积累复制的细胞。结论：在患者感染的preS / S的变异，HBV DNA复制和HBsAg合成/分泌似乎是分离的。因此，乙肝表面抗原滴度作为诊断/预测工具的使用，考虑到在慢性乙肝病毒感染的preS / S的变种频繁出现。 （肝病2012 ;)

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