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1. 发明授权

US08846891B2 Infectious genotype 1a, 1b, 2a, 2b, 3a, 5a, 6a and 7a hepatitis C virus lacking the hypervariable region 1 (HVR1) 有权
标题翻译：传染性基因型1a，1b，2a，2b，3a，5a，6a和7a丙型肝炎病毒缺乏高变区1（HVR1）
公开(公告)号：US08846891B2
公开(公告)日：2014-09-30
申请号：US13060533
申请日：2009-08-07
申请人： Jannick Prento , Judith M. Gottwein , Troels Kasper Hoyer Scheel , Tanja Bertelsen Jensen , Jens Bukh
发明人： Jannick Prento , Judith M. Gottwein , Troels Kasper Hoyer Scheel , Tanja Bertelsen Jensen , Jens Bukh
IPC分类号： C12N7/00 , C12N5/10 , C12N15/51 , A61K39/29 , C07K14/005 , A61K39/00
CPC分类号： C12N7/00 , A61K39/12 , A61K39/29 , A61K2039/5254 , C07K14/005 , C12N2770/24222 , C12N2770/24234 , C12N2770/24261
摘要： The present inventors used the previously developed H77/JFH 1T27OOC,A4O8OT (1a/2a), J4/JFH 1T2996C,A4827T,ΔHVRI (1b/2a), J6/JFH 1ΔHVRI (2a/2a), J8/JFH 1ΔHVRI (2b/2a), S52/JFH 1T27i8G,τ7i6oc (3a/2a), SA13/JFH 1C34O5G,A3696G (5a/2a) and HK6a/JFH 1T1389c,A1590G (6a/2a) constructs for the deletion of Hypervariable Region 1 (HVR1) to construct viable, JFH 1 (genotype 2a) based, genomes. The present inventors serially passaged the viruses in cell culture obtaining relatively high HCV RNA titers and infectivity titers. Sequence analysis of the viruses identified mutations adapting H77/JFH 1T27OOC,A4O8OT,ΔHVR1 (1a/2a), J8/JFH 1ΔHVR1 (2b/2a), S52/JFH 1T2718G,T716OC,ΔHVR1 (3a/2a) and J4/JFH 1T2996C,A4827T,ΔHVR1 (1b/2a) to the HVR1 deletion.
摘要翻译：本发明人使用先前开发的H77 / JFH 1T27OOC，A4O8OT（1a / 2a），J4 / JFH 1T2996C，A4827T，＆Dgr; HVRI（1b / 2a），J6 / JFH1＆Dgr; HVRI（2a / 2a），J8 / 1 / Dgr; HVRI（2b / 2a），S52 / JFH 1T27i8G，τ7i6oc（3a / 2a），SA13 / JFH 1C34O5G，A3696G（5a / 2a）和HK6a / JFH 1T1389c，A1590G（6a / 2a）区域1（HVR1）构建可行的，基于基因型2a（基因型2a）的基因组。本发明人在细胞培养物中连续传代病毒获得相对高的HCV RNA滴度和感染滴度。病毒的序列分析鉴定了H77 / JFH 1T27OOC，A4O8OT，＆Dgr; HVR1（1a / 2a），J8 / JFH 1＆Dgr; HVR1（2b / 2a），S52 / JFH 1T2718G，T716OC和Dgr; HVR1（3a / 2a））和J4 / JFH 1T2996C，A4827T，＆Dgr; HVR1（1b / 2a）的HVR1缺失。

