Single-molecule sequencing of the whole HCV genome revealed envelope deletions in decompensated cirrhosis associated with NS2 and NS5A mutations.

IF 6.9 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Journal of Gastroenterology Pub Date : 2024-11-01 Epub Date: 2024-09-03 DOI:10.1007/s00535-024-02146-3
Kozue Yamauchi, Shinya Maekawa, Leona Osawa, Yasuyuki Komiyama, Natsuko Nakakuki, Hitomi Takada, Masaru Muraoka, Yuichiro Suzuki, Mitsuaki Sato, Shinichi Takano, Nobuyuki Enomoto
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Abstract

Background: Defective hepatitis C virus (HCV) genomes with deletion of the envelope region have been occasionally reported by short-read sequencing analyses. However, the clinical and virological details of such deletion HCV have not been fully elucidated.

Methods: We developed a highly accurate single-molecule sequencing system for full-length HCV genes by combining the third-generation nanopore sequencing with rolling circle amplification (RCA) and investigated the characteristics of deletion HCV through the analysis of 21 patients chronically infected with genotype-1b HCV.

Result: In 5 of the 21 patients, a defective HCV genome with approximately 2000 bp deletion from the E1 to NS2 region was detected, with the read frequencies of 34-77%, suggesting the trans-complementation of the co-infecting complete HCV. Deletion HCV was found exclusively in decompensated cirrhosis (5/12 patients), and no deletion HCV was observed in nine compensated patients. Comparing the amino acid substitutions between the deletion and complete HCV (DAS, deletion-associated substitutions), the deletion HCV showed higher amino acid mutations in the ISDR (interferon sensitivity-determining region) in NS5A, and also in the TMS (transmembrane segment) 3 to H (helix) 2 region of NS2.

Conclusions: Defective HCV genome with deletion of envelope genes is associated with decompensated cirrhosis. The deletion HCV seems susceptible to innate immunity, such as endogenous interferon with NS5A mutations, escaping from acquired immunity with deletion of envelope proteins with potential modulation of replication capabilities with NS2 mutations. The relationship between these mutations and liver damage caused by HCV deletion is worth investigating.

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全 HCV 基因组的单分子测序显示,失代偿期肝硬化患者的包膜缺失与 NS2 和 NS5A 突变有关。
背景:短线程测序分析偶尔报告了包膜区缺失的丙型肝炎病毒(HCV)基因组。然而,这种缺失 HCV 的临床和病毒学细节尚未完全阐明:方法:我们通过将第三代纳米孔测序与滚动圈扩增(RCA)相结合,开发了一种高精度的全长 HCV 基因单分子测序系统,并通过对 21 例长期感染基因型-1b HCV 的患者进行分析,研究了缺失型 HCV 的特征:结果:在 21 例患者中的 5 例中,检测到了从 E1 到 NS2 区缺失约 2000 bp 的缺陷 HCV 基因组,读取频率为 34-77%,表明合并感染的完整 HCV 存在反式互补。缺失的 HCV 只出现在失代偿期肝硬化患者中(5/12 例),在 9 例代偿期患者中未发现缺失的 HCV。比较缺失型HCV和完全型HCV的氨基酸替换(DAS,缺失相关替换),缺失型HCV在NS5A的ISDR(干扰素敏感性决定区)和NS2的TMS(跨膜段)3至H(螺旋)2区的氨基酸突变较多:结论:包膜基因缺失的缺陷型 HCV 基因组与失代偿性肝硬化有关。缺失的HCV似乎易受先天性免疫的影响,如NS5A突变时易受内源性干扰素的影响,NS2突变时易受后天免疫的影响,包膜蛋白的缺失可能会调节复制能力。这些突变与 HCV 基因缺失造成的肝损伤之间的关系值得研究。
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来源期刊
Journal of Gastroenterology
Journal of Gastroenterology 医学-胃肠肝病学
CiteScore
12.20
自引率
1.60%
发文量
99
审稿时长
4-8 weeks
期刊介绍: The Journal of Gastroenterology, which is the official publication of the Japanese Society of Gastroenterology, publishes Original Articles (Alimentary Tract/Liver, Pancreas, and Biliary Tract), Review Articles, Letters to the Editors and other articles on all aspects of the field of gastroenterology. Significant contributions relating to basic research, theory, and practice are welcomed. These publications are designed to disseminate knowledge in this field to a worldwide audience, and accordingly, its editorial board has an international membership.
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