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1. 发明授权

US08663653B2 Efficient cell culture system for hepatitis C virus genotype 2B 失效
标题翻译：丙型肝炎病毒基因型2B的高效细胞培养系统
公开(公告)号：US08663653B2
公开(公告)日：2014-03-04
申请号：US13059130
申请日：2009-07-24
申请人： Judith M. Gottwein , Maria Lisa Knudsen , Troels Kasper Høyer Scheel , Jens Bukh
发明人： Judith M. Gottwein , Maria Lisa Knudsen , Troels Kasper Høyer Scheel , Jens Bukh
IPC分类号： A61K39/12 , A61K39/29 , C12Q1/70 , C12N15/00 , C12N5/071 , C12N1/20
CPC分类号： C12N7/00 , A61K2039/53 , C07K14/005 , C07K16/109 , C07K2317/76 , C12N2770/24221 , C12N2770/24222
摘要： The present inventors developed hepatitis C virus 2b/2a intergenotypic recombinants in which the JFH1 structural genes (Core, E1 and E2), p7 and the complete NS2 were replaced by the corresponding genes of the genotype 2b reference strain J8. Sequence analysis of recovered 2b/2a recombinants from 2 transfection experiments revealed that 2b/2a was genetically stable. Conclusion: The developed 2b/2a viruses provide a robust in vitro tool for research in HCV genotype 2b, including vaccine studies and functional analysis.
摘要翻译：本发明人开发了丙型肝炎病毒2b / 2a基因型重组体，其中JFH1结构基因（Core，E1和E2），p7和完整的NS2被基因型2b参照菌株J8的相应基因替代。来自2个转染实验的回收的2b / 2a重组体的序列分析显示2b / 2a在遗传上是稳定的。结论：开发的2b / 2a病毒为HCV基因型2b的研究提供了强大的体外工具，包括疫苗研究和功能分析。

2. 发明授权

US08454974B2 Adaptive mutations allow establishment of JFH1-based cell culture systems for hepatitis C virus genotype 4A 有权
标题翻译：自适应突变允许建立基于JFH1的丙型肝炎病毒基因型4A的细胞培养系统
公开(公告)号：US08454974B2
公开(公告)日：2013-06-04
申请号：US12595825
申请日：2008-04-11
申请人： Troels Kasper Høyer Scheel , Judith M. Gottwein , Jesper Eugen-Olsen , Jens Bukh
发明人： Troels Kasper Høyer Scheel , Judith M. Gottwein , Jesper Eugen-Olsen , Jens Bukh
IPC分类号： A61K39/29 , C12N7/02 , C12N15/06 , C12Q1/02 , C07H21/00
CPC分类号： C12N7/00 , A61K2039/5254 , C12N2770/24221
摘要： The present inventors developed three 4a/2a intergenotypic recombinants in which the JFH1 structural genes (Core, E1 and E2), p7 and all of or part of NS2 were replaced by the corresponding genes of the genotype 4a reference strain ED43. The 4a/2a junction in NS2 was placed after the first transmembrane domain (α), in the cytoplasmic part (β) or at the NS2/NS3 cleavage site (y). Following transfection of Huh7.5 cells with RNA transcripts, infectious viruses were produced in the ED43/JFH1-β and -y cultures only. Compared to the 2a control virus, production of infectious viruses was significantly delayed. However, in subsequent passages efficient spread of infection and high HCV RNA titers were obtained. Infectivity titers were approximately 10-fold lower than for the 2a control virus. Sequence analysis of recovered 4a/2a recombinants from 3 serial passages and subsequent reverse genetic studies revealed a vital dependence on a mutation in the NS2 4a part. ED43/JFH1-γ further depended on a second NS2 mutation. Infectivity of the 4a/2a viruses was CD81 dependent. Conclusion: The developed 4a/2a viruses provide a robust in vitro tool for research in HCV genotype 4, including vaccine studies and functional analyses of an increasingly important genotype in the Middle East and Europe.
摘要翻译：本发明人开发了三种4a / 2a基因型重组体，其中JFH1结构基因（Core，E1和E2），p7以及NS2的全部或部分被基因型4a参考菌株ED43的相应基因替代。 NS2中的4a / 2a连接处置于第一跨膜结构域（α），细胞质部分（β）或NS2 / NS3切割位点（y）之后。在用RNA转录物转染Huh7.5细胞后，仅在ED43 / JFH1-β和-y培养物中产生感染性病毒。与2a对照病毒相比，感染性病毒的产生显着延迟。然而，在随后的传代中，获得了有效的感染传播和高HCV RNA滴度。感染滴度比2a对照病毒低约10倍。来自3个连续传代和随后的反向遗传研究的回收的4a / 2a重组体的序列分析揭示了对NS2a4部分突变的重要依赖性。 ED43 / JFH1-gamma进一步依赖于第二NS2突变。 4a / 2a病毒的感染率依赖于CD81。结论：开发的4a / 2a病毒为HCV基因型4的研究提供了强大的体外工具，包括中东和欧洲越来越重要的基因型的疫苗研究和功能分析。

