乙肝病毒免疫逃逸机制有新解

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乙肝病毒免疫逃逸机制有新解
发布日期：2014-01-23　 来源：健康报　
　
　　本报讯  （记者胡德荣  通讯员韩  悦）上海交通大学医学院附属瑞金医院感染科张欣欣课题组提出，乙肝病毒表面抗原的糖基化突变是病毒免疫逃逸的主要原因。相关论文日前在线发表在《肝脏病学杂志》上。

　　据介绍，受到乙型肝炎病毒（HBV）感染的机体出现针对表面抗原（HBsAg）的抗体anti-HBs，通常被认为是病毒清除的标志，但是，在部分乙肝患者和接种乙肝疫苗的人群中存在着HBsAg与anti-HBs同时被检测到的现象，这种情况一直困扰着临床医生和病毒学家。以往的研究认为，发生在HBsAg主要亲水区的氨基酸突变，如G145R是导致病毒“躲过”宿主免疫监控的主要原因，但是这些突变对病毒生物学特性的真正影响并未得到深入研究。

　　张欣欣课题组将长期以来建立的病毒变异表型研究技术平台，应用于临床HBV免疫逃逸株的检测和体外生物学功能研究，从近年来在瑞金医院感染科就诊和体检的13.6万名患者中筛选出216名发生免疫逃逸的病例，除了验证既往学术界的研究结果外，还发现有22%的患者发生了病毒抗原的糖基化突变，如此高的突变率是在国际上首次报道。同时，科研人员在对病毒适应性的体外功能研究中发现，这种糖基化突变对病毒的抗原性和分泌能力均发生影响，显示出在宿主免疫应答的压力下，病毒突变株具有更好的适应性。

　　在研究中，科研人员还发现了糖基化突变株可在人群中水平传播，其中包括被成功免疫接种乙肝疫苗的病例。

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http://www.ncbi.nlm.nih.gov/pubmed/?term=24239777

J Hepatol. 2013 Nov 13. pii: S0168-8278(13)00795-2. doi: 10.1016/j.jhep.2013.11.004. [Epub ahead of print]
N-glycosylation mutations within hepatitis B virus surface major hydrophilic region contribute mostly to immune escape.
Yu DM1, Li XH2, Mom V3, Lu ZH4, Liao XW1, Han Y1, Pichoud C3, Gong QM1, Zhang DH1, Zhang Y5, Deny P6, Zoulim F7, Zhang XX8.
Author information
Abstract
BACKGROUND & AIMS:
HBV immune escape represents a challenge to prevention, diagnosis, and treatment of hepatitis B. Here, we analyzed the molecular and clinical characteristics of HBV immune escape mutants in a Chinese cohort of chronically infected patients.
METHODS:
Two hundred sixteen patients with HBsAg and anti-HBs were studied, with one hundred eighty-two HBV carriers without anti-HBs as a control group. Recombinant HBsAg bearing the most frequent N-glycosylation mutations were expressed in CHO and HuH7 cells. After confirming N-glycosylation at the most frequent sites (129 and 131), together with inserted mutations, functional analysis were performed to study antigenicity and secretion capacity.
RESULTS:
One hundred twenty-three patients had the wild-type HBs gene sequence, 93 patients (43%) had mutants in the major hydrophilic region (MHR), and 47 of the 93 patients had additional N-glycosylation mutations, which were transmitted horizontally to at least 2 patients, one of whom was efficiently vaccinated. The frequency of N-glycosylation mutation in the case group was much higher than that of the control group (47/216 vs. 1/182). Compared with wild-type HBsAg, HBsAg mutants reacted weakly with anti-HBs using a chemiluminescent microparticle enzyme immunoassay. Native gel analysis of secreted virion in supernatants of transfected HuH7 cells indicated that mutants had better virion enveloping and secretion capacity than wild-type HBV.
CONCLUSIONS:
Our results suggest that specific HBsAg MHR N-glycosylation mutations are implicated in HBV immune escape in a high endemic area.
Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
KEYWORDS:
AHB, ALT, Acute Hepatitis B, CHB, CMIA, Chronic Hepatitis B, HBV, HBsAg, HCC, Immune escape, LC, MHR, Major hydrophilic region, Mutation, N-glycosylation, PCR, Polymerase chain reaction, aa, amino acid, anti-HBs, anti-HBs antibodies, aspartate aminotransferase, chemiluminescent microparticle enzyme immunoassay, hepatitis B virus, hepatitis B virus surface antigen, hepatocellular carcinoma, liver cirrhosis, major hydrophilic region, rHBsAg, recombinant hepatitis B virus surface antigen

PMID: 24239777 [PubMed - as supplied by publisher]