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公开(公告)号：US20100093841A1
公开(公告)日：2010-04-15
申请号：US12595822
申请日：2008-04-11
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。
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2.发明授权Adaptive mutations allow establishment of JFH1-based cell culture systems for hepatitis C virus genotype 4A 有权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
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。
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公开(公告)号：US08945584B2
公开(公告)日：2015-02-03
申请号：US12595822
申请日：2008-04-11
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。
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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。
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5.发明申请公开(公告)号：US20110021611A1
公开(公告)日：2011-01-27
申请号：US12600349
申请日：2008-05-19
申请人： Tanja Bertelsen Jensen , Judith M. Gottwein , Troels Kasper Hoyer Scheel , Jesper Eugen-Olsen , Jens Bukh
发明人： Tanja Bertelsen Jensen , Judith M. Gottwein , Troels Kasper Hoyer Scheel , Jesper Eugen-Olsen , Jens Bukh
IPC分类号： A61K31/7088 , C07H21/00 , C12N15/63 , C12N15/85 , C12P21/00 , C12N5/10 , C12Q1/70 , C07K16/10 , A61P31/14
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。
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6.发明申请ADAPTIVE MUTATIONS ALLOW ESTABLISHMENT OF JFH1-BASED CELL CULTURE SYSTEMS FOR HEPATITIS C VIRUS GENOTYPE 4A 有权适应性突变允许建立基于JFH1的细胞培养系统，用于HEPATITIS C病毒基因组4A公开(公告)号：US20100158948A1
公开(公告)日：2010-06-24
申请号：US12595825
申请日：2008-04-11
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 (a), 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结合位于第一个跨膜结构域（a），细胞质部分（/ bgr）或NS2 / NS3切割位点（y）之后。 在用RNA转录物转染Huh7.5细胞后，在ED43 / JFH1-＆bgr中产生感染性病毒; 和 - 只有文化。 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-γ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。
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公开(公告)号：US20120015386A1
公开(公告)日：2012-01-19
申请号：US13245521
申请日：2011-09-26
IPC分类号： C12Q1/04 , G01N33/569
CPC分类号： G01N33/6863 , C12Q1/6883 , C12Q1/689 , C12Q2600/158 , G01N33/505 , G01N33/56911 , G01N33/56927 , G01N2333/02 , G01N2333/16 , G01N2333/295 , G01N2333/35 , G01N2333/44 , Y02A50/451 , Y02A50/55
摘要： The present invention relates to an immunological method and, more particularly, a method for measuring cell-mediated immune reactivity (CMI) in mammals based on the production of IP-10. The invention further discloses an assay and a kit for measuring CMI to an antigen using whole blood or other suitable biological samples. The methods of the present invention are useful in therapeutic and diagnostic protocols for human, livestock and veterinary and wild life applications, thus the invention further relates to a method for diagnosing an infection in a mammal.
摘要翻译： 本发明涉及免疫学方法，更具体地说，涉及一种基于IP-10生产测定哺乳动物细胞介导的免疫反应性（CMI）的方法。 本发明还公开了使用全血或其它合适的生物样品测量CMI至抗原的测定和试剂盒。 本发明的方法可用于人类，家畜和兽医和野生生物应用的治疗和诊断方案，因此本发明还涉及用于诊断哺乳动物感染的方法。
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公开(公告)号：US20100086950A1
公开(公告)日：2010-04-08
申请号：US12438515
申请日：2007-09-05
申请人： Morten Ruhwald , Pemille Ravn , Jesper Eugen-Olsen
发明人： Morten Ruhwald , Pemille Ravn , Jesper Eugen-Olsen
IPC分类号： G01N33/53
CPC分类号： G01N33/6863 , C12Q1/6883 , C12Q1/689 , C12Q2600/158 , G01N33/505 , G01N33/56911 , G01N33/56927 , G01N2333/02 , G01N2333/16 , G01N2333/295 , G01N2333/35 , G01N2333/44 , Y02A50/451 , Y02A50/55
摘要： The present invention relates to an immunological method and, more particularly, a method for measuring cell-mediated immune reactivity (CMI) in mammals based on the production of IP-10. The invention further discloses an assay and a kit for measuring CMI to an antigen using whole blood or other suitable biological samples. The methods of the present invention are useful in therapeutic and diagnostic protocols for human, livestock and veterinary and wild life applications, thus the invention further relates to a method for diagnosing an infection in a mammal.
