CN111108116A - 逆转录病毒载体 - Google Patents
逆转录病毒载体 Download PDFInfo
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- CN111108116A CN111108116A CN201880058492.6A CN201880058492A CN111108116A CN 111108116 A CN111108116 A CN 111108116A CN 201880058492 A CN201880058492 A CN 201880058492A CN 111108116 A CN111108116 A CN 111108116A
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明涉及包含病毒基因或其衍生物的核酸分子,用于生产逆转录病毒包装载体以及逆转录病毒包装和生产细胞系。在一个实施方式中,核酸分子包含env基因和gag‑pol基因,其中,env基因的编码序列和gag‑pol基因的编码序列处于相反方向。
Description
技术领域
本发明涉及包含病毒基因或其衍生物的核酸分子,用于生产逆转录病毒包装载体以及逆转录病毒包装和生产细胞系。在一个实施方式中,核酸分子包含env基因和gag-pol基因,其中,env基因和gag-pol基因的编码序列处于相反方向。
背景技术
逆转录病毒(包括慢病毒)是经历复杂生命周期的正义RNA病毒,生命周期涉及其基因组逆转录为脱氧核糖核酸(DNA),其随后在病毒感染之后整合到宿主细胞基因组中。它们能够将其基因组作为DNA插入靶细胞的基因组中的几乎任何基因座中并且能够介导病毒基因的长期表达,其中,DNA在感染的细胞分裂时被复制到每个子细胞中。它们通过使用用于转录的细胞RNA聚合酶而产生其基因组作为未剪接的mRNA分子。然后使用称为Rev的病毒蛋白将病毒基因组转运到细胞质中。然后使用病毒编码的结构蛋白包膜(Env)、Gag和聚合酶(Pol)将基因组包装成细胞溶胶中的病毒颗粒。逆转录病毒基因组的长度通常为7kb-10kb,在通常研究的HIV病毒的情况下,基因组长度为9.7kb。它以每病毒粒子2个拷贝存在于每个病毒颗粒中。
逆转录病毒生命周期及其结构灵活性提供了许多生物技术应用,比如将DNA递送到哺乳动物细胞的基因组中。此外,逆转录病毒可以被修饰以在其表面中包含非逆转录病毒糖蛋白,从而赋予逆转录病毒颗粒以糖蛋白所源自的病毒的细胞取向性。这在天然逆转录病毒糖蛋白具有有限的细胞嗜性时是特别重要的。一个这种实例是HIV-1的GP160糖蛋白,其已经进化以结合CD4受体并且仅感染在表面上携带该蛋白的细胞。在HIV-1的情况下,病毒颗粒在称为假型包装的过程中经常被修饰以含有不同于天然糖蛋白的糖蛋白。最常见的是,这是用来自水泡性口炎病毒(VSV-G)的糖蛋白来提供广泛得多的细胞嗜性来实现的。
当在实验室中使用逆转录病毒作为工具时,它们通常被修饰以形成可以表达一个或更多个转基因或shRNA分子的复制缺陷型载体,并且这些修饰的病毒为细胞转基因表达和工程提供通用载体。逆转录病毒包装过程的灵活性还允许适应变化的基因组尺寸:可以包装小至3kb且大至18kb的基因组,尽管在这些极端情况下病毒滴定可能会受损。
现在已经使用逆转录病毒(和近来慢病毒)来执行若干临床试验,以离体感染干细胞进而表达在遗传性单基因病症的治疗中待补充的转基因,然后再将它们引入患者。这通常在自体同源基础上进行,尽管一些干细胞也可以作为异源移植物应用。
逆转录病毒/慢病毒也在过继细胞转移领域中发现有重要应用,最值得注意的是允许在细胞扩增并再输注到患者之前在T细胞内表达杂合“嵌合抗原受体”(CAR)。CAR通常具有细胞外抗体结构和基于T细胞受体的细胞内结构,但CAR被修饰(在第2代CAR和第3代CAR中)用以在外侧部分结合至其抗原之后提高细胞刺激的质量。这种“CAR T细胞”方法已经显示在B细胞淋巴瘤的临床治疗中使用编码识别CD19的CAR的慢病毒获得了巨大的成功,并且第一份美国产品许可证预期在不久的将来将被授予Novartis关于其CD19特异性CAR T细胞(称为CTL019)。现在正在扩展应用领域以解决其他分子靶标和其他恶性肿瘤。因此,存在对大规模慢病毒制造的扩展需要,使用现有病毒生产系统实现起来是具有挑战性的。
除了临床使用之外,许多实验室经常使用慢病毒载体进行研究和开发,其中需要将外源DNA插入到细胞基因组中。慢病毒的多功能性已经允许它们用于将DNA引入到广范围的细胞类型中,包括但不限于人和小鼠干细胞、癌细胞、原代组织细胞(例如,肝脏、神经元和成纤维细胞)。
这些细胞的感染仅可能通过用广泛嗜性糖蛋白、最常见的是VSV-G表面糖蛋白包被病毒或假型包装病毒而实现。该蛋白使得能够感染来自几乎所有器官的细胞和跨越许多物种感染,所述许多物种包括但不限于人、小鼠、大鼠、仓鼠、猴、兔、驴和马、绵羊、牛和古世纪猿。
尽管野生型逆转录病毒/慢病毒可以在宿主细胞中复制,但是用于转基因和shRNA表达的逆转录病毒/慢病毒载体通常会以多种方式进行缺陷,以消除其复制以及引起疾病的能力。这意味着为了生长一批能够进行单感染轮的感染性病毒颗粒用于实验或临床用途,有必要将从病毒基因组中遗传性地去除的若干病毒基因(以及由此的病毒蛋白)同时提供到用于病毒包装的细胞中。这些基因通常以三个或四个单独的质粒提供,并且共转染到细胞中。中心组分是编码病毒载体基因组的质粒(包括调节靶细胞转录的任何转基因和相关启动子),其含有包装信号用以指导组装病毒颗粒将对应的RNA掺入新的病毒颗粒中。其他病毒蛋白比如Gag-Pol、Tat和Rev的基因通常由共转染的其他质粒提供,而另一质粒提供了待掺入到新形成的病毒颗粒的包膜中的糖蛋白,该糖蛋白将指导它们的感染性嗜性。gag-pol表达盒编码病毒衣壳和内部结构蛋白以及聚合酶和蛋白酶活性。rev基因用于通过与称为Rev反应元件(RRE)的病毒基因组的特定区域结合而增强逆转录病毒/慢病毒基因组的核输出。
逆转录病毒和慢病毒包装系统的复杂性导致了许多“代”,每一代都提高了先前系统的安全性。在“第一代”包装系统中,使用了三个质粒:一个编码除包膜(envelope)基因之外的所有HIV基因的质粒;提供表面糖蛋白(最常见的是VSV-G)的第二质粒;以及一个含有待包装的病毒基因组的质粒。该系统的缺点是含有病毒基因的质粒含有与病毒基因组质粒同源的DNA的大区域,可能允许质粒之间的重组。这可能导致产生能够引起疾病的感染性病毒。其他问题包括存在许多病毒生产不需要的病毒基因,包括VPU、VIF、VPR和Nef。
在“第二代”系统中,从系统中移除了九个HIV-1基因编码区中的5个。此方法还产生了三质粒系统,其中,一个质粒包含gag-pol基因以及Tat和Rev蛋白的辅助基因,第二质粒编码糖蛋白(最常见的是VSV-G),第三质粒编码待包装的病毒基因组。该系统中的病毒基因组通常包含野生型5’长末端重复序列(LTR),并且因此需要tat基因进行转录激活和基因组生产。该系统的优点在于病毒基因组与包装质粒之间同源性的降低降低了潜在危险的复制型逆转录病毒形成的可能性。
在最新的“第三代”慢病毒载体系统中,使用了四个质粒而不是三个质粒。通过将系统分为4个质粒(3个辅助质粒和1个包含载体基因组加转基因的质粒),“第三代”系统具有许多优势(主要是通过增加形成复制型病毒所需的重组事件的数量)。然而,“第三代”系统也具有另一个显著优势,因为它们具有包含启动子的修饰的5-LTR,并且因此基因组的转录不依赖于Tat蛋白的转录激活,从而消除了系统中对待编码的Tat的需要。它们在使用的任何质粒上均不包含Tat蛋白。rev基因也被置于单个质粒上。因此,在第三代系统中,四个质粒包含1:gag-pol,2:糖蛋白(最常见的是VSV-G),3:rev,以及4:编码包含感兴趣的转基因或RNA的自灭活慢病毒基因组的质粒。具体谈到糖蛋白质粒,可以获得和使用了若干种包膜糖蛋白,但是使用最广泛的是来自水泡性口炎病毒的糖蛋白,称为VSV-G。
这些慢病毒包装基因中的一些(特别是VSV-G和gag-pol组分)被广泛报道对哺乳动物细胞是有毒的(Burns等,Proc.Natl.Acad.Sci.90,8033-8037(1993);Yee等,Proc.Natl.Acad.Sci.,90,9564-9568(1994);Hoffman等,J.Gen.Virol,91,2782-2793(2010)。这为开发表达许多所需包装蛋白的稳定包装细胞提供了实质性的障碍。因此,通过需要在细胞中通过瞬时转染同时表达所有质粒的低效方法制备了批量慢病毒。这种转染方法价格昂贵,难以大规模复制,并且经常导致质粒和细胞碎片污染病毒制品。
非常需要为逆转录病毒和慢病毒创建“包装”细胞系,所述逆转录病毒和慢病毒编码在细胞基因组内产生新病毒颗粒所需的一些或全部组分。这可以降低病毒包装所需的质粒转染的复杂性,并且具有每个细胞都将表达病毒生产所需的基因的主要优势。创建表达相对于彼此具有特定化学计量的病毒蛋白的细胞系的能力将是另一显著的优势。已经进行了几种尝试来稳定地或在条件启动子或诱导型启动子下表达病毒蛋白,例如由Ikeda等生产的STAR细胞(Nature Biotechnology,21,560-572(2003))使用密码子优化的HIV Gag、Pol和Rev的逆转录病毒转导来实现在包装细胞中的持续表达。然而,使用这些细胞产生的病毒的滴度通常低于工业标准1×107-1×108/ml。一些基因也必须是诱导型的或者需要独立的抗生素选择剂的要求显著增加了系统的复杂性,并且使得按比例扩大生产规模更具挑战性。迄今为止,由于所报道的毒性,还没有生产稳定和组成性表达最常用的逆转录病毒和慢病毒糖蛋白VSV-G的细胞系。
在单个质粒/载体上具有编码Env蛋白和Gag/Pol蛋白的序列的优点是减少了产生病毒颗粒所需的质粒数量,从而提高了病毒生产系统的效率。然而,这种布置具有明显的缺点,即,它增加了形成潜在危险的复制型逆转录病毒的可能性。如果在相同的5’至3’方向上包含Env编码序列和Gag-Pol编码序列这两者的细胞中产生单个mRNA,则两种蛋白质都可以由相同的mRNA分子产生,那么发生这种情况的机会就会大大增加。
发明内容
发明人现已发现,将Env蛋白的编码序列放在同一质粒/载体的一条链上,而将Gag/Pol蛋白的编码序列放在同一质粒/载体的相对链上,确保不可能从产生编码Env序列和Gag-Pol序列的单个mRNA的启动子进行通读,从而降低了形成复制型病毒的风险。
因此,本发明的一个目的是提供核酸分子和逆转录病毒包装载体,特别地其可以用于减少目前生产病毒颗粒所需的质粒的数量,从而提高病毒生产系统的整体效率。
在一个实施方式中,本发明提供了一种双链核酸分子,其包含:
(a)包含env基因的第一核酸;以及
(b)包含gag-pol基因的第二核酸;
其中,所述第一核酸的编码序列和所述第二核酸的编码序列在所述双链核酸分子的相对链上,其中,env基因和gag-pol基因独立地与第一诱导型启动子和第二诱导型启动子可操作地相关联,所述第一诱导型启动子和所述第二诱导型启动子在它们之间具有小于95%的核苷酸序列同一性,并且其中,所述双链核酸分子包含1个或多个编码凋亡抑制剂的核苷酸序列。
在一些实施方式中,所述双链核酸分子另外包含含有rev基因的核酸。在一些实施方式中,所述双链核酸分子另外包含含有转基因的核酸。优选地,所述双链核酸分子是逆转录病毒载体,更优选地是慢病毒载体。
所述双链核酸分子中的核酸可以是DNA或RNA,优选为DNA。
优选地,所述双链核酸分子是逆转录病毒载体。如本文中所使用的,术语“逆转录病毒载体”是指可用于产生逆转录病毒的载体或质粒。逆转录病毒载体的实例包括γ-逆转录病毒载体(例如,衍生自鼠白血病病毒的载体)和慢病毒载体。
优选地,所述逆转录病毒载体是慢病毒载体。如本文中所使用的,术语“慢病毒载体”是指可用于生产慢病毒的载体或质粒。例如,所述慢病毒载体可以是包装载体、包膜载体或包装/包膜载体。
env基因、gag基因、pol基因和rev基因优选地是病毒基因或衍生自病毒基因。更优选地,它们是逆转录病毒基因或衍生自逆转录病毒基因。逆转录病毒的实例包括慢病毒、α-逆转录病毒、γ-逆转录病毒(例如,鼠白血病病毒)和泡沫逆转录病毒。优选地,所述逆转录病毒是慢病毒。
慢病毒是逆转录病毒科家族的一个亚类,其越来越多地用于转基因递送和蛋白质表达,特别地用于祖细胞群比如造血干细胞和T细胞中。与大多数逆转录病毒不同,慢病毒能够独立于细胞周期递送它们的基因组或其修饰形式,并且常常在较短的时间范围内实现更高的细胞感染效率。这使得它们成为用于研究和临床使用的有效得多的病毒载体。