2. 发明申请

US20110059513A1 EFFICIENT CELL CULTURE SYSTEM FOR HEPATITIS C VIRUS GENOTYPE 1A AND 1B 有权
标题翻译：有效的细胞培养系统用于丙型肝炎病毒基因组1A和1B
公开(公告)号：US20110059513A1
公开(公告)日：2011-03-10
申请号：US12809345
申请日：2008-12-19
申请人： Troels Kasper Hoyer Scheel , Judith M. Gottwein , Jannick Prento , Tanja Bertelsen Jensen , Jens Bukh
发明人： Troels Kasper Hoyer Scheel , Judith M. Gottwein , Jannick Prento , Tanja Bertelsen Jensen , Jens Bukh
IPC分类号： C12N7/00 , C07H21/04
CPC分类号： C12N7/00 , A61K39/12 , A61K39/29 , A61K2039/525 , A61K2039/53 , C07K14/005 , C12N2770/24221 , C12N2770/24222 , C12N2770/24234
摘要： The present inventors developed hepatitis C virus 1a/2a and 1b/2a intergenotypic recombinants in which the JFH1 structural genes (Core, E1 and E2), p7 and NS2 were replaced by the corresponding genes of the genotype Ia reference strain H77C or TN or the corresponding genes of the genotype Ib reference strain J4. Sequence analysis of recovered 1a/2a and 1b/2a recombinants from 2 serial passages and subsequent reverse genetic studies revealed adaptive mutations in e.g. p7, NS2 and/or NS3. In addition, the inventors demonstrate the possibility of using adaptive mutations identified for one HCV isolate in generating efficient cell culture systems for other isolates by transfer of mutations across isolates, subtypes or major genotypes. Furthermore neutralization studies showed that viruses of e.g. genotype 1 were efficiently neutralized by genotype Ia, 4a and 5a serum, an effect that could be utilized e.g. in vaccine development and immunological prophylaxis. The inventors in addition demonstrate the use of the developed systems for screening of antiviral substances in vitro and functional studies of the virus, e.g. identification of receptors required for HCV entry
摘要翻译：本发明人开发了丙型肝炎病毒1a / 2a和1b / 2a基因间重组体，其中JFH1结构基因（Core，E1和E2），p7和NS2被基因型1a参考菌株H77C或TN的相应基因替代，或基因型1b参考菌株J4的相应基因。来自2个连续传代和随后的反向遗传研究的回收的1a / 2a和1b / 2a重组体的序列分析揭示了例如， p7，NS2和/或NS3。此外，本发明人证明了通过在分离株，亚型或主要基因型上转移突变，可以使用为一种HCV分离株鉴定的适应性突变来产生用于其他分离物的有效细胞培养系统。此外，中和研究表明，基因型1被基因型1a，4a和5a血清有效地中和，可以使用例如，在疫苗开发和免疫预防中。本发明人另外证明了所开发的系统在体外筛选抗病毒物质的用途和病毒的功能研究，例如，鉴定HCV进入所需的受体

3. 发明授权

US08569472B2 Efficient cell culture system for hepatitis C virus genotype 6A 失效
标题翻译：丙型肝炎病毒基因型6A的高效细胞培养系统
公开(公告)号：US08569472B2
公开(公告)日：2013-10-29
申请号：US12808565
申请日：2008-12-19
申请人： Judith M. Gottwein , Troels Kasper Hoyer Scheel , Tanja Bertelsen Jensen , Jens Bukh
发明人： Judith M. Gottwein , Troels Kasper Hoyer Scheel , Tanja Bertelsen Jensen , Jens Bukh
IPC分类号： C07H21/00 , A61K39/12 , A61K39/29 , A61K39/295 , C12N7/00
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 analysis.
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。

4. 发明授权

US08506969B2 Efficient cell culture system for hepatitis C virus genotype 7a 失效
标题翻译：丙型肝炎病毒基因型7a高效细胞培养系统
公开(公告)号：US08506969B2
公开(公告)日：2013-08-13
申请号：US13059137
申请日：2009-07-31
申请人： Judith M. Gottwein , Troels Kasper Hoyer Scheel , Tanja Bertelsen Jensen , Jens Bukh
发明人： Judith M. Gottwein , Troels Kasper Hoyer Scheel , Tanja Bertelsen Jensen , Jens Bukh
IPC分类号： A61K39/12 , A61K39/29 , C12Q1/70 , C12N15/00 , C12N5/071 , C12N1/20
CPC分类号： C12N7/00 , A61K2039/525 , C07K14/005 , C07K2319/00 , C12N2770/24221 , C12N2770/24222
摘要： Genotype 7a has been identified recently, thus not much is known about the biology of this new, major HCV genotype. The present inventors developed hepatitis C virus 7a/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 7a strain QC69 and characterized them in Huh7.5 cells. Sequence analysis of 7a/JFH1 recombinants recovered after viral passage in Huh7.5 cells following 4 independent transfection experiments revealed adaptive mutations in Core, E2, NS2, NS5A and NS5B. In reverse genetic studies the importance of these mutations for improved growth kinetics was shown. Adapted 7a/JFH1 viruses showed growth kinetics, infectivity and RNA titers comparable to a previously developed 3a/JFH1 reference virus. Conclusion: The developed 7a/JFH1 viruses provide a robust in vitro tool for research in HCV genotype 7, including vaccine studies and functional analyses.
摘要翻译：最近鉴定了基因型7a，因此对这种新的主要HCV基因型的生物学知之甚少。本发明人开发了丙型肝炎病毒7a / 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7a菌株QC69的相应基因替代，并在Huh7.5中表征细胞。在4次独立转染实验后Huh7.5细胞病毒传代后恢复的7a / JFH1重组体的序列分析显示核心，E2，NS2，NS5A和NS5B中的适应性突变。在反向遗传研究中，显示了这些突变对改善生长动力学的重要性。适应的7a / JFH1病毒显示与先前开发的3a / JFH1参考病毒相当的生长动力学，感染性和RNA滴度。结论：开发的7a / JFH1病毒为HCV基因型7研究提供了强大的体外工具，包括疫苗研究和功能分析。

