Adeno-associated virus in the liver: natural history and consequences in tumour development
Adeno-associated virus in the liver: natural history and consequences in tumour development
复制标题
DOI：
10.1136/gutjnl-2019-318281
复制
发表时间：
2020-04-01
期刊：
影响因子：
24.5
通讯作者：
Zucman-Rossi, Jessica
中科院分区：
文献类型：
--
作者：
La Bella, Tiziana;Imbeaud, Sandrine;Zucman-Rossi, Jessica
目的腺相关病毒（Adeno-associated virus，AAV）是一种单链DNA缺陷型病毒，在人群中流行（35%~ 80%）。复发性克隆性AAV 2插入与在正常肝脏上发展的罕见人类肝细胞癌（HCC）的发病机制相关。本研究旨在阐明AAV感染在肝脏中的自然史及其在肿瘤发展中的后果。设计病毒DNA在1461例患者的肿瘤和非肿瘤肝组织中进行定量。使用基于DNAse/TaqMan的测定和定量RT-PCR分析游离型形式和病毒mRNA表达的存在。结果在21%的患者中检测到AAV DNA，包括8%的肿瘤组织，平均分布在两种主要的病毒亚型中：一种类似于AAV 2，另一种是AAV 2和AAV 13序列之间的杂交。在4%的非肿瘤组织中发现了附加体病毒形式，通常与病毒RNA表达和人类疱疹病毒6型（候选天然AAV辅助病毒）相关。在30例HCC中，在CCNA 2、CCNE 1、TERT、TNFSF 10、KMT 2B和GLI 1/INHBE中反复鉴定到克隆性AAV插入。AAV插入通过多种机制，根据不同的本地化的integration site.Conclusion引发致癌基因过表达，我们提供了一个综合分析的野生型AAV感染在肝脏中的病毒基因型，分子形式，辅助病毒的关系和病毒整合的鉴定。在HCC发展过程中，在非肝硬化肝脏上选择克隆AAV插入是阳性的，这挑战了AAV作为非致病性病毒的概念。
Objective Adeno-associated virus (AAV) is a defective mono-stranded DNA virus, endemic in human population (35%-80%). Recurrent clonal AAV2 insertions are associated with the pathogenesis of rare human hepatocellular carcinoma (HCC) developed on normal liver. This study aimed to characterise the natural history of AAV infection in the liver and its consequence in tumour development.Design Viral DNA was quantified in tumour and non-tumour liver tissues of 1461 patients. Presence of episomal form and viral mRNA expression were analysed using a DNAse/TaqMan-based assay and quantitative RT-PCR. In silico analyses using viral capture data explored viral variants and new clonal insertions.Results AAV DNA was detected in 21% of the patients, including 8% of the tumour tissues, equally distributed in two major viral subtypes: one similar to AAV2, the other hybrid between AAV2 and AAV13 sequences. Episomal viral forms were found in 4% of the non-tumour tissues, frequently associated with viral RNA expression and human herpesvirus type 6, the candidate natural AAV helper virus. In 30 HCC, clonal AAV insertions were recurrently identified in CCNA2, CCNE1, TERT, TNFSF10, KMT2B and GLI1/INHBE. AAV insertion triggered oncogenic overexpression through multiple mechanisms that differ according to the localisation of the integration site.Conclusion We provided an integrated analysis of the wild-type AAV infection in the liver with the identification of viral genotypes, molecular forms, helper virus relationship and viral integrations. Clonal AAV insertions were positive selected during HCC development on non-cirrhotic liver challenging the notion of AAV as a non-pathogenic virus.