慢病毒家族目前由10种病毒组成。这些物种分为五个组,包括:牛慢病毒组(牛免疫缺陷病毒和Jembrana病病毒)、马慢病毒组(马传染性贫血病毒、猫慢病毒组、猫免疫缺陷病毒、美洲狮慢病毒)、绵羊/山羊慢病毒组(山羊关节炎脑炎病毒、梅迪-维斯纳病毒)、灵长类慢病毒组(人类免疫缺陷病毒1、人类免疫缺陷病毒2、猿猴免疫缺陷病毒)。
在一个优选的实施方式中,所述慢病毒是人类免疫缺陷病毒1、猿猴免疫缺陷病毒或马传染性贫血病毒。在一个更优选的实施方式中,所述慢病毒是人类免疫缺陷病毒1或马传染性贫血病毒。
env基因、gag基因、pol基因和rev基因可以来自一种或多种不同的病毒(例如2种、3种或4种不同的病毒)。例如,env基因可以来自弹状病毒科(例如,VSV-G),而其他gag基因、pol基因和rev基因可以来自HIV-1。
本领域技术人员认识到,逆转录病毒的env基因、gag基因、pol基因和rev基因依进化枝和分离物而异。来自所有这些进化枝和分离物的这些基因的序列及其衍生物也包括在本文中。
第一核酸包含env基因。env是编码形成病毒包膜的蛋白的基因。env基因的表达使逆转录病毒能够靶向并附着于特定的细胞类型并能够渗入靶细胞膜。env基因的实例包括HIV-1env基因及其衍生物。
在HIV中,env基因编码gp160蛋白,所述gp160蛋白形成同源三聚体并且被宿主细胞蛋白酶弗林蛋白酶切割为gp120和gp41。HIV-1env核苷酸和氨基酸序列分别在SEQ IDNO:1和SEQ ID NO:2中给出。
如本文中所使用的,术语“HIV-1env基因”优选地是指具有SEQ ID NO:1中给出的序列的核苷酸序列或编码SEQ ID NO:2的核苷酸序列、或与其具有至少80%、85%、90%、95%或99%序列同一性且编码gp160蛋白的核苷酸序列,所述gp160蛋白能够形成同源三聚体并且能够被HIV-1蛋白酶切割成gp120和gp41多肽。
可以通过使用来自诸如水泡性口炎病毒(VSV)比如VGV-G基因或其衍生物之类的病毒的env基因来假型病毒包膜。
VSV-G蛋白是单通膜糖蛋白。它介导了广泛的传染嗜性。该基因由1536bp的开放阅读框编码,并且产生由511个氨基酸组成的蛋白。该蛋白在N-末端含有一个16个氨基的信号肽(氨基酸序列:MLSYLIFALAVSPILG,SEQ ID NO:14),该蛋白在通过分泌途径输出到细胞表面的过程中从成熟蛋白上裂解下来。该糖蛋白包含458个氨基酸的细胞外区域、21个氨基酸的膜跨越区域(跨膜区)、然后是22个氨基酸的细胞内(胞质)C末端区域。VSV-G蛋白从内质网穿梭是快速的,这是通过C-末端尾巴中的特定运输信号实现的,包括含有DxE基序的更广泛运输信号Tyr-Thr-Asp-Ile-Glu-Met内的DxE基序(其中,x是任意氨基酸)(Sevier等,Mol.Biol.Cell.2000年1月;11(1):13-22)。VSV-G蛋白的输出效率可能部分有助于其对逆转录病毒和慢病毒生产的有效性。VSV-G受体经常被描述为非特异性融合蛋白;然而,最近确定了VSV-G与低密度脂质受体(LDL-R)结合(Finkelstein等,Proc.Natl.Acad.Sci.美国2013;110(18):7306-7311),这解释了其广泛的细胞嗜性以及其在逆转录病毒和慢病毒假型包装中的广泛应用。
如本文中所使用的,术语“VGV-G基因”优选地是指具有SEQ ID NO:3中给出的序列的核苷酸序列或编码SEQ ID NO:4的核苷酸序列、或与其具有至少80%、85%、90%、95%或99%序列同一性且编码能够附着于LDL受体的多肽的核苷酸序列。
第二核酸包含gag-pol基因。如本文中所使用的,术语“gag-pol”包括连续/重叠的gag-pol基因以及独立的gag基因和pol基因。
慢病毒的Gag-Pol蛋白以编码蛋白酶的单一多蛋白形式产生,该蛋白酶使得能够将Gag-Pol蛋白进行蛋白水解切割成许多具有许多病毒功能的较小蛋白。HIV-1Gag蛋白是从病毒基因组的5’端的第一翻译的开放阅读中产生的,并且包含称为移码序列的序列。该信号使翻译核糖体在翻译期间大约每20个翻译运行中的1个翻译运行在mRNA分子上向后移动一个碱基。该过程产生Gag-Pol蛋白。结果是慢病毒以大约1:20的比例产生Gag和Gag-Pol。Gag蛋白编码三种主要的结构蛋白:p18、p24和p15。Pol蛋白片段也编码三种主要蛋白:称为p10(蛋白酶)、p66/55(逆转录酶)和p32(整合酶)。该蛋白酶负责通过蛋白水解切割产生这些蛋白中的每种蛋白所需的所有切割事件。然而,定义这些切割事件的蛋白酶识别序列没有被很好定义,表明该蛋白酶具有广泛的特异性。因此,这很可能导致与病毒无关的蛋白质裂解。实际上,Gag-Pol蛋白的表达因此被报道对细胞具有高毒性(Blanco等,TheJournal of Biochemistry,278,2,1086-1093,2003)。
在一些病毒中,gag基因的编码序列和pol基因的编码序列重叠。本发明的gag基因的编码序列和pol基因的编码序列可以是连续的、不连续的、重叠的或不重叠的。
优选地,gag-pol序列来自慢病毒。gag基因、pol基因和gag-pol基因的实例包括HIV-1gag-pol基因及其衍生物。
在HIV-1中,gag基因的阅读框和pol基因的阅读框重叠,即,重叠在gag-pol基因中。HIV-1gag-pol核苷酸序列在SEQ ID NO:5中给出。
如本文中所使用的,术语“HIV-1gag-pol基因”优选地是指具有SEQ ID NO:5中给出的序列的核苷酸序列、或与其具有至少80%、85%、90%、95%或99%序列同一性且编码基质、衣壳和核衣壳蛋白、以及逆转录酶、整合酶和蛋白酶的核苷酸序列。
在本发明的双链核酸分子中,第一核酸的多肽编码序列和第二核酸的多肽编码序列在双链核酸分子的相对链上。双链核酸分子的两条链通常称为正义/反义链或正/负链。因此,如果将包括env基因的编码序列的核酸链定义为正义链或正链,则gag基因的编码序列和pol基因的编码序列将在反义链或负链上。
在一些实施方式中,双链核酸分子另外包含含rev基因的核酸。Rev是一种对调节HIV-1蛋白表达所必需的反式激活蛋白。rev基因中编码核定位信号,该信号允许Rev蛋白定位于细胞核中并在那里参与未剪接及不完全剪接的mRNA的输出。Rev与慢病毒基因组中称为Rev响应元件的区域结合,该区域允许未剪接的全长基因组的核输出,这对于慢病毒的生产是必需的。rev基因的实例包括HIV-1rev基因及其衍生物。HIV-1rev核苷酸序列和Rev氨基酸序列分别在SEQ ID NO:6和SEQ ID NO:7中给出。
如本文中所使用的,术语“HIV-1rev基因”优选地是指具有SEQ ID NO:6中给出的序列的核苷酸序列或编码SEQ ID NO:7的核苷酸序列、或与其具有至少80%、85%、90%、95%或99%序列同一性且编码能够结合Rev响应元件(RRE)的蛋白质的核苷酸序列。
在一些其他实施方式中,双链核酸分子不包含含rev基因的核酸。
VSV-G通常对细胞具有细胞毒性。VSV-G能够诱导细胞融合和合胞体的形成。一些gag-pol基因产物也具有细胞毒性。特别地,pol基因编码一种切割细胞内的蛋白质并导致细胞死亡的蛋白酶。
一种或多种凋亡抑制剂的表达减轻或阻止了细胞的细胞凋亡,否则该细胞凋亡将由细胞毒性多肽的细胞毒性引发。因此,本发明的双链核酸另外包含一个或多个编码凋亡抑制剂的核苷酸序列。所述一种或多种凋亡抑制剂可以独立地例如是多肽或RNA。
优选地,本发明的双链核酸另外包含1个、2个、3个、4个或5个,更优选1个或2个编码凋亡抑制剂的核苷酸序列。在一些实施方式中,所述凋亡抑制剂是APAF-1(例如,AVEN)、Caspase 9(例如,IAP或XIAP)、BAK、BAX、BOK或BAD(例如,BCL2、E1B-19K或BCL-XL)途径的抑制剂。优选地,使用抑制多于一个细胞凋亡途径或步骤(例如,AVEN与E1B-19K组合)的多于一个基因,用以提供对细胞凋亡的提高的抗性。
在一些实施方式中,所述一种或多种凋亡抑制剂是抑制凋亡蛋白的凋亡抑制剂或者是通过切割细胞内蛋白质的蛋白酶来刺激的凋亡抑制剂,其中,该凋亡蛋白的产生是通过细胞膜完整性的丧失、细胞-细胞融合或合胞体形成来刺激的。
抑制细胞凋亡的多肽的实例包括鸡胚致死孤病毒GAM1、腺病毒E4 Orf6、腺病毒E1B 55K、腺病毒E1B 19K、粘液瘤病毒M11L、巨细胞病毒IE1、巨细胞病毒IE2、杆状病毒p35、杆状病毒IAP-1、疱疹病毒US3、松鼠猴疱疹病毒ORF16、单纯疱疹2LAT ORF1、人XIAP、非洲猪瘟ASFV-5-HL(LMW-5-HL/A179L)、卡波西肉瘤病毒KSbcl2、痘苗病毒SPI-2、牛痘病毒CrmA、爱泼斯坦巴尔病毒BHRF1、爱泼斯坦巴尔病毒EBNA-5、爱泼斯坦巴尔病毒BZLF-1、乳头瘤病毒E6、人Aven、人BCL2和人BCL-XL。
在一些实施方式中,所述一种或多种凋亡抑制剂是RNA,优选反义或shRNA。RNA凋亡抑制剂的其他实例包括疱疹病毒LAT和腺病毒VA1。
优选地,所述凋亡抑制剂选自由IAP1、EBNA5和BCL-XL组成的组。凋亡抑制剂的特别优选的组合包括:IAP1+EBNA5、IAP1+BCL-XL、和EBNA5+BCL-XL。凋亡抑制剂IAP1、EBNA5和BCL-XL的核苷酸序列在本文中分别以SEQ ID NO:11、SEQ ID NO:12和SEQ ID NO:13给出。
特别优选的是本发明的双链核酸,其另外包含编码包含SEQ ID NO:11、SEQ IDNO:12或SEQ ID NO:13的凋亡抑制剂的核苷酸序列或与其具有至少80%、85%、90%、95%或99%序列同一性的核苷酸序列。
在哺乳动物培养物中稳定细胞系的产生通常需要选择方法以促进含有任何外源添加的DNA的细胞的生长。优选地,本发明的双链核酸分子还包含选择基因或抗生素抗性基因。为此,已知了在将编码特定化合物的DNA插入哺乳动物细胞基因组时可对特定化合物产生抗性的一系列基因。
优选地,所述选择基因是嘌呤霉素N-乙酰基转移酶(Puro)、潮霉素磷酸转移酶(Hygro)、杀稻瘟素脱氨酶(Blast)、新霉素磷酸转移酶(Neo)、谷胱甘肽S-转移酶(GS)、博来霉素抗性基因(Sh ble)或二氢叶酸还原酶(DHFR)。这些基因中的每个基因均提供了对已知为对哺乳动物细胞有毒性的小分子的抗性,或者在GS的情况下提供了一种细胞在生长培养基中没有谷胱甘肽时产生谷胱甘肽的方法。
在本发明的一个优选实施方式中,所述抗性基因是Puro。该基因特别有效,这是因为普通组织培养物中使用的许多细胞系均不具有抗性;对于Neo不是这样,其中许多特别是HEK293衍生物因研究人员先前的基因操作而已经具有Neo抗性(例如,HEK 293T细胞)。Puro选择还具有以下优点,在短时间窗内(<72小时)是有毒的,并且因此它允许快速测试变量,并且将不携带待插入基因组中的外源DNA的细胞从培养物系统中快速去除。对于一些其他选择方法不是这样,比如Hygro,其中毒性起效要慢得多。
使用选择基因(例如,Puro)开发稳定的细胞系需要抗性基因必须在细胞中表达。这可以通过多种方法实现,包括但不限于内部核糖体进入位点(IRES)、2A裂解系统、选择性剪接和专用启动子。
在本发明的一个优选实施方式中,所述选择基因将从专用启动子表达。该启动子将优选地在人细胞中以比驱动VSV-G基因或gag-pol基因的专用启动子低的水平转录。
双链核酸分子中编码多肽或RNA的基因中的每个基因优选地与一个或多个调节元件可操作地相关联。这确保了多肽或RNA以所需水平和在所需时间表达。
在该上下文中,术语“调控元件”包括增强子、启动子、内含子、polyA、绝缘子或终止子中的一种或多种。
在本文载体中使用的基因优选地被polyA信号和/或绝缘子隔开,以保持对其他基因的转录通读最小,并且也将正常情况下需要抑制的基因(VSV-G和gag-pol)与需要表达的基因(例如TetR和凋亡抑制剂)隔离。
尽管通过对多于一个的编码多肽或RNA的核苷酸序列(就其协同表达而言)使用相同的调控元件(例如,启动子序列)的拷贝可以获得一些优势,但在本发明的上下文中,非常希望对每个编码多肽或RNA的核苷酸序列使用不同的调控元件。
因此,优选地,env基因和gag-pol基因与不同的调控元件(例如,不同的启动子、不同的内含子、不同的polyA、不同的绝缘子和/或不同的终止子序列)可操作地相关联。
