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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Development of JFH1-based cell culture systems for hepatitis C virus genotype 4a and evidence for cross-genotype neutralization
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Development of JFH1-based cell culture systems for hepatitis C virus genotype 4a and evidence for cross-genotype neutralization

机译：基于JFH1的丙型肝炎病毒基因型4a细胞培养系统的开发和交叉基因型中和的证据

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摘要

Efficient in vitro systems to study the life cycle of hepatitis C virus (HCV) were recently developed for JFH1 (genotype 2a), which has unique replication capacity in Huh7 cells. We developed 4a/JFH1 intergenotypic recombinants containing the structural genes (Core, E1, and E2), p7, and all or part of NS2 of the 4a prototype strain ED43 that, after transfection of Huh7.5 cells with RNA transcripts, produced infectious viruses. Compared with the J6/JFH control virus, production of viruses was delayed. However, efficient spread of infection and high HCV RNA and infectivity titers were obtained in serial passages. Sequence analysis of recovered viruses and subsequent reverse genetic studies revealed a vital dependence on one or two NS2 mutations, depending on the 4a/2a junction. Infectivity of ED43/JFH1 viruses was CD81 dependent. The genotype 4 cell culture systems permit functional analyses as well as drug and vaccine research on an increasingly important genotype in the Middle East, Africa, and Europe. We also developed genotype 1a intergenotypic recombinants from H77C with vital mutations in NS3. Using H77C/JFH1 and ED43/JFH1 viruses, we demonstrated high homologous neutralizing antibody titers in 1a and 4a patient sera, respectively. Furthermore, availability of JFH1 viruses with envelope proteins of the six major HCV genotypes permitted cross-neutralization studies; 1a and 4a serum cross-neutralized 1a, 4a, 5a, and 6a but not 2a and 3a viruses. Thus, the JFH1 intergenotypic recombinants will be of importance for future studies of HCV neutralization and accelerate the development of passive and active immunoprophylaxis.
机译：最近开发了用于研究丙型肝炎病毒（HCV）生命周期的高效体外系统，用于JFH1（基因型2a），该基因在Huh7细胞中具有独特的复制能力。我们开发了包含结构基因（核心，E1和E2），p7以及4a原型菌株ED43的全部或部分NS2的4a / JFH1基因型重组体，在用RNA转录本转染Huh7.5细胞后，产生了感染性病毒。与J6 / JFH对照病毒相比，病毒的产生被延迟。然而，在连续传代中获得了有效的感染传播以及高HCV RNA和感染力滴度。回收病毒的序列分析和随后的逆向遗传研究表明，取决于4a / 2a连接，它对一个或两个NS2突变至关重要。 ED43 / JFH1病毒的感染性是CD81依赖性的。基因型4细胞培养系统可以对中东，非洲和欧洲日益重要的基因型进行功能分析以及药物和疫苗研究。我们还从NS3的重要突变体H77C开发了基因型1a基因型重组。使用H77C / JFH1和ED43 / JFH1病毒，我们分别在1a和4a患者血清中证明了高同源中和抗体滴度。此外，具有六种主要HCV基因型包膜蛋白的JFH1病毒的可得性允许交叉中和研究； 1a和4a血清交叉中和了1a，4a，5a和6a病毒，但未中和2a和3a病毒。因此，JFH1基因型间的重组体将对HCV中和的未来研究和加速被动和主动免疫预防的发展具有重要意义。

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