5. 发明申请

US20120003719A1 INFECTIOUS GENOTYPE 1a, 1b, 2a, 2b, 3a, 5a, 6a and 7a HEPATITIS C VIRUS LACKING THE HYPERVARIABLE REGION 1 (HVR1) 有权
标题翻译：感染基因1a，1b，2a，2b，3a，5a，6a和7a HEPATITIS C VIRUS LACKING THE HYPERVARIABLE REGION 1（HVR1）
公开(公告)号：US20120003719A1
公开(公告)日：2012-01-05
申请号：US13060533
申请日：2009-08-07
申请人： Jannick Prento , Judith M. Gottwein , Troels Kasper Hoyer Scheel , Tanja Bertelsen Jensen , Jens Bukh
发明人： Jannick Prento , Judith M. Gottwein , Troels Kasper Hoyer Scheel , Tanja Bertelsen Jensen , Jens Bukh
IPC分类号： C12N7/00 , C12N5/10 , C12N15/51
CPC分类号： C12N7/00 , A61K39/12 , A61K39/29 , A61K2039/5254 , C07K14/005 , C12N2770/24222 , C12N2770/24234 , C12N2770/24261
摘要： The present inventors used the previously developed H77/JFH1T27OOC,A4O8OT (1a/2a), J4/JFH1T2996C,A4827T,ΔHVRI (1b/2a), J6/JFH1ΔHVRI (2a/2a), J8/JFH1ΔHVRI (2b/2a), S52/JFH1T27i8G,τ7i6oc (3a/2a), SA13/JFH1C34O5G,A3696G (5a/2a) and HK6a/JFH1T1389c,A1590G (6a/2a) constructs for the deletion of Hypervariable Region 1 (HVR1) to construct viable, JFH1 (geno-type 2a) based, genomes. The present inventors serially passaged the viruses in cell culture obtaining relatively high HCV RNA titers and infectivity titers. Sequence analysis of the viruses identified mutations adapting H77/JFH1T27OOC,A4O8OT,ΔHVR1 (1a/2a), J8/JFH1ΔHVR1 (2b/2a), S52/JFH1T2718G,T716OC,ΔHVR1 (3a/2a) and J4/JFH1T2996C,A4827T,ΔHVR1 (1b/2a) to the HVR1 deletion.
摘要翻译：本发明人使用先前开发的H77 / JFH1T27OOC，A4O8OT（1a / 2a），J4 / JFH1T2996C，A4827T，＆Dgr; HVRI（1b / 2a），J6 / JFH1＆Dgr; HVRI（2a / 2a），J8 / JFH1＆Dgr; HVRI 2b / 2a），S52 / JFH1T27i8G，τ7i6oc（3a / 2a），SA13 / JFH1C34O5G，A3696G（5a / 2a）和HK6a / JFH1T1389c，用于缺失高变区1（HVR1）构建的A1590G（6a / 2a）可行，基于JFH1（基因型2a）的基因组。本发明人在细胞培养物中连续传代病毒获得相对高的HCV RNA滴度和感染滴度。病毒的序列分析鉴定了H77 / JFH1T27OOC，A4O8OT，＆Dgr; HVR1（1a / 2a），J8 / JFH1和Dgr; HVR1（2b / 2a），S52 / JFH1T2718G，T716OC，＆Dgr; HVR1（3a / 2a）和J4 / JFH1T2996C，A4827T，＆Dgr; HVR1（1b / 2a）至HVR1缺失。