更优选地,env启动子与gag-pol启动子之间的核苷酸序列同一性程度小于95%或小于90%,更优选地小于85%、80%、70%或60%。更优选地,env终止子与gag-pol终止子之间的核苷酸序列同一性程度小于95%或小于90%,更优选地小于85%、80%、70%或60%。以这种方式,降低了这些调节元件之间同源重组的风险。
env基因和gag-pol基因独立地与诱导型启动子序列可操作地相关联。凋亡抑制剂基因在存在时也将与一个或多个启动子可操作地相关联;这些可以是诱导型、抑制型或组成型的。
诱导型启动子可以是用强力霉素、四环素、IPTG或乳糖诱导的启动子。优选地,诱导型启动子元件包含Tet阻遏蛋白(TetR)能够结合的多个Tet操纵子序列。在结合状态下,获得了对转录的严格抑制。然而,在强力霉素(或不太优选地为四环素)的存在下,抑制被减轻,从而使启动子获得完全的转录活性。这种诱导型启动子元件优选地置于另一启动子(例如CMV启动子)的下游。
TetR结合位点可以具有野生型序列,其中许多是本领域已知的。优选地,通过掺入较小的序列改变对TetR结合位点进行了一种或多种改善。可以在本发明的实施方式中使用的一个优选形式具有以下序列:tccctatcagtgatagaga(SEQ ID NO:8)。结合TetR蛋白或TetR蛋白衍生物的阻遏物元件的替代形式也可以用于本发明的实施方式中,条件是TetR阻遏物蛋白与所用的TetR结合序列变体结合。一些阻遏物/结合位点变体彼此之间的亲和力要高于野生型;这些在本发明的实施方式中是优选的。
TetR基因将整合到人类(宿主)细胞的染色体中。该基因可以或不可以邻近env基因或gag-pol基因整合,或者与env基因或gag-pol基因结合。
在一个优选的实施方式中,TetR基因的编码链在邻近env基因或gag-pol基因放置时在相对于Gag-Pol蛋白的编码序列反向方向5’至3’上的DNA的相对链中。在一些实施方式中,TetR基因与gag-pol基因共表达。
在本发明的一个实施方式中,TetR蛋白的核苷酸序列是如在SEQ ID NO:9中给出的序列,或者是与其具有至少80%、更优选地至少85%、90%或95%序列同一性且编码TetR蛋白的核苷酸序列。
在本发明的另一实施方式中,TetR蛋白的氨基酸序列是如在SEQ ID NO:10中给出的序列,或者是与其具有至少80%、更优选地至少85%、90%或95%序列同一性且编码TetR蛋白的氨基酸序列。
在一些优选实施方式中,与env基因(优选地VSV-G基因)和gag-pol基因可操作地相关联的启动子是通常可诱导的(即,可一起诱导的)诱导型启动子。
更优选地,与env基因(优选地,VSV-G基因)和gag-pol基因可操作地相关联的启动子均包含TetR结合位点,其允许同时抑制和共表达env基因(优选地VSV-G基因)和gag-pol基因。
优选地,凋亡抑制剂启动子选自由RSV、CMV、SV40、PGK和泛素启动子组成的组。
在使用多于一种的凋亡抑制剂的本发明的实施方式中,每种凋亡抑制剂优选地由不同的启动子独立地驱动,并且每个启动子优选地属于不同类型(例如CMV、SV40等)。
优选的是,每个编码凋亡抑制剂的核酸在提供给细胞最佳凋亡抑制的启动子的控制下表达。
在一些优选的实施方式中,本发明的双链核酸分子包括以下启动子-凋亡抑制剂组合的使用:
RSV–人类凋亡抑制剂(IAP)1
RSV-爱泼斯坦巴尔EBNA5
RSV-BCL-XL
SV40–人类凋亡抑制剂(IAP)1
SV40-爱泼斯坦巴尔EBNA5
SV40-BCL-XL
PGK–人类凋亡抑制剂(IAP)1
PGK-爱泼斯坦巴尔EBNA5
PGK-BCL-XL
泛素–人类凋亡抑制剂(IAP)1
泛素-爱泼斯坦巴尔EBNA5
泛素-BCL-XL
优选地,双链核酸分子包含IAP1、EBNA5和BCL-XL中的至少两者的组合,其中,IAP1、EBNA5和BCL-XL的表达优选地由选自以下启动子中的任意启动子所驱动:RSV、CMV、SV40、PGK、GRP78、EF1-α、SFFV、CHEF-1、腺病毒E1A、鸡β肌动蛋白、CAG、CMV-β-球蛋白和泛素启动子。
本发明的双链核酸分子可以另外包含至少一个转基因。在其他实施方式中,提供了一种试剂盒,其包含本发明的双链核酸分子并包含含有转基因的载体或质粒。
在一些实施方式中,env基因和gag-pol基因的侧翼是位点特异性重组位点,优选LoxP位点或FRT位点,更优选LoxP位点。
本发明特别提供了一种包含本发明的双链核酸的逆转录病毒包装质粒。
本发明的优选实施方式的实例包括依次包含以下元件的双链核酸分子:
TetR基因(反向)-(诱导型启动子,例如,Tet抑制性启动子)VSV-G基因-(组成型启动子,例如,EF1a)嘌呤霉素抗性-gag-pol基因(反向;诱导型启动子,例如Tet抑制性启动子)-凋亡抑制剂1-凋亡抑制剂2。
TetR基因(反向)-(诱导型启动子,例如Tet抑制性启动子)VSV-G基因-(IRES,启动子)嘌呤霉素抗性-gag-pol基因(反向;诱导型启动子,例如Tet抑制性启动子)-凋亡抑制剂1-凋亡抑制剂2。
(组成型启动子)VSV-G基因-(组成型启动子)嘌呤霉素抗性-gag-pol基因(反向;组成型启动子)-凋亡抑制剂1-凋亡抑制剂2。
(组成型启动子)VSV-G基因-IRES-嘌呤霉素抗性-gag-pol基因(反向;组成型启动子)-凋亡抑制剂1-凋亡抑制剂2。
有许多已建立的算法可用于比对两个氨基酸或核酸序列。通常,一个序列充当参考序列,测试序列可以与该参考序列进行比较。序列比较算法基于指定的程序参数来计算测试序列相对于参考序列的百分比序列同一性。用于比较的氨基酸或核酸序列的比对可以例如通过计算机实施的算法(例如,GAP、BESTFIT、FASTA或TFASTA)或BLAST和BLAST 2.0算法来进行。
氨基酸序列同一性和核苷酸序列同一性的百分比可以使用比对的BLAST方法获得(Altschul等(1997),“Gapped BLASTand PSI-BLAST:a new generation of proteindatabase search programs”,Nucleic Acids Res.25:3389-3402;以及http://www.ncbi.nlm.nih.gov/BLAST)。优选地,使用标准对准参数或默认对准参数。
标准蛋白质-蛋白质BLAST(blastp)可以用于在蛋白质数据库中查找相似的序列,像其他BLAST程序一样,blastp设计成查找相似性的局部区域。当序列相似性跨越整个序列时,blastp还将报告全局比对,这是出于蛋白质鉴定目的的优选结果。优选地,使用标准或默认对准参数。在一些情况下,“低复杂度过滤器”可能会被删除。
BLAST蛋白检索也可以使用BLASTX程序进行,得分=50,字长=3。为了获得用于比较目的的空位比对,如Altschul等(1997)Nucleic Acids Res.25:3389所述,可以利用空位BLAST(在BLAST 2.0中)。替代性地,PSI-BLAST(在BLAST 2.0中)可以用于执行迭代检索,用以检测分子之间的远距离关系。(参见上文的Altschul等(1997))。当使用BLAST、空位BLAST、PSI-BLAST时,可以使用相应程序的默认参数。
关于核苷酸序列比较,可以使用MEGABLAST、不连续megablast和blastn来实现这一目标。优选地,使用标准或默认对准参数。MEGABLAST是为有效发现非常相似序列之间的长序列对比而特别设计的。不连续MEGABLAST可以用于发现与本发明的核酸相似但不相同的核苷酸序列。
BLAST核苷酸算法通过将查询分为称为字段的短子序列来找到相似的序列。该程序首先确定与查询字段的完全匹配(字段匹配)。然后,BLAST程序将这些字段匹配扩展为多个步骤,以生成最终的空位比对。在一些实施方式中,BLAST核苷酸检索可以用BLASTN程序进行,得分=100,字长=12。
决定BLAST检索灵敏性的重要参数之一是字长。blastn比MEGABLAST更灵敏的最重要原因是它使用了较短的默认字长(11)。因此,在寻找与来自其他生物体的相关核苷酸序列的比对方面,blastn优于MEGABLAST。字长在blastn中是可以调整的,并且可以从默认值减小至最小为7,以提高检索灵敏度。
通过使用新引入的不连续的megablast页面(www.ncbi.nlm.nih.gov/Web/Newsltr/FallWinter02/blastlab.html)可以实现更灵敏的检索。该页面使用与Ma等(Bioinformatics.2002年3月;18(3):440-5)报道的算法相似的算法。不连续megablast在模板的较长窗口内使用不连接字段,而不是要求精确字段匹配作为用于比对扩展的种子。在编码模式下,通过专注于在第一密码子位置和第二密码子位置找到匹配而忽略第三位置的不匹配来考虑第三碱基摆动。使用相同字长的不连续MEGABLAST来检索比使用相同字长的标准blastn更为灵敏和高效。不连续megablast的独特参数是:字长:11或12;模板:16、18或21;模板类型:编码(0)、非编码(1)、或两者(2)。
在一些实施方式中,可以使用默认参数来使用BLASTP 2.5.0+算法(比如可从NCBI获得的算法)。
在其他实施方式中,可以使用两个蛋白质序列的Needleman-Wunsch比对来使用BLAST全局比对程序(比如可从NCBI获得的程序),空位罚分为:初始11和延伸1。
本发明还提供了一种试剂盒,其包括:
(i)包含本发明的双链核酸的逆转录病毒包装载体,
以及以下一种或多种:
(ii)逆转录病毒转移载体,其包含转基因和逆转录病毒rev基因;
(iii)适于产生病毒颗粒的细胞系的细胞。
本发明还提供了一种试剂盒,其包括:
(i)包含本发明的双链核酸的逆转录病毒包装载体,所述双链核酸还包含rev基因,
以及下述一种或多种:
(ii)包含转基因的逆转录病毒转移载体;
(iii)适于产生病毒颗粒的细胞系的细胞。
所述逆转录病毒转移载体含有用于将转基因插入细胞基因组中的位点(例如,LTR)。
优选地,5’-LTR在转移载体中包含启动子,从而消除了对Tat蛋白的需要。
所述试剂盒还可以包含用于纯化病毒颗粒的材料,比如与病毒颗粒的密度条带和纯化有关的那些,例如离心管、碘克沙醇、透析缓冲液和透析盒中的一种或多种。
本发明还提供一种包含本发明的双链核酸的哺乳动物细胞。本发明的双链核酸可以稳定地整合到哺乳动物细胞的核基因组中或者存在于细胞内的载体或质粒中。优选地,本发明的双链核酸被稳定地整合到哺乳动物细胞的核基因组中。
所述细胞可以是分离的细胞,例如,所述细胞不位于活的动物体内。哺乳动物细胞的实例包括来自人、小鼠、大鼠、仓鼠、猴子、兔子、驴、马、绵羊、牛和猿的任何器官或组织的细胞。优选地,所述细胞是人细胞。所述细胞可以是原代或永生化细胞。优选的细胞包括HEK-293、HEK 293T、HEK-293E、HEK-293FT、HEK-293S、HEK-293SG、HEK-293 FTM、HEK-293SGGD、HEK-293A、MDCK、C127、A549、HeLa、CHO、小鼠骨髓瘤、PerC6、911和Vero细胞系。HEK-293细胞已被修饰为包含E1A和E1B蛋白,这允许创建具有E1A和E1B区域缺失的病毒,以通过反式互补在该细胞系中生长。类似地,PerC6和911细胞包含类似的修饰并且也可以被使用。最优选地,人细胞是HEK293、HEK293T、HEK293A、PerC6或911。其他优选的细胞包括CHO细胞和VERO细胞。优选地,本发明的细胞能够诱导表达env基因和gag-pol基因。
本发明还提供了一种包含本发明的双链核酸分子的逆转录病毒包装细胞,优选哺乳动物细胞,更优选人细胞。
因此,在另一实施方式中,提供了一种用于产生逆转录病毒包装细胞的方法,该方法包括以下步骤:
(i)将本发明的双链核酸分子稳定地整合到哺乳动物细胞中,由此产生表达逆转录病毒env基因和gag-pol基因以及可选的rev基因的哺乳动物细胞。
本发明还提供了一种本发明的逆转录病毒包装细胞在逆转录病毒颗粒的生产中的用途。
本发明还提供了一种用于产生逆转录病毒的方法,该方法包括以下步骤:
(a)将包含5’和3’逆转录病毒LTR的逆转录病毒转移载体、逆转录病毒包装信号和逆转录病毒rev基因引入到本发明的逆转录病毒包装细胞中,其中,所述逆转录病毒包装细胞包含稳定地整合到逆转录病毒包装细胞的基因组中的逆转录病毒env基因和gag-pol基因;
(b)在一定条件下培养细胞,使得逆转录病毒由细胞组装和分泌;以及
(c)从上清液中收获包装的逆转录病毒。
本发明还提供了一种用于产生逆转录病毒的方法,该方法包括以下步骤:
(a)将包含转基因的逆转录病毒转移载体引入到本发明的逆转录病毒包装细胞中,其中,所述逆转录病毒包装细胞包含稳定地整合到逆转录病毒包装细胞的基因组中的逆转录病毒env基因、gag-pol基因和rev基因;
(b)在一定条件下培养细胞,使得逆转录病毒由细胞组装和分泌;以及
(c)从上清液中收获包装的逆转录病毒。
优选地,所述病毒载体是复制缺陷型或无复制能力的。
如本文中所使用的,术语“引入”一个或多个载体到细胞中包括转化、以及任何形式的电穿孔、接合、感染、转导或转染等。这种引入的方法在本领域中是众所周知的(例如,Proc.Natl.Acad.Sci.美国.1995年8月1日;92(16):7297-301)。优选地,随后对收获的逆转录病毒进行纯化。
本文中所示的每个参考文献的公开的全部内容通过引用具体地并入本文中。
附图说明
图1为表达VSV-G+凋亡抑制剂的稳定细胞系的产生。
图2为来自VSV-G稳定细胞系的慢病毒颗粒的表达。
图3为在表达VSV-G基因和gag-pol基因的载体中的主要表达盒的排列的示意图。诱导型启动子表示为:i和组成型启动子:c。A.I.表示凋亡抑制剂。
图4为示出了主要表达盒的排列的示意图。LTR表示长末端重复序列,RSV表示劳斯肉瘤病毒启动子,PGK表示人磷酸甘油酸激酶启动子,G418表示G418(遗传霉素)抗性基因,并且Blast表示杀稻瘟素抗性基因。
图5为用于包装和生产细胞系产生的慢病毒载体的瞬时评估。
图6为嘌呤霉素选择期间不同包装细胞系的生存力。
图7为通过%FITC阳性群评估的在所鉴定的感兴趣的克隆中诱导后的表面VSV-G表达。
图8为用于转录通读评估的VSV-G表达构建体。
图9为在AMBR生物反应器系统中使用不同工艺条件对优选包装系(CV170)进行分析。
图10为从未诱导的生产细胞系至诱导的生产细胞系的病毒滴度的倍数变化。
具体实施方式
通过以下实施例对本发明进行进一步说明,除非另有说明,在以下实施例中份数和百分数均以重量计并且度为摄氏度。应当理解的是,这些实施例虽然表明了本发明的优选实施方式,但仅通过说明的方式给出。从以上讨论和这些实施例,本领域技术人员可以确定本发明的本质特征,并且在不脱离本发明的精神和范围的情况下,可以对本发明进行各种改变和变型以使其适应各种用途和条件。因此,除了本文中示出和描述的那些变型之外,根据前面的描述,本发明的各种变型对于本领域技术人员而言将是明显的。这样的变型也意图落入所附权利要求的范围内。
实施例1:支持病毒蛋白表达的因子的鉴定
来自水泡性口炎病毒的病毒糖蛋白VSV-G与一组凋亡抑制剂共表达。能够鉴定出支持VSV-G组成型表达的若干种分子,并且能够通过抗生素选择来建立稳定的细胞系。该数据随后用于选择优选的凋亡抑制剂,以包括在最终的慢病毒包装和生产细胞系中,如后面的实施例所描述的那样。
使用PEI试剂用一系列表达载体转染HEK293悬浮细胞,所述一系列表达载体编码经由IRES与嘌呤霉素选择标记可操作地连接的VSV-G、以及许多凋亡抑制剂基因。每3-4天通过在选择性培养基中进行培养基更换来建立稳定池。由于组成型表达的VSV-G基因具有毒性,因此建立稳定池需要较长的时间。结果显示在图1中。如所示的,相对于仅VSV-G的构建体,选择的凋亡抑制剂增加了稳定池回收率。
使用PEI试剂用编码慢病毒表达所需的所有因子的3种载体(GagPol、Rev、Genome)转染稳定池,例外是VSV-G是由稳定整合的拷贝表达的。出于控制目的,将亲本HEK293系用相同的质粒组转染,但也包括VSV-G载体。该基因组包含eGFP基因,并且用于在贴壁的HEK293细胞中进行滴定(以估计病毒感染滴度)。结果显示在图2中。该实验证明,组成型细胞系在凋亡抑制剂共同表达的支持下能够提供功能性VSV-G表达。这种表达在包装细胞系的稳定生产者的背景下被认为足以支持高水平病毒颗粒的生产。
实施例2:用于慢病毒包装和生产细胞系构建的构建体生产
如图3所示,产生了四个构建体。该构建体使用嘌呤霉素选择标记将VSV-G基因和gag-pol基因配对,并且使用G418或杀稻瘟素选择标记将rev和基因组配对。
每个盒均可以分解成如下功能部件:
VSV-G盒
·诱导型启动子(通过在策略位置添加两个TetO位点将PGK CMV融合启动子转化为诱导型启动子)或组成型启动子(PGK CMV融合启动子)
·5’UTR=人磷酸丙糖异构酶(TPI)内含子
·CDS(为在HEK293细胞中表达而优化的VSV-G密码子)
·兔β-球蛋白polyA信号
GagPol盒
·诱导型启动子(通过在策略位置添加两个TetO位点将CMV转化为诱导型启动子)或组成型启动子(CMV)
·5’UTR(人β-球蛋白内含子)
·CDS(野生型HIV1 GagPol)
·来自HIV-1的RRE
·人β-球蛋白polyA信号
TetR蛋白表达盒(仅存在于诱导型载体中)
·启动子(CMV)
·TetR序列(为在HEK293细胞中表达而优化的密码子)
·PolyA
抗生素抗性标记
·Puro(IRES-Puro或EF1-α-puro)
凋亡抑制剂盒
·IAP1和EBNA5
Rev/基因组载体
Rev/基因组载体设计成稳定地整合到VSV-G/GagPol稳定细胞系中,以生成包含慢病毒颗粒产生所需的所有因子的生产细胞系。显示Rev/基因组构建体的示意图显示在图4中。
Rev/基因组载体盒中的每个均可以分解成如下功能部件:
基因组
·第三代慢病毒基因组
·嵌合5’LTR与异源CMV启动子融合,从而驱动慢病毒基因组转录
转基因盒
·转基因是绿色荧光蛋白(GFP)或抗CD19嵌合抗原受体(CAR)
·转基因由脾脏病灶形成病毒(SFFV)启动子表达
Rev盒
·组成型RSV启动子
·Rev CDS
抗生素抗性标记
·PGK-G418或PGK-Blast
实施例3:在瞬时情况下用于慢病毒包装和生产细胞系构建的构建体分析
为了评估在稳定细胞系中使用的载体的功能,首先在贴壁细胞的瞬时实验中将载体用于产生慢病毒颗粒。这允许针对标准的4载体瞬时表达载体进行基准测试。
用2、3或4质粒慢病毒包装系统转染贴壁的293T细胞,该系统包括为稳定慢病毒生产细胞系构建而产生的构建体(组成型或诱导型)。在整个过程中,eGFP用作基因组载体中的转基因。
72小时后收集含有慢病毒的上清液,将该上清液在DMEM中连续稀释并用于感染贴壁的293细胞。在72小时之后,将细胞胰蛋白酶化,并在流式细胞仪上分析eGFP信号。
然后将来自已经达到10%-20%eGFP阳性(即,转导的)细胞的系列稀释液的数据用于计算感染性颗粒浓度。这用于评价所评估的不同包装/生产构建体的性能。
第0天:将293T细胞以预定的密度接种到补充有10%胎牛血清的DMEM的6孔板中,准备在第二天进行转染。将细胞在37℃、5%CO2的潮湿培养箱中孵育过夜。
第1天:不管所评估的构建体是组成型还是诱导型,使用分支的PEI用表1中详述的质粒的组合在有或没有强力霉素的情况下转染细胞。
第3天:将293细胞以预定的密度接种到DMEM+10%FBS的48孔板中,准备在第二天进行感染。将细胞在37℃、5%CO2的潮湿培养箱中孵育过夜。
第4天:收获慢病毒上清液,然后离心除去细胞碎片。慢病毒被连续稀释并用于感染293细胞。
第7天:收获转导的细胞并通过流式细胞术进行分析。然后使用已经达到10%-20%的eGFP阳性(即,转导的)细胞的稀释度来计算感染性颗粒浓度。
测试了4、3和2质粒系统构建体的组合,以在贴壁的293T细胞中生产瞬时慢病毒。下表1中显示了这些组合。
表1:
从这些数据得出许多结论:
·慢病毒载体中的所有组分均功能齐全。
·2质粒系统能够提供高的慢病毒滴度,并且在许多情况下优于或等同于3质粒或4质粒系统。
·与缺少这些盒的相同构建体相比,在2质粒系统中也编码凋亡抑制剂的组成型VSV-G/GagPol构建体显示出增强的慢病毒生产(图5,框A对比框B)。
·具有或不具有凋亡抑制剂的诱导型VSV-G/GagPol构建体均显示高水平的病毒颗粒表达,仅略低于组成型构建体(图5,框C对比框B)。
·诱导型构建体(框C)显示出非常严格的基因调控,如无Dox时的表达水平所指示的。
·总的来说,强力霉素处理增加病毒颗粒的表达,而与诱导系统无关。
实施例4:VSV-G/GagPol包装细胞系的产生和分析
使用线性PEI用编码VSV-G或者VSV-G和GagPol的线性化的可诱导包装构建体来转染悬浮的HEK293细胞,所述构建体具有或不具有凋亡抑制剂(在下表2中详述)。随后,选择具有稳定整合基因的细胞进行嘌呤霉素处理,直至获得≥90%的活力为止,其中,生长特性与宿主细胞系相似(图1)。将VSV-G/GagPol细胞池进行单细胞克隆,以获得单克隆高表达细胞系。这是通过使用Sony SH800细胞分选仪将单细胞分选到96孔板中的准备好的克隆培养基中进行的。然后将形成集落的单细胞通过几个放大阶段,直到获得足够数量的细胞用于VSV-G蛋白表达评估为止。为此,将细胞克隆与媒介物对照(DMSO)或强力霉素孵育24小时,以诱导VSV-G/GagPol表达。将细胞用抗VSV-G抗体和对应的FITC偶联的第二抗体进行染色,并且通过流式细胞术来分析FITC阳性细胞。结果如图6所示。
表2用于稳定包装细胞系生成的构建体
克隆实验后产生了大量克隆细胞系。来自两个克隆的代表性数据如图7所示。在强力霉素处理后,克隆CV02和CV35这两者均显示出高水平表达VSV-G。然而,CV 35也显示了VSV-G的高基础表达,表明Tet调节系统的功能性泄漏。这表明通过使用产生的包装构建体可以在可诱导的背景下实现VSV-G/GagPol基因的稳定高表达。
实施例5:生产细胞系的产生和分析
使用线性PEI用仅编码Rev或者编码Rev和病毒基因组(eGFP或CD19)的组合的线性化组成型构建体转染单克隆VSV-G/GagPol悬浮液HEK293细胞系(如实施例4中所详述的)(构建体详情请参见表3)。随后,选择具有稳定整合的基因的细胞用于杀稻瘟素选择,直到获得≥90%的活力为止,其中,生长特性与宿主细胞系相似。用强力霉素诱导产生的生产细胞,在设定的生产时间后收集培养上清液,并且从细胞碎片中澄清。随后,该病毒上清液被连续稀释并且用于Jurkat细胞(eGFP和CD19)或贴壁的293细胞(仅eGFP)感染72小时。通过流式细胞术直接分析被eGFP慢病毒感染的Jurkat和293细胞,从而使用产生10%-20%eGFP阳性(即,转导的)细胞的稀释液来计算感染性颗粒浓度。
在CD19的情况下,受感染的Jurkat细胞通过蛋白L进行染色以检测表面CD19的表达,并且与eGFP相似,估算感染颗粒的浓度。使用同时强力霉素诱导VSV-G/GagPol表达和瞬时转染eGFP病毒基因组来评估包装细胞系(VSV-G/GagPol+Rev)。产生的病毒上清液随后被连续稀释并且用于感染Jurkat和293细胞以建立感染性颗粒浓度。优选的生产池被用于使用Sony SH800细胞分选仪将单细胞分选到96孔板中的制备的克隆培养基中。然后,形成集落的单细胞经历若干放大阶段,直到获得足够数量的细胞用于以上述方式评估强力霉素诱导后的慢病毒生产为止。
表3用于转染单克隆包装细胞系以产生稳定生产细胞系的构建体
实施例6:分析病毒基因之间的转录通读和产生有复制能力的慢病毒(RCL)的潜力
使用逆转录病毒载体的主要安全隐患是产生具有复制能力的颗粒的风险。第三代系统在瞬时慢病毒表达的背景下已经解决了这一问题,该第三代系统结合了用于包装因子的单独载体,并结合了LTR区域内的缺失以消除启动子活性,从而使转基因的转录依赖于内部启动子。
为了对用于产生稳定的生物生产细胞系的构建体中VSV-G基因和gag-pol基因的构型及其降低RCL产生的风险的潜力进行评估,还生成了另外两个构建体,其中,VSV-G与荧光素酶报告基因以正向和反向串联表达。这在图8中示出。
随后将这两个构建体瞬时转染到贴壁的HEK293T细胞中,用强力霉素处理以诱导转录,并且在24小时后测定荧光素酶活性。正向构建体中荧光素酶活性的存在指示通读转录,其直接涉及安全性问题,通过在稳定细胞系背景下用于本发明的基因配置而避免了该安全性问题。
实施例7:VSV-G/GagPol包装细胞系的分析
通过与实施例4中描述的那些方法相同的方法来生产另外的包装细胞系。包装细胞系在摇瓶和微型生物反应器系统(AMBR15)中生长,以分析和优化生产参数。这里所示的包装细胞系是通过线性化Q1850质粒的稳定整合而产生的。
为了研究生产参数,在基于PEI的Rev/基因组质粒(Q1847)转染后,将包装细胞系培养72小时并用强力霉素诱导。收集上清液,并通过基于流式细胞仪的感染滴度测定法对所收集的上清液进行分析。数据显示在图9中,并且代表在AMBR生物反应器系统中使用不同工艺条件对优选包装系(CV170)的分析。