3. 发明申请

US20110294194A1 EFFICIENT CELL CULTURE SYSTEM FOR HEPATITIS C VIRUS GENOTYPE 2B 失效
标题翻译： HEPATITIS C病毒基因组2B的有效细胞培养系统
公开(公告)号：US20110294194A1
公开(公告)日：2011-12-01
申请号：US13059130
申请日：2009-07-24
申请人： Judith M. Gottwein , Maria Lisa Knudsen , Troels Kasper Høyer Scheel , Jens Bukh
发明人： Judith M. Gottwein , Maria Lisa Knudsen , Troels Kasper Høyer Scheel , Jens Bukh
IPC分类号： C12N7/00 , C12N5/10 , C07H21/04
CPC分类号： C12N7/00 , A61K2039/53 , C07K14/005 , C07K16/109 , C07K2317/76 , C12N2770/24221 , C12N2770/24222
摘要： The present inventors developed hepatitis C virus 2b/2a intergenotypic recombinants in which the JFH1 structural genes (Core, E1 and E2), p7 and the complete NS2 were replaced by the corresponding genes of the genotype 2b reference strain J8. Sequence analysis of recovered 2b/2a recombinants from 2 transfection experiments revealed that 2b/2a was genetically stable. Conclusion: The developed 2b/2a viruses provide a robust in vitro tool for research in HCV genotype 2b, including vaccine studies and functional analyses.
摘要翻译：本发明人开发了丙型肝炎病毒2b / 2a基因型重组体，其中JFH1结构基因（Core，E1和E2），p7和完整的NS2被基因型2b参照菌株J8的相应基因替代。来自2个转染实验的回收的2b / 2a重组体的序列分析显示2b / 2a在遗传上是稳定的。结论：开发的2b / 2a病毒为HCV基因型2b的研究提供了强大的体外工具，包括疫苗研究和功能分析。