6. 发明申请

US20110294195A1 EFFICIENT CELL CULTURE SYSTEM FOR HEPATITIS C VIRUS GENOTYPE 7a 失效
标题翻译： HEPATITIS C病毒基因组的有效细胞培养系统7a
公开(公告)号：US20110294195A1
公开(公告)日：2011-12-01
申请号：US13059137
申请日：2009-07-31
申请人： Judith M. Gottwein , Troels Kasper Hoyer Scheel , Tanja Bertelsen Jensen , Jens Bukh
发明人： Judith M. Gottwein , Troels Kasper Hoyer Scheel , Tanja Bertelsen Jensen , Jens Bukh
IPC分类号： C12N7/00 , C12N5/10 , C07H21/04
CPC分类号： C12N7/00 , A61K2039/525 , C07K14/005 , C07K2319/00 , C12N2770/24221 , C12N2770/24222
摘要： Genotype 7a has been identified recently, thus not much is known about the biology of this new, major HCV genotype. The present inventors developed hepatitis C virus 7a/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 7a strain QC69 and characterized them in Huh7.5 cells. Sequence analysis of 7a/JFH1 recombinants recovered after viral passage in Huh7.5 cells following 4 independent transfection experiments revealed adaptive mutations in Core, E2, NS2, NS5A and NS5B. In reverse genetic studies the importance of these mutations for improved growth kinetics was shown. Adapted 7a/JFH1 viruses showed growth kinetics, infectivity and RNA titers comparable to a previously developed 3a/JFH1 reference virus. Conclusion: The developed 7a/JFH1 viruses provide a robust in vitro tool for research in HCV genotype 7, including vaccine studies and functional analyses.
摘要翻译：最近鉴定了基因型7a，因此对这种新的主要HCV基因型的生物学知之甚少。本发明人开发了丙型肝炎病毒7a / 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7a菌株QC69的相应基因替代，并在Huh7.5中表征细胞。在4次独立转染实验后Huh7.5细胞病毒传代后恢复的7a / JFH1重组体的序列分析显示核心，E2，NS2，NS5A和NS5B中的适应性突变。在反向遗传研究中，显示了这些突变对改善生长动力学的重要性。适应的7a / JFH1病毒显示与先前开发的3a / JFH1参考病毒相当的生长动力学，感染性和RNA滴度。结论：开发的7a / JFH1病毒为HCV基因型7研究提供了强大的体外工具，包括疫苗研究和功能分析。

7. 发明授权

US08772022B2 Hepatitis C virus expressing reporter tagged NS5A protein 失效
标题翻译：丙型肝炎病毒表达报告基因标记NS5A蛋白
公开(公告)号：US08772022B2
公开(公告)日：2014-07-08
申请号：US13121565
申请日：2009-10-05
申请人： Judith M. Gottwein , Troels Kasper Hoyer Scheel , Jens Bukh , Jannick Prento , Tanja Bertelsen Jensen , Jacob Bo Lademann , Yiping Li
发明人： Judith M. Gottwein , Troels Kasper Hoyer Scheel , Jens Bukh , Jannick Prento , Tanja Bertelsen Jensen , Jacob Bo Lademann , Yiping Li
IPC分类号： C12N15/00 , C12N15/64 , C12N7/00 , C12N7/01 , C12N5/00 , A61K39/29
CPC分类号： C12N15/86 , A61K2039/525 , C07K14/005 , C12N7/00 , C12N2770/24222 , C12N2770/24243 , C12N2770/24251
摘要： Hepatitis C reporter viruses containing Core through NS2 of prototype isolates of all major HCV genotypes and the remaining genes of isolate JFH1, by insertion of reporter genes in domain III of HCV NS5A were developed. A deletion upstream of the inserted reporter gene sequence conferred favorable growth kinetics in Huh7.5 cells to these viruses. These reporter viruses can be used for high throughput analysis of drug and vaccine candidates as well as patient samples. JFH1-based intergenotypic recombinants with genotype specific homotypic 5′UTR, or heterotypic 5′UTR (either of genotype 1a (strain H77) or of genotype 3a (strain S52)) were also developed. The present inventors additionally developed J6/JFH1 recombinants with the 5′UTR of genotypes 1-6. These recombinants with different 5′UTRs are a useful to study the function of the 5′UTR in a genotype specific manner.
摘要翻译：开发了通过NS2的III型插入报告基因，通过NS2的核心通过NS2的所有主要HCV基因型的原型分离株和分离株JFH1的剩余基因的丙型肝炎报告病毒。插入报道基因序列上游的缺失在Huh7.5细胞中赋予这些病毒有利的生长动力学。这些报告病毒可用于药物和疫苗候选物以及患者样品的高通量分析。还开发了具有基因型特异性同种型5'UTR或异型5'UTR（基因型1a（菌株H77）或基因型3a（菌株S52））的基于JFH1的基因间重组体。本发明人还开发了具有基因型1-6的5'UTR的J6 / JFH1重组体。具有不同5'UTR的这些重组体可用于以基因型特异性方式研究5'UTR的功能。