实施例8:生产细胞系的分析
优选的包装细胞系(CV170)被用作生成完全稳定的生产细胞系的起点。通过线性化Q3928质粒的稳定整合来创建稳定池,并且然后通过FACS分选进行克隆。然后扩增克隆系,并且在深孔摇板中对该克隆系进行分析。基于此数据,将选择的克隆细胞系扩大到摇瓶培养物中。
一旦转移到摇瓶中,通过向细胞培养基中加入强力霉素来诱导生产细胞系。诱导后72小时,收集上清液并通过基于流式细胞仪的感染滴度测定法进行分析。数据在图10中以从未诱导至诱导的病毒滴度的倍数变化表示。
序列
SEQ ID NO:1-HIV-1env核苷酸
ATGAGAGTGAAGGAGAAATATCAGCACTTGTGGAGATGGGGGTGGAGATGGGGCACCATGCTCCTTGGGATGTTGATGATCTGTAGTGCTACAGAAAAATTGTGGGTCACAGTCTATTATGGGGTACCTGTGTGGAAGGAAGCAACCACCACTCTATTTTGTGCATCAGATGCTAAAGCATATGATACAGAGGTACATAATGTTTGGGCCACACATGCCTGTGTACCCACAGACCCCAACCCACAAGAAGTAGTATTGGTAAATGTGACAGAAAATTTTAACATGTGGAAAAATGACATGGTAGAACAGATGCATGAGGATATAATCAGTTTATGGGATCAAAGCCTAAAGCCATGTGTAAAATTAACCCCACTCTGTGTTAGTTTAAAGTGCACTGATTTGAAGAATGATACTAATACCAATAGTAGTAGCGGGAGAATGATAATGGAGAAAGGAGAGATAAAAAACTGCTCTTTCAATATCAGCACAAGCATAAGAGGTAAGGTGCAGAAAGAATATGCATTTTTTTATAAACTTGATATAATACCAATAGATAATGATACTACCAGCTATAAGTTGACAAGTTGTAACACCTCAGTCATTACACAGGCCTGTCCAAAGGTATCCTTTGAGCCAATTCCCATACATTATTGTGCCCCGGCTGGTTTTGCGATTCTAAAATGTAATAATAAGACGTTCAATGGAACAGGACCATGTACAAATGTCAGCACAGTACAATGTACACATGGAATTAGGCCAGTAGTATCAACTCAACTGCTGTTAAATGGCAGTCTAGCAGAAGAAGAGGTAGTAATTAGATCTGTCAATTTCACGGACAATGCTAAAACCATAATAGTACAGCTGAACACATCTGTAGAAATTAATTGTACAAGACCCAACAACAATACAAGAAAAAGAATCCGTATCCAGAGAGGACCAGGGAGAGCATTTGTTACAATAGGAAAAATAGGAAATATGAGACAAGCACATTGTAACATTAGTAGAGCAAAATGGAATAACACTTTAAAACAGATAGCTAGCAAATTAAGAGAACAATTTGGAAATAATAAAACAATAATCTTTAAGCAATCCTCAGGAGGGGACCCAGAAATTGTAACGCACAGTTTTAATTGTGGAGGGGAATTTTTCTACTGTAATTCAACACAACTGTTTAATAGTACTTGGTTTAATAGTACTTGGAGTACTGAAGGGTCAAATAACACTGAAGGAAGTGACACAATCACCCTCCCATGCAGAATAAAACAAATTATAAACATGTGGCAGAAAGTAGGAAAAGCAATGTATGCCCCTCCCATCAGTGGACAAATTAGATGTTCATCAAATATTACAGGGCTGCTATTAACAAGAGATGGTGGTAATAGCAACAATGAGTCCGAGATCTTCAGACCTGGAGGAGGAGATATGAGGGACAATTGGAGAAGTGAATTATATAAATATAAAGTAGTAAAAATTGAACCATTAGGAGTAGCACCCACCAAGGCAAAGAGAAGAGTGGTGCAGAGAGAAAAAAGAGCAGTGGGAATAGGAGCTTTGTTCCTTGGGTTCTTGGGAGCAGCAGGAAGCACTATGGGCGCAGCCTCAATGACGCTGACGGTACAGGCCAGACAATTATTGTCTGGTATAGTGCAGCAGCAGAACAATTTGCTGAGGGCTATTGAGGCGCAACAGCATCTGTTGCAACTCACAGTCTGGGGCATCAAGCAGCTCCAGGCAAGAATCCTGGCTGTGGAAAGATACCTAAAGGATCAACAGCTCCTGGGGATTTGGGGTTGCTCTGGAAAACTCATTTGCACCACTGCTGTGCCTTGGAATGCTAGTTGGAGTAATAAATCTCTGGAACAGATTTGGAATCACACGACCTGGATGGAGTGGGACAGAGAAATTAACAATTACACAAGCTTAATACACTCCTTAATTGAAGAATCGCAAAACCAGCAAGAAAAGAATGAACAAGAATTATTGGAATTAGATAAATGGGCAAGTTTGTGGAATTGGTTTAACATAACAAATTGGCTGTGGTATATAAAATTATTCATAATGATAGTAGGAGGCTTGGTAGGTTTAAGAATAGTTTTTGCTGTACTTTCTATAGTGAATAGAGTTAGGCAGGGATATTCACCATTATCGTTTCAGACCCACCTCCCAACCCCGAGGGGACCCGACAGGCCCGAAGGAATAGAAGAAGAAGGTGGAGAGAGAGACAGAGACAGATCCATTCGATTAGTGAACGGATCCTTGGCACTTATCTGGGACGATCTGCGGAGCCTGTGCCTCTTCAGCTACCACCGCTTGAGAGACTTACTCTTGATTGTAACGAGGATTGTGGAACTTCTGGGACGCAGGGGGTGGGAAGCCCTCAAATATTGGTGGAATCTCCTACAGTATTGGAGTCAGGAACTAAAGAATAGTGCTGTTAGCTTGCTCAATGCCACAGCCATAGCAGTAGCTGAGGGGACAGATAGGGTTATAGAAGTAGTACAAGGAGCTTGTAGAGCTATTCGCCACATACCTAGAAGAATAAGACAGGGCTTGGAAAGGATTTTGCTATAA
SEQ ID NO: 2-HIV-1 Env氨基酸
MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTVYYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDPNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPCVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYKLTSCNTSVITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSVNFTDNAKTIIVQLNTSVEINCTRPNNNTRKRIRIQRGPGRAFVTIGKIGNMRQAHCNISRAKWNNTLKQIASKLREQFGNNKTIIFKQSSGGDPEIVTHSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTITLPCRIKQIINMWQKVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSNNESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKRRVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVERYLKDQQLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNHTTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSIVNRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRLVNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQGACRAIRHIPRRIRQGLERILL
SEQ ID NO: 3-VSV-G核苷酸
atgaagtgtctgctgtacctggcgttcctgtttatcggggtgaactgcaagttcactatcgtgtttccgcacaaccaaaagggcaactggaaaaacgtgccttcaaattaccattattgccccagcagctcggacctgaactggcacaatgacctcattggaaccgcgctgcaggtgaagatgccaaagagccacaaggctatccaggctgacggatggatgtgccacgcgtcaaaatgggtgactacctgcgatttccgctggtacggaccaaaatacatcacgcacagcatcagatcattcaccccgtcagtggaacaatgcaaagaatccatcgaacagactaagcagggaacctggctgaaccctggatttccgccgcagtcgtgtgggtacgcaaccgtgaccgatgcagaggccgtgatcgtgcaagtcacgccgcatcacgtgcttgtggacgagtacaccggagaatgggtcgattcccagttcatcaacggcaagtgctccaactacatttgcccaaccgtgcacaacagcactacttggcacagcgactacaaagtgaagggtctgtgtgattccaacctgatctccatggatatcactttcttctcggaagacggcgaactgtcctcactgggcaaagaaggaactgggtttcgctcaaattacttcgcctacgaaactggaggaaaagcctgcaagatgcagtactgcaagcactggggcgtgagactacccagcggtgtctggttcgagatggccgataaggacctgtttgcagcagcgagattcccggaatgccctgagggatcgagcatctccgctccaagccaaacttcagtggacgtgagcctgatccaggacgtggaacggattctcgactactcgctgtgccaggagacctggtcgaagatcagagcgggactgcccatctcaccggtggacctgtcctacctggcgccaaagaatccgggcactggaccggcgttcaccatcatcaacggcaccctcaaatacttcgagacgcggtacatccgggtggacatcgcagctccgatcctctcccggatggtgggaatgatctcggggactactaccgaacgcgagctctgggacgactgggcaccttacgaggatgtcgagatcggacctaacggagtgctccggacctcctccgggtacaagttccctctgtacatgatcggccatggcatgctggactcggatctgcatctgtcgtccaaagcacaggtgtttgaacacccacacattcaagacgccgccagccagctgccggacgatgagtcgctgttcttcggagacacgggcttgtcaaagaatcccatcgagctggtggaaggatggttttcatcctggaaaagcagcatcgcttcattcttcttcatcattggcctgatcatcggcctatttctagtcctgcgggtgggaattcatctgtgcatcaagctcaagcacactaagaagcggcaaatctacactgatatcgagatgaatcgcctgggcaag
SEQ ID NO: 4-VSV-G氨基酸