4. 发明申请

US20100093841A1 CELL CULTURE SYSTEM OF A HEPATITIS C GENOTYPE 3A AND 2A CHIMERA 有权
标题翻译：乙型肝炎病毒基因组3A和2A型细胞培养系统
公开(公告)号：US20100093841A1
公开(公告)日：2010-04-15
申请号：US12595822
申请日：2008-04-11
申请人： Judith M. Gottwein , Troels Kasper Høyer Scheel , Jesper Eugen-Olsen , Jens Bukh
发明人： Judith M. Gottwein , Troels Kasper Høyer Scheel , Jesper Eugen-Olsen , Jens Bukh
IPC分类号： A61K31/7052 , C07H21/00 , C12N15/63 , C12P21/00 , C12Q1/70 , C12Q1/68 , C12N7/00 , C07K16/00 , A61P31/12
CPC分类号： C12N7/00 , A61K2039/5254 , C12N2770/24251
摘要： The present inventors have developed a culture system for genotype 3a, which has a high prevalence worldwide. Since intergenotypic recombinant genomes exploiting the replication characteristics of JFH1 will be a valuable tool for the genotype specific study of the replaced genes and related therapeutics, the present inventors constructed a genotype 3a/2a (S52/JFH1) recombinant containing the structural genes (Core, E1, E2), p7 and NS2 of strain S52 and characterized it in Huh7.5 cells. S52/JFH1 and J6/JFH viruses passaged in cell culture had comparable growth kinetics and yielded similar peak HCV RNA titers and infectivity titers. Direct genome sequencing of cell culture derived S52/JFH1 viruses identified putative adaptive mutations in Core, E2, p7, NS3 and NS5A; clonal analysis revealed, that all genomes analyzed exhibited different combinations of these mutations. Finally, viruses resulting from transfection with RNA transcripts of five S52/JFH1 recombinant containing these combinations of putative adaptive mutations performed as efficiently as J6/JFH viruses in Huh7.5 15 cells and were all genetically stable after viral passage. In conclusion, the present inventors have developed a robust and genetically stable cell culture system for HCV genotype 3a.
摘要翻译：本发明人已经开发了一种在全球范围内具有高流行性的基因型3a的培养系统。由于利用JFH1的复制特征的基因型重组基因组将成为替代基因和相关治疗剂的基因型特异性研究的有价值的工具，本发明人构建了一种含有结构基因（核心，核苷酸）的基因型3a / 2a（S52 / JFH1） E1，E2），p7和NS2，并在Huh7.5细胞中表征。在细胞培养物中传代的S52 / JFH1和J6 / JFH病毒具有相似的生长动力学，并产生相似的HCV RNA滴度和感染性滴度。来自S52 / JFH1病毒的细胞培养物的直接基因组测序鉴定了核心，E2，p7，NS3和NS5A中的推定适应性突变; 克隆分析显示，所有分析的基因组都显示出这些突变的不同组合。最后，含有这些组合推定的适应性突变的5种S52 / JFH1重组RNA转录物转染的病毒与Huh7.515细胞中的J6 / JFH病毒一样有效地进行，并且在病毒传代后都具有遗传稳定性。总之，本发明人已经开发了用于HCV基因型3a的稳健和遗传稳定的细胞培养系统。

5. 发明授权

US09388389B2 JFH-1 based HCV cell culture systems for NS5A of genotypes 1-7 有权
标题翻译：基于JFH-1的HCV细胞培养系统NS5A基因型1-7
公开(公告)号：US09388389B2
公开(公告)日：2016-07-12
申请号：US13499788
申请日：2010-10-01
申请人： Troels Kasper Høyer Scheel , Judith M. Gottwein , Tanja Bertelsen Jensen , Jens Bukh
发明人： Troels Kasper Høyer Scheel , Judith M. Gottwein , Tanja Bertelsen Jensen , Jens Bukh
IPC分类号： C12N7/00 , C07K14/005 , C12Q1/18 , G01N33/569 , A61K39/00
CPC分类号： C12N7/00 , A61K39/00 , C07K14/005 , C12N2770/24222 , C12N2770/24251 , C12Q1/18 , G01N33/56983 , G01N2333/18
摘要： The present inventors developed hepatitis C virus recombinants expressing NS5A from genotype 1a, 1b, 2a, 3a, 4a, 5a, 6a or 7a in the context of a genotype 2a backbone. Additional recombinants express NS5A and the structural proteins (Core, E1 and E2), p7 and NS2 from genotype 1a, 1b, 3a, 4a, 5a, 6a or 7a in the genotype 2a backbone. Sequence analysis of the recombinants recovered after viral passage in Huh7.5 cells revealed adaptive mutations in NS5A and/or NS3. The importance of these mutations for improved growth kinetics was shown in reverse genetic studies.
摘要翻译：在基因型2a骨架的上下文中，本发明人从基因型1a，1b，2a，3a，4a，5a，6a或7a开发了表达NS5A的丙型肝炎病毒重组体。其他重组体在基因型2a骨架中表达NS5A和基因型1a，1b，3a，4a，5a，6a或7a的结构蛋白（核心，E1和E2），p7和NS2。 Huh7.5细胞病毒传代后回收的重组体的序列分析显示NS5A和/或NS3的适应性突变。这些突变对改善生长动力学的重要性在反向遗传研究中显示。