摘要翻译： 本发明涉及免疫学方法，更具体地说，涉及一种基于IP-10生产测定哺乳动物细胞介导的免疫反应性（CMI）的方法。 本发明还公开了使用全血或其它合适的生物样品测量CMI至抗原的测定和试剂盒。 本发明的方法可用于人类，家畜和兽医和野生生物应用的治疗和诊断方案，因此本发明还涉及用于诊断哺乳动物感染的方法。
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9.发明授权Method of prognosticating respiratory bacterial infection using urokinse receptor measurement 有权使用尿激酶受体测量预测呼吸细菌感染的方法公开(公告)号：US07399602B2
公开(公告)日：2008-07-15
申请号：US10478331
申请日：2002-05-21
申请人： Jesper Eugen-Olsen
发明人： Jesper Eugen-Olsen
IPC分类号： G01N33/569 , G01N33/566
CPC分类号： G01N33/5695 , G01N33/566 , G01N33/56944 , G01N2333/705
摘要： Method of diagnosing and/or prognosticating HIV infection in a subject comprising the steps of: (a) performing in vitro a measurement of the level of a marker in the form of (i) urokinase plasminogen activator receptor (uPAR), (ii) soluble urokinase plasminogen activator receptor (suPAR), (iii) urokinase-type plasminogen activator (uPA), (iv) one or more degradation products of (i), (ii) or (iii), and/or (v) an mRNA for (i), (ii) or (iii), in a biological fluid sample from a subject, and (b) using the measurement value obtained to evaluate the state of the subject.
摘要翻译： 在受试者中诊断和/或预测HIV感染的方法，包括以下步骤：（a）体外测量以（i）尿激酶纤溶酶原激活物受体（uPAR）形式的标志物的水平，（ii）可溶性 尿激酶纤溶酶原激活物受体（suPAR），（iii）尿激酶型纤溶酶原激活物（uPA），（iv）（i），（ii）或（iii）的一种或多种降解产物和/或（v） （i），（ii）或（iii）），和（b）使用所获得的测量值来评估受试者的状态。
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公开(公告)号：US08815519B2
公开(公告)日：2014-08-26
申请号：US12520718
申请日：2007-12-12
IPC分类号： G01N33/53
CPC分类号： G01N33/6893 , G01N2333/70596 , G01N2800/04 , G01N2800/52 , G01N2800/7095
摘要： The invention concerns a marker for low-grade inflammation and metabolic syndrome (MS) and MS-related diseases and/or low-grade inflammation-related diseases such as cardiovasculardisease, ischemic heart disease and type 2 diabetes. More particularly it concerns the measurement of the concentration of soluble urokinase plasminogen activator receptor (suPAR) in human biological fluids (sputum, cystic fluid, ascites, serum, plasma, urine) as a tool of diagnosing and/or prognosticating low-grade inflammation and metabolic syndrome and the risk of development of the related diseases such as cancer, cardiovascular disease, ischemic heart disease and type 2 diabetes.
摘要翻译： 本发明涉及低度炎症和代谢综合征（MS）和MS相关疾病和/或低度炎症相关疾病如心血管疾病，缺血性心脏病和2型糖尿病的标志物。 更具体地说，它涉及测量人体生物液体（痰液，囊性液体，腹水，血清，血浆，尿液）中可溶性尿激酶纤溶酶原激活物受体（suPAR）的浓度，作为诊断和/或预测低度炎症的工具， 代谢综合征和相关疾病如癌症，心血管疾病，缺血性心脏病和2型糖尿病发展的风险。
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