8. 发明授权

US08563706B2 Efficient cell culture system for hepatitis C virus genotype 1A and 1B 有权
标题翻译：丙型肝炎病毒基因型1A和1B的高效细胞培养系统
公开(公告)号：US08563706B2
公开(公告)日：2013-10-22
申请号：US12809345
申请日：2008-12-19
申请人： Troels Kasper Hoyer Scheel , Judith M. Gottwein , Jannick Prento , Tanja Bertelsen Jensen , Jens Bukh
发明人： Troels Kasper Hoyer Scheel , Judith M. Gottwein , Jannick Prento , Tanja Bertelsen Jensen , Jens Bukh
IPC分类号： C07H21/00 , A61K39/12 , A61K39/29 , A61K39/295 , C12N7/00
CPC分类号： C12N7/00 , A61K39/12 , A61K39/29 , A61K2039/525 , A61K2039/53 , C07K14/005 , C12N2770/24221 , C12N2770/24222 , C12N2770/24234
摘要： The present inventors developed hepatitis C virus 1a/2a and 1b/2a intergenotypic recombinants in which the JFH1 structural genes (Core, E1 and E2), p7 and NS2 were replaced by the corresponding genes of the genotype Ia reference strain H77C or TN or the corresponding genes of the genotype Ib reference strain J4. Sequence analysis of recovered 1a/2a and 1b/2a recombinants from 2 serial passages and subsequent reverse genetic studies revealed adaptive mutations in e.g. p7, NS2 and/or NS3. In addition, the inventors demonstrate the possibility of using adaptive mutations identified for one HCV isolate in generating efficient cell culture systems for other isolates by transfer of mutations across isolates, subtypes or major genotypes. Furthermore neutralization studies showed that viruses of e.g. genotype 1 were efficiently neutralized by genotype Ia, 4a and 5a serum, an effect that could be utilized e.g. in vaccine development and immunological prophylaxis. The inventors in addition demonstrate the use of the developed systems for screening of antiviral substances in vitro and functional studies of the virus, e.g. identification of receptors required for HCV entry.
摘要翻译：本发明人开发了丙型肝炎病毒1a / 2a和1b / 2a基因间重组体，其中JFH1结构基因（Core，E1和E2），p7和NS2被基因型1a参考菌株H77C或TN的相应基因替代，或基因型1b参考菌株J4的相应基因。来自2个连续传代和随后的反向遗传研究的回收的1a / 2a和1b / 2a重组体的序列分析揭示了例如， p7，NS2和/或NS3。此外，本发明人证明了通过在分离株，亚型或主要基因型上转移突变，可以使用为一种HCV分离株鉴定的适应性突变来产生用于其他分离物的有效细胞培养系统。此外，中和研究表明，基因型1被基因型1a，4a和5a血清有效地中和，可以使用例如，在疫苗开发和免疫预防中。本发明人另外证明了所开发的系统在体外筛选抗病毒物质的用途和病毒的功能研究，例如，鉴定HCV进入所需的受体。