6. 发明授权

US08945584B2 Cell culture system of a hepatitis C genotype 3a and 2a chimera 有权
标题翻译：丙型肝炎基因型3a和2a嵌合体的细胞培养系统
公开(公告)号：US08945584B2
公开(公告)日：2015-02-03
申请号：US12595822
申请日：2008-04-11
申请人： Judith M. Gottwein , Troels Kasper Høyer Scheel , Jesper Eugen-Olsen , Jens Bukh
发明人： Judith M. Gottwein , Troels Kasper Høyer Scheel , Jesper Eugen-Olsen , Jens Bukh
IPC分类号： A61K39/29 , A61K39/12 , C12N7/02 , C12N15/06 , C12Q1/02 , C07H21/00 , C12N7/00 , A61K39/00
CPC分类号： C12N7/00 , A61K2039/5254 , C12N2770/24251
摘要： A robust and genetically stable cell culture system for Hepatitis C Virus (HCV) genotype 3a is provided. A genotype 3a/2a (S52/JFH1) recombinant containing the structural genes (Core, E1, E2), p7 and NS2 of strain S52 was constructed and characterized in Huh7.5 cells. S52/JFH1 and J6/JFH viruses passaged in cell culture had comparable growth kinetics and yielded similar peak HCV RNA titers and infectivity titers. Direct genome sequencing of cell culture derived S52/JFH1 viruses identified putative adaptive mutations in Core, E2, p7, NS3, and NS5A; clonal analysis revealed that all genomes analyzed exhibited different combinations of these mutations. Finally, viruses resulting from transfection with RNA transcripts of five S52/JFH1 recombinants containing these combinations of putative adaptive mutations performed as efficiently as J6/JFH viruses in Huh7.5 cells and were all genetically stable after viral passage.
摘要翻译：提供了一种用于丙型肝炎病毒（HCV）基因型3a的强大且遗传稳定的细胞培养系统。在Huh7.5细胞中构建并表征了包含菌株S52的结构基因（Core，E1，E2），p7和NS2的基因型3a / 2a（S52 / JFH1）重组体。在细胞培养物中传代的S52 / JFH1和J6 / JFH病毒具有相似的生长动力学，并产生相似的HCV RNA滴度和感染性滴度。来自S52 / JFH1病毒的细胞培养物的直接基因组测序鉴定了核心，E2，p7，NS3和NS5A中的推定的适应性突变; 克隆分析显示，所有分析的基因组都显示出这些突变的不同组合。最后，将含有这些假定适应性突变的组合的5种S52 / JFH1重组体的RNA转录物转染的病毒与Huh7.5细胞中J6 / JFH病毒一样有效地进行，并且在病毒传代后均具有遗传稳定性。