MKCLLYLAFLFIGVNCKFTIVFPHNQKGNWKNVPSNYHYCPSSSDLNWHNDLIGTALQVKMPKSHKAIQADGWMCHASKWVTTCDFRWYGPKYITHSIRSFTPSVEQCKESIEQTKQGTWLNPGFPPQSCGYATVTDAEAVIVQVTPHHVLVDEYTGEWVDSQFINGKCSNYICPTVHNSTTWHSDYKVKGLCDSNLISMDITFFSEDGELSSLGKEGTGFRSNYFAYETGGKACKMQYCKHWGVRLPSGVWFEMADKDLFAAARFPECPEGSSISAPSQTSVDVSLIQDVERILDYSLCQETWSKIRAGLPISPVDLSYLAPKNPGTGPAFTIINGTLKYFETRYIRVDIAAPILSRMVGMISGTTTERELWDDWAPYEDVEIGPNGVLRTSSGYKFPLYMIGHGMLDSDLHLSSKAQVFEHPHIQDAASQLPDDESLFFGDTGLSKNPIELVEGWFSSWKSSIASFFFIIGLIIGLFLVLRVGIHLCIKLKHTKKRQIYTDIEMNRLGK
SEQ ID NO: 5-HIV-1 gag-pol核苷酸
atgggtgcgagagcgtcagtattaagcgggggagaattagatcgatgggaaaaaattcggttaaggccagggggaaagaaaaaatataaattaaaacatatagtatgggcaagcagggagctagaacgattcgcagttaatcctggcctgttagaaacatcagaaggctgtagacaaatactgggacagctacaaccatcccttcagacaggatcagaagaacttagatcattatataatacagtagcaaccctctattgtgtgcatcaaaggatagagataaaagacaccaaggaagctttagacaagatagaggaagagcaaaacaaaagtaagaaaaaagcacagcaagcagcagctgacacaggacacagcaatcaggtcagccaaaattaccctatagtgcagaacatccaggggcaaatggtacatcaggccatatcacctagaactttaaatgcatgggtaaaagtagtagaagagaaggctttcagcccagaagtgatacccatgttttcagcattatcagaaggagccaccccacaagatttaaacaccatgctaaacacagtggggggacatcaagcagccatgcaaatgttaaaagagaccatcaatgaggaagctgcagaatgggatagagtgcatccagtgcatgcagggcctattgcaccaggccagatgagagaaccaaggggaagtgacatagcaggaactactagtacccttcaggaacaaataggatggatgacacataatccacctatcccagtaggagaaatctataaaagatggataatcctgggattaaataaaatagtaagaatgtatagccctaccagcattctggacataagacaaggaccaaaggaaccctttagagactatgtagaccgattctataaaactctaagagccgagcaagcttcacaagaggtaaaaaattggatgacagaaaccttgttggtccaaaatgcgaacccagattgtaagactattttaaaagcattgggaccaggagcgacactagaagaaatgatgacagcatgtcagggagtggggggacccggccataaagcaagagttttggctgaagcaatgagccaagtaacaaatccagctaccataatgatacagaaaggcaattttaggaaccaaagaaagactgttaagtgtttcaattgtggcaaagaagggcacatagccaaaaattgcagggcccctaggaaaaagggctgttggaaatgtggaaaggaaggacaccaaatgaaagattgtactgagagacaggctaattttttagggaagatctggccttcccacaagggaaggccagggaattttcttcagagcagaccagagccaacagccccaccagaagagagcttcaggtttggggaagagacaacaactccctctcagaagcaggagccgatagacaaggaactgtatcctttagcttccctcagatcactctttggcagcgacccctcgtcacaataaagataggggggcaattaaaggaagctctattagatacaggagcagatgatacagtattagaagaaatgaatttgccaggaagatggaaaccaaaaatgatagggggaattggaggttttatcaaagtaagacagtatgatcagatactcatagaaatctgcggacataaagctataggtacagtattagtaggacctacacctgtcaacataattggaagaaatctgttgactcagattggctgcactttaaattttcccattagtcctattgagactgtaccagtaaaattaaagccaggaatggatggcccaaaagttaaacaatggccattgacagaagaaaaaataaaagcattagtagaaatttgtacagaaatggaaaaggaaggaaaaatttcaaaaattgggcctgaaaatccatacaatactccagtatttgccataaagaaaaaagacagtactaaatggagaaaattagtagatttcagagaacttaataagagaactcaagatttctgggaagttcaattaggaataccacatcctgcagggttaaaacagaaaaaatcagtaacagtactggatgtgggcgatgcatatttttcagttcccttagataaagacttcaggaagtatactgcatttaccatacctagtataaacaatgagacaccagggattagatatcagtacaatgtgcttccacagggatggaaaggatcaccagcaatattccagtgtagcatgacaaaaatcttagagccttttagaaaacaaaatccagacatagtcatctatcaatacatggatgatttgtatgtaggatctgacttagaaatagggcagcatagaacaaaaatagaggaactgagacaacatctgttgaggtggggatttaccacaccagacaaaaaacatcagaaagaacctccattcctttggatgggttatgaactccatcctgataaatggacagtacagcctatagtgctgccagaaaaggacagctggactgtcaatgacatacagaaattagtgggaaaattgaattgggcaagtcagatttatgcagggattaaagtaaggcaattatgtaaacttcttaggggaaccaaagcactaacagaagtagtaccactaacagaagaagcagagctagaactggcagaaaacagggagattctaaaagaaccggtacatggagtgtattatgacccatcaaaagacttaatagcagaaatacagaagcaggggcaaggccaatggacatatcaaatttatcaagagccatttaaaaatctgaaaacaggaaagtatgcaagaatgaagggtgcccacactaatgatgtgaaacaattaacagaggcagtacaaaaaatagccacagaaagcatagtaatatggggaaagactcctaaatttaaattacccatacaaaaggaaacatgggaagcatggtggacagagtattggcaagccacctggattcctgagtgggagtttgtcaatacccctcccttagtgaagttatggtaccagttagagaaagaacccataataggagcagaaactttctatgtagatggggcagccaatagggaaactaaattaggaaaagcaggatatgtaactgacagaggaagacaaaaagttgtccccctaacggacacaacaaatcagaagactgagttacaagcaattcatctagctttgcaggattcgggattagaagtaaacatagtgacagactcacaatatgcattgggaatcattcaagcacaaccagataagagtgaatcagagttagtcagtcaaataatagagcagttaataaaaaaggaaaaagtctacctggcatgggtaccagcacacaaaggaattggaggaaatgaacaagtagataaattggtcagtgctggaatcaggaaagtactatttttagatggaatagataaggcccaagaagaacatgagaaatatcacagtaattggagagcaatggctagtgattttaacctaccacctgtagtagcaaaagaaatagtagccagctgtgataaatgtcagctaaaaggggaagccatgcatggacaagtagactgtagcccaggaatatggcagctagattgtacacatttagaaggaaaagttatcttggtagcagttcatgtagccagtggatatatagaagcagaagtaattccagcagagacagggcaagaaacagcatacttcctcttaaaattagcaggaagatggccagtaaaaacagtacatacagacaatggcagcaatttcaccagtactacagttaaggccgcctgttggtgggcggggatcaagcaggaatttggcattccctacaatccccaaagtcaaggagtaatagaatctatgaataaagaattaaagaaaattataggacaggtaagagatcaggctgaacatcttaagacagcagtacaaatggcagtattcatccacaattttaaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacatacaaactaaagaattacaaaaacaaattacaaaaattcaaaattttcgggtttattacagggacagcagagatccagtttggaaaggaccagcaaagctcctctggaaaggtgaaggggcagtagtaatacaagataatagtgacataaaagtagtgccaagaagaaaagcaaagatcatcagggattatggaaaacagatggcaggtgatgattgtgtggcaagtagacaggatgaggattaa
SEQ ID NO:6-HIV-1 rev核苷酸
ATGGCAGGCCGCTCAGGGGACTCGGATGAGGATCTGCTGAAGGCGGTGCGGCTCATCAAATTCCTGTACCAGAGCAACCCGCCACCGAACCCCGAAGGAACTCGCCAGGCTCGCAGGAACCGCCGCAGACGCTGGCGCGAACGGCAGCGCCAGATCCACAGCATCAGCGAACGCATCCTGTCAACTTACTTGGGACGGTCAGCGGAACCTGTCCCGCTGCAGCTGCCGCCGCTGGAGCGCCTGACTCTGGATTGCAACGAAGACTGCGGAACCAGCGGAACCCAGGGCGTGGGAAGCCCACAGATCCTGGTGGAATCGCCTACCATCTTGGAAAGCGGCGCGAAAGAA
SEQ ID NO:7-HIV-1 Rev氨基酸
MAGRSGDSDEDLLKAVRLIKFLYQSNPPPNPEGTRQARRNRRRRWRERQRQIHSISERILSTYLGRSAEPVPLQLPPLERLTLDCNEDCGTSGTQGVGSPQILVESPTILESGAKE
SEQ ID NO:8-TetR结合位点
tccctatcagtgatagaga
SEQ ID NO:9-TetR蛋白的核苷酸序列
Atgtcgcgcctggacaaaagcaaagtgattaactcagcgctggaactgttgaatgaggtgggaattgaaggactcactactcgcaagctggcacagaagctgggcgtcgagcagccaacgctgtactggcatgtgaagaataaacgggcgctcctagacgcgcttgccatcgaaatgctggaccgccatcacacccacttttgccccctggagggcgaatcctggcaagattttctgcggaacaatgcaaagtcgttccggtgcgctctgctgtcccaccgcgatggcgcaaaagtgcacctgggcactcggcccaccgagaaacaatacgaaaccctggaaaaccaactggctttcctttgccaacagggattttcactggagaatgccctgtacgcactatccgcggtcggccactttaccctgggatgcgtcctcgaagatcaggagcaccaagtcgccaaggaggaaagagaaactcctaccactgactcaatgcctccgctcctgagacaagccatcgagctgttcgaccaccagggtgctgaacctgcatttctgttcgggcttgaactgattatctgcggcctggagaaacagttgaagtgcgagtcgggatcctag
SEQ ID NO:10-TetR蛋白的氨基酸序列
MSRLDKSKVINSALELLNEVGIEGLTTRKLAQKLGVEQPTLYWHVKNKRALLDALAIEMLDRHHTHFCPLEGESWQDFLRNNAKSFRCALLSHRDGAKVHLGTRPTEKQYETLENQLAFLCQQGFSLENALYALSAVGHFTLGCVLEDQEHQVAKEERETPTTDSMPPLLRQAIELFDHQGAEPAFLFGLELIICGLEKQLKCESGS
SEQ ID NO:11-凋亡抑制剂IAP1
ATGAACGAGGACACTCCGCCGTTTTATTTTATCAATACGCGCGACAACTTTCGCGATAACATCGCCGAACACGTATTCGATATGTTACTAGAAAGACATGGCTCGTTTGAAAATTATCCCATTGTAAACACGGCATTCATCAACAGCTTGATCGTTAACGGGTTTAAATACAATCAAGTCGATGACCACGTTGTGTGCGAGTATTGTGAAGCAGAAATAAAAAATTGGTCCGAAGACGAGTGTATTGAATATGCACACGTAACCTTGTCGCCGTATTGCGCCTACGCCAATAAGATTGCTGAGCATGAATCGTTTGGCGACAACATTACCATCAACGCTGTACTGGTAAAAGAAGGCAGACCCAAGTGTGTGTACAGATGCATGTCCAATTTACAGTCGCGTATGGATACGTTTGTTACTTTTTGGCCTGCCGCATTGCGTGACATGATTATAAACATCGCGGAAGCGGGACTTTTTTACACGGGTCGCGGAGACGAAACTGTATGTTTCTTTTGCGATTGTTGCGTACGTGATTGGCATACTAACGAAGACGCCTGGCAGCGACACGCCACCGAAAACCCGCAATGCTACTTTGTGCTGTCGGTGAAAGGTAAAGAATTTTGTCAAAACGCAATTACTGCCACTCACGTTGATAAACGTGACGATGACGACGACGACGATGATAATTTAAACGAGAGCGTCGATGACATTGAGGAAAAATACGAATGCAAAGTCTGTCTTGAACGCCAACGCGACGCAGTGCTTATGCCTTGTCGGCATTTTTGTGTTTGCGTTCAGTGTTATTTTGGTTTAGATCAAAAGTGTCCGACCTGTCGTCAAGACGTCACCGATTTCATAAAAATATTTGTGGTGTAG
SEQ ID NO:12-凋亡抑制剂EBNA5
ATGGGAGATCGTAGCGAAGTCCCCGGTCCGGCACGCCCCGGACCTCCGGGAATTGGCCCCGAAGGCCCTCTAGGACAGCTCCTGCGTCGGCACCGCAGTCCCTCCCCGACCCGTGGAGGCCAAGAGCCCCGGCGGGTCAGACGCCGCGTATTAGTCCAGCAGGAAGAGGAAGTAGTAAGTGGCTCACCATCAGGGCCCCGGGGAGACAGGTCAGAGGTCCCAGGCCCAGCCCGCCCTGGCCCGCCGGGTATCGGACCCGAAGGGCCCCTGGGCCAGCTGTTGCGCCGGCACAGATCACCCAGCCCCACCCGCGGCGGTCAGGAACCTCGCCGGGTCAGACGGCGGGTGCTCGTACAACAGGAAGAGGAAGTTGTTTCTGGATCGCCCTCGGGCCCGCGCGGCGACCGCTCAGAGGTGCCTGGACCAGCCCGGCCTGGGCCCCCCGGAATCGGACCTGAAGGACCGCTGGGTCAGTTACTACGCCGGCACCGGTCCCCTTCGCCGACTCGGGGCGGGCAGGAACCCCGGCGCGTGAGGCGTCGCGTCCTGGTCCAGCAGGAGGAAGAGGTTGTCAGCGGCAGCCCATCCGGGCCGAGGGGGGATCGTTCGGAAGTGCCCGGCCCAGCACGCCCGGGCCCGCCAGGTATTGGGCCCGAAGGTCCGTTAGGTCAGCTGCTCCGGCGGCATAGGTCACCATCCCCGACTCGGGGCGGCCAGGAACCGCGGAGAGTGCGCCGGAGAGTGCTGGTGCAACAGGAGGAAGAAGTCGTGTCCGGGTCGCCGTCAGGTCCTCGGGGCGACCGGTCAGAAGTACCTGGACCGGCCCGCCCCGGACCGCCGGGCATCGGGCCGGAAGGCCCCCTGGGACAGCTGCTGCGGAGACATAGATCGCCATCCCCCACCAGAGGCGGACAGGAACCGCGCCGCGTGCGCCGCCGGGTGCTGGTTCAGCAAGAAGAAGAGGTTGTGTCGGGTTCACCTAGCGGCCCGAGAGGCGACCGGAGCGAAGTGCCAGGACCAGCACGTCCGGGCCCTCCAGGTATCGGCCCAGAAGGACCACTGGGACAACTGCTGAGACGCCATCGCTCGCCGAGCCCTACGCGCGGAGGTCAAGAACCGAGACGGGTCCGCAGACGAGTCCTCGTTCAACAAGAAGAAGAGGTCGTGTCTGGAAGCCCGTCTGGCCCAAGAGGGGACAGAAGCGAGGTGCCGGGACCGGCGCGGCCGGGGCCGCCGGGGATCGGGCCTGAAGGTCCGCTGGGGCAGCTCTTGCGCAGACACCGCTCGCCCAGCCCAACCCGCGGTGGACAAGAACCCCGACGGGTGCGGCGGCGCGTGCTCGTGCAACAAGAAGAAGAGGTTGTCTCGGGCTCGCCATCTGGCCCGCTCAGACCAAGACCGCGACCGCCGGCCCGGTCCCTCCGCGAATGGCTGCTGCGCATCAGAGACAGATTCGAGCCGCCAACTGAAACCACCCAGCGGCAGTCCATCTACATTGAGGAAGAGGAAGATGAGGATTAG
SEQ ID NO:13-凋亡抑制剂BCL-XLATGAGCCAGTCAAATCGGGAACTGGTGGTGGATTTTCTGAGCTACAAGCTCTCGCAAAAGGGCTACTCATGGAGCCAGTTTTCGGATGTCGAAGAAAACCGGACCGAGGCTCCAGAGGGCACCGAATCGGAGATGGAAACTCCGTCAGCAATCAACGGAAATCCATCATGGCACCTGGCAGATAGCCCGGCGGTGAACGGAGCAACCGGACATTCAAGCTCCCTGGACGCCAGAGAAGTGATTCCGATGGCGGCAGTGAAGCAGGCGCTACGCGAAGCGGGAGACGAGTTCGAGCTGCGGTACAGGAGAGCTTTTAGCGACCTGACTAGCCAGCTCCACATCACTCCGGGGACCGCCTACCAGTCGTTTGAACAGGTGGTGAACGAGCTGTTTCGGGATGGAGTCAACTGGGGCAGAATCGTGGCCTTCTTTTCCTTCGGCGGTGCGCTGTGCGTCGAATCCGTGGACAAGGAGATGCAGGTCCTGGTCAGCCGGATCGCAGCGTGGATGGCCACTTATCTCAACGATCACCTGGAGCCGTGGATTCAAGAGAATGGGGGCTGGGACACCTTCGTGGAACTGTATGGAAACAACGCGGCAGCAGAGTCGAGGAAGGGCCAAGAACGCTTTAATCGGTGGTTCCTGACTGGAATGACGGTGGCAGGAGTGGTGCTACTGGGCTCGCTTTTCAGCCGCAAATAA
SEQ ID NO:14-来自VSV-G的N末端信号肽
MLSYLIFALAVSPILG
序列表
<110> 牛津遗传学有限公司
<120> 逆转录病毒载体
<130> 489.412.134452/01
<160> 14
<170> PatentIn version 3.5
<210> 1
<211> 2571
<212> DNA
<213> 1型人类免疫缺陷病毒
<400> 1
atgagagtga aggagaaata tcagcacttg tggagatggg ggtggagatg gggcaccatg 60
ctccttggga tgttgatgat ctgtagtgct acagaaaaat tgtgggtcac agtctattat 120
ggggtacctg tgtggaagga agcaaccacc actctatttt gtgcatcaga tgctaaagca 180
tatgatacag aggtacataa tgtttgggcc acacatgcct gtgtacccac agaccccaac 240
ccacaagaag tagtattggt aaatgtgaca gaaaatttta acatgtggaa aaatgacatg 300
gtagaacaga tgcatgagga tataatcagt ttatgggatc aaagcctaaa gccatgtgta 360
aaattaaccc cactctgtgt tagtttaaag tgcactgatt tgaagaatga tactaatacc 420
aatagtagta gcgggagaat gataatggag aaaggagaga taaaaaactg ctctttcaat 480
atcagcacaa gcataagagg taaggtgcag aaagaatatg cattttttta taaacttgat 540
ataataccaa tagataatga tactaccagc tataagttga caagttgtaa cacctcagtc 600
attacacagg cctgtccaaa ggtatccttt gagccaattc ccatacatta ttgtgccccg 660
gctggttttg cgattctaaa atgtaataat aagacgttca atggaacagg accatgtaca 720
aatgtcagca cagtacaatg tacacatgga attaggccag tagtatcaac tcaactgctg 780
ttaaatggca gtctagcaga agaagaggta gtaattagat ctgtcaattt cacggacaat 840
gctaaaacca taatagtaca gctgaacaca tctgtagaaa ttaattgtac aagacccaac 900
aacaatacaa gaaaaagaat ccgtatccag agaggaccag ggagagcatt tgttacaata 960
ggaaaaatag gaaatatgag acaagcacat tgtaacatta gtagagcaaa atggaataac 1020
actttaaaac agatagctag caaattaaga gaacaatttg gaaataataa aacaataatc 1080
tttaagcaat cctcaggagg ggacccagaa attgtaacgc acagttttaa ttgtggaggg 1140
gaatttttct actgtaattc aacacaactg tttaatagta cttggtttaa tagtacttgg 1200
agtactgaag ggtcaaataa cactgaagga agtgacacaa tcaccctccc atgcagaata 1260
aaacaaatta taaacatgtg gcagaaagta ggaaaagcaa tgtatgcccc tcccatcagt 1320
ggacaaatta gatgttcatc aaatattaca gggctgctat taacaagaga tggtggtaat 1380
agcaacaatg agtccgagat cttcagacct ggaggaggag atatgaggga caattggaga 1440
agtgaattat ataaatataa agtagtaaaa attgaaccat taggagtagc acccaccaag 1500
gcaaagagaa gagtggtgca gagagaaaaa agagcagtgg gaataggagc tttgttcctt 1560
gggttcttgg gagcagcagg aagcactatg ggcgcagcct caatgacgct gacggtacag 1620
gccagacaat tattgtctgg tatagtgcag cagcagaaca atttgctgag ggctattgag 1680
gcgcaacagc atctgttgca actcacagtc tggggcatca agcagctcca ggcaagaatc 1740
ctggctgtgg aaagatacct aaaggatcaa cagctcctgg ggatttgggg ttgctctgga 1800
aaactcattt gcaccactgc tgtgccttgg aatgctagtt ggagtaataa atctctggaa 1860
cagatttgga atcacacgac ctggatggag tgggacagag aaattaacaa ttacacaagc 1920
ttaatacact ccttaattga agaatcgcaa aaccagcaag aaaagaatga acaagaatta 1980
ttggaattag ataaatgggc aagtttgtgg aattggttta acataacaaa ttggctgtgg 2040
tatataaaat tattcataat gatagtagga ggcttggtag gtttaagaat agtttttgct 2100
gtactttcta tagtgaatag agttaggcag ggatattcac cattatcgtt tcagacccac 2160
ctcccaaccc cgaggggacc cgacaggccc gaaggaatag aagaagaagg tggagagaga 2220
gacagagaca gatccattcg attagtgaac ggatccttgg cacttatctg ggacgatctg 2280
cggagcctgt gcctcttcag ctaccaccgc ttgagagact tactcttgat tgtaacgagg 2340
attgtggaac ttctgggacg cagggggtgg gaagccctca aatattggtg gaatctccta 2400
cagtattgga gtcaggaact aaagaatagt gctgttagct tgctcaatgc cacagccata 2460
gcagtagctg aggggacaga tagggttata gaagtagtac aaggagcttg tagagctatt 2520
cgccacatac ctagaagaat aagacagggc ttggaaagga ttttgctata a 2571
<210> 2
<211> 856
<212> PRT
<213> 1型人类免疫缺陷病毒
<400> 2
Met Arg Val Lys Glu Lys Tyr Gln His Leu Trp Arg Trp Gly Trp Arg
1 5 10 15
Trp Gly Thr Met Leu Leu Gly Met Leu Met Ile Cys Ser Ala Thr Glu
20 25 30
Lys Leu Trp Val Thr Val Tyr Tyr Gly Val Pro Val Trp Lys Glu Ala
35 40 45
Thr Thr Thr Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asp Thr Glu
50 55 60
Val His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro Asn
65 70 75 80
Pro Gln Glu Val Val Leu Val Asn Val Thr Glu Asn Phe Asn Met Trp
85 90 95
Lys Asn Asp Met Val Glu Gln Met His Glu Asp Ile Ile Ser Leu Trp
100 105 110
Asp Gln Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Ser
115 120 125
Leu Lys Cys Thr Asp Leu Lys Asn Asp Thr Asn Thr Asn Ser Ser Ser
130 135 140
Gly Arg Met Ile Met Glu Lys Gly Glu Ile Lys Asn Cys Ser Phe Asn
145 150 155 160
Ile Ser Thr Ser Ile Arg Gly Lys Val Gln Lys Glu Tyr Ala Phe Phe
165 170 175
Tyr Lys Leu Asp Ile Ile Pro Ile Asp Asn Asp Thr Thr Ser Tyr Lys
180 185 190
Leu Thr Ser Cys Asn Thr Ser Val Ile Thr Gln Ala Cys Pro Lys Val
195 200 205
Ser Phe Glu Pro Ile Pro Ile His Tyr Cys Ala Pro Ala Gly Phe Ala
210 215 220
Ile Leu Lys Cys Asn Asn Lys Thr Phe Asn Gly Thr Gly Pro Cys Thr
225 230 235 240
Asn Val Ser Thr Val Gln Cys Thr His Gly Ile Arg Pro Val Val Ser
245 250 255
Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu Glu Val Val Ile
260 265 270
Arg Ser Val Asn Phe Thr Asp Asn Ala Lys Thr Ile Ile Val Gln Leu
275 280 285
Asn Thr Ser Val Glu Ile Asn Cys Thr Arg Pro Asn Asn Asn Thr Arg
290 295 300
Lys Arg Ile Arg Ile Gln Arg Gly Pro Gly Arg Ala Phe Val Thr Ile
305 310 315 320
Gly Lys Ile Gly Asn Met Arg Gln Ala His Cys Asn Ile Ser Arg Ala
325 330 335
Lys Trp Asn Asn Thr Leu Lys Gln Ile Ala Ser Lys Leu Arg Glu Gln
340 345 350
Phe Gly Asn Asn Lys Thr Ile Ile Phe Lys Gln Ser Ser Gly Gly Asp
355 360 365
Pro Glu Ile Val Thr His Ser Phe Asn Cys Gly Gly Glu Phe Phe Tyr
370 375 380
Cys Asn Ser Thr Gln Leu Phe Asn Ser Thr Trp Phe Asn Ser Thr Trp
385 390 395 400
Ser Thr Glu Gly Ser Asn Asn Thr Glu Gly Ser Asp Thr Ile Thr Leu
405 410 415
Pro Cys Arg Ile Lys Gln Ile Ile Asn Met Trp Gln Lys Val Gly Lys
420 425 430
Ala Met Tyr Ala Pro Pro Ile Ser Gly Gln Ile Arg Cys Ser Ser Asn
435 440 445
Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly Asn Ser Asn Asn Glu
450 455 460
Ser Glu Ile Phe Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp Arg
465 470 475 480
Ser Glu Leu Tyr Lys Tyr Lys Val Val Lys Ile Glu Pro Leu Gly Val
485 490 495
Ala Pro Thr Lys Ala Lys Arg Arg Val Val Gln Arg Glu Lys Arg Ala
500 505 510
Val Gly Ile Gly Ala Leu Phe Leu Gly Phe Leu Gly Ala Ala Gly Ser
515 520 525
Thr Met Gly Ala Ala Ser Met Thr Leu Thr Val Gln Ala Arg Gln Leu
530 535 540
Leu Ser Gly Ile Val Gln Gln Gln Asn Asn Leu Leu Arg Ala Ile Glu
545 550 555 560
Ala Gln Gln His Leu Leu Gln Leu Thr Val Trp Gly Ile Lys Gln Leu
565 570 575
Gln Ala Arg Ile Leu Ala Val Glu Arg Tyr Leu Lys Asp Gln Gln Leu
580 585 590
Leu Gly Ile Trp Gly Cys Ser Gly Lys Leu Ile Cys Thr Thr Ala Val
595 600 605
Pro Trp Asn Ala Ser Trp Ser Asn Lys Ser Leu Glu Gln Ile Trp Asn
610 615 620
His Thr Thr Trp Met Glu Trp Asp Arg Glu Ile Asn Asn Tyr Thr Ser
625 630 635 640
Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn
645 650 655
Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu Trp Asn Trp
660 665 670
Phe Asn Ile Thr Asn Trp Leu Trp Tyr Ile Lys Leu Phe Ile Met Ile
675 680 685
Val Gly Gly Leu Val Gly Leu Arg Ile Val Phe Ala Val Leu Ser Ile
690 695 700
Val Asn Arg Val Arg Gln Gly Tyr Ser Pro Leu Ser Phe