9. 发明申请

US20130052716A1 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基因组1-7
公开(公告)号：US20130052716A1
公开(公告)日：2013-02-28
申请号：US13499788
申请日：2010-10-01
申请人： Troels Kasper Hoyer Scheel , Judith M. Gottwein , Tanja Bertelsen Jensen , Jens Bukh
发明人： Troels Kasper Hoyer Scheel , Judith M. Gottwein , Tanja Bertelsen Jensen , Jens Bukh
IPC分类号： C12N7/00 , C12N15/51 , C12N5/10
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。

10. 发明申请

US20120003741A1 HEPATITIS C VIRUS EXPRESSING REPORTER TAGGED NS5A PROTEIN 失效
公开(公告)号：US20120003741A1
公开(公告)日：2012-01-05
申请号：US13121565
申请日：2009-10-05
申请人： Judith M. Gottwein , Troels Kasper Hoyer Scheel , Jens Bukh , Jannick Prento , Tanja Bertelsen Jensen , Yiping Li , Jacob Bo Lademann
发明人： Judith M. Gottwein , Troels Kasper Hoyer Scheel , Jens Bukh , Jannick Prento , Tanja Bertelsen Jensen , Yiping Li , Jacob Bo Lademann
IPC分类号： C12N7/01 , C12N5/10 , C12N15/85 , C12N15/51
CPC分类号： C12N15/86 , A61K2039/525 , C07K14/005 , C12N7/00 , C12N2770/24222 , C12N2770/24243 , C12N2770/24251
摘要： The present inventors developed hepatitis C reporter viruses containing Core through NS2 of prototype isolates of all major HCV genotypes and the remaining genes of isolate JFH1, by insertion of reporter genes in domain III of HCV NS5A. The inventors have identified a deletion upstream of the inserted reporter gene sequence, which conferred favourable growth kinetics in Huh7.5 cells to these viruses. These reporter viruses can be used for high throughput analysis of drug and vaccine candidates as well as patient samples. Drugs could be evaluated for their potential to prevent infection or cure infected cells. The neutralizing capacity of antibodies induced by vaccine candidates could be evaluated in order to define successful vaccination strategies. Broadly neutralizing antibodies could be identified testing engineered antibodies and antibodies derived from serum of HCV infected individuals; thus this technique could contribute to the development of immunotherapy. The developed systems could aid individualized treatment of HCV infected: Patient isolates could be tested for resistance to drugs by introduction of genome regions involved in drug resistance in the developed constructs and subsequent treatment with the drug of interest. The present inventors also developed JFH1-based intergenotypic recombinants with genotype specific homotypic 5UTR, or heterotypic 5′UTR (either of genotype 1a (strain H77) or of genotype 3a (strain S52)). The present inventors additionally developed J6/JFH1 recombinants with the 5′UTR of genotypes 1-6. These recombinants with different 5UTRs are a useful to study the function of the 5′UTR in a genotype specific manner.
摘要翻译：本发明人通过在HCV NS5A的结构域III插入报道基因，开发了通过NS2的核心通过NS2分析所有主要HCV基因型的原型分离株和分离株JFH1的剩余基因的丙型肝炎报告病毒。发明人已经鉴定了插入的报道基因序列上游的缺失，其赋予Huh7.5细胞对这些病毒有利的生长动力学。这些报告病毒可用于药物和疫苗候选物以及患者样品的高通量分析。可以评估药物的潜力，以防止感染或治愈感染细胞。可以评估疫苗候选者诱导的抗体的中和能力，以确定成功的疫苗接种策略。可以鉴定出广泛中和抗体测试工程化抗体和源自HCV感染个体的血清的抗体; 因此这种技术可能有助于免疫治疗的发展。开发的系统可以帮助HCV感染的个体化治疗：可以通过在开发的构建体中引入参与耐药性的基因组区域并随后用感兴趣的药物进行治疗来测试患者分离物对药物的抗药性。本发明人还开发了具有基因型特异性同种型5UTR或异型5'UTR（基因型1a（菌株H77）或基因型3a（菌株S52））的基于JFH1的基因间重组体。本发明人还开发了具有基因型1-6的5'UTR的J6 / JFH1重组体。具有不同5UTR的这些重组体可用于以基因型特异性方式研究5'UTR的功能。

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