7. 发明授权

US08618275B2 Efficient cell culture system for hepatitis C virus genotype 5A 失效
标题翻译：丙型肝炎病毒基因型5A的高效细胞培养系统
公开(公告)号：US08618275B2
公开(公告)日：2013-12-31
申请号：US12600349
申请日：2008-05-19
申请人： Tanja Bertelsen Jensen , Judith M. Gottwein , Troels Kasper Høyer Scheel , Jesper Eugen-Olsen , Jens Bukh
发明人： Tanja Bertelsen Jensen , Judith M. Gottwein , Troels Kasper Høyer Scheel , Jesper Eugen-Olsen , Jens Bukh
IPC分类号： C07H21/00 , A61K39/12 , A61K39/29 , A61K39/295 , C12N7/00
CPC分类号： C12N7/00 , A61K2039/525 , C07K14/005 , C12N2770/24221 , C12N2770/24222 , C12N2770/24251
摘要： The present inventors developed 5a/2a intergenotypic recombinants in which the JFH1 structural genes (Core, E1 and E2), p7 and all of or part of NS2 were replaced by the corresponding genes of the genotype 5a reference strain SA13. Compared to the J6/JFH control virus, after transfection of in vitro transcripts in Huh7.5 cells, production of infectious viruses was delayed. However, in subsequent viral passages efficient spread of infection and HCV RNA titers as high as for J6/JFH were obtained. Infectivity titers were at all time points analyzed comparable to J6/JFH control virus. Sequence analysis of recovered 5a/2a recombinants from 2 serial passages and subsequent reverse genetic studies revealed adaptive mutations in p7, NS2 and/or NS3. Infectivity of the 5a/2a viruses was CD81 and SR-BI dependant, and the recombinant viruses could be neutralized by chronic phase sera from patients infected with genotype 5a. Conclusion: The developed 5a/2a viruses provide a robust in vitro tool for research in HCV genotype 5, including vaccine studies and functional analyses of an increasingly important genotype in South Africa and Europe.
摘要翻译：本发明人开发了5a / 2a基因型重组体，其中JFH1结构基因（Core，E1和E2），p7以及NS2的全部或部分被基因型5a参照菌株SA13的相应基因替代。与J6 / JFH对照病毒相比，转染Huh7.5细胞体外转录本后，传染性病毒的产生延迟。然而，在随后的病毒传代中，获得与J6 / JFH一样高的感染和HCV RNA滴度的有效扩散。在与J6 / JFH对照病毒相比较的所有时间点，感染滴度。来自2个连续传代和随后的反向遗传研究的回收的5a / 2a重组体的序列分析显示p7，NS2和/或NS3中的适应性突变。 5a / 2a病毒的感染率为CD81和SR-BI依赖性，重组病毒可以用来自感染基因型5a的患者的慢性期血清中和。结论：开发的5a / 2a病毒为HCV基因型5的研究提供了强大的体外工具，包括南非和欧洲越来越重要的基因型的疫苗研究和功能分析。

8. 发明申请

US20110059512A1 EFFICIENT CELL CULTURE SYSTEM FOR HEPATITIS C VIRUS GENOTYPE 6A 失效
标题翻译： HEPATITIS C病毒基因组6A的高效细胞培养系统
公开(公告)号：US20110059512A1
公开(公告)日：2011-03-10
申请号：US12808565
申请日：2008-12-19
申请人： Judith M. Gottwein , Troels Kasper Høyer Scheel , Tanja Bertelsen Jensen , Jens Bukh
发明人： Judith M. Gottwein , Troels Kasper Høyer Scheel , Tanja Bertelsen Jensen , Jens Bukh
IPC分类号： C12N7/01 , C07H21/00
CPC分类号： A61K39/29 , A61K39/12 , A61K2039/525 , A61K2039/53 , C07K14/005 , C12N7/00 , C12N2770/24221 , C12N2770/24222 , C12N2770/24234
摘要： The present inventors developed hepatitis C virus 6a/2a intergenotypic recombinants in which the JFH1 structural genes (Core, E1 and E2), p7 and the complete NS2 were replaced by the corresponding genes of the genotype 6a reference strain HK6a. Sequence analysis of recovered 6a/2a recombinants from 2 transfection experiments and subsequent reverse genetic studies revealed adaptive mutations in E1 and E2. Conclusion: The developed 6a/2a viruses provide a robust in vitro tool for research in HCV genotype 6, including vaccine studies and functional analyses.
摘要翻译：本发明人开发了丙型肝炎病毒6a / 2a基因型重组体，其中JFH1结构基因（Core，E1和E2），p7和完整的NS2被基因型6a参照菌株HK6a的相应基因替代。从2个转染实验和随后的反向遗传研究中回收的6a / 2a重组体的序列分析显示E1和E2中的适应性突变。结论：开发的6a / 2a病毒为HCV基因型6的研究提供了强大的体外工具，包括疫苗研究和功能分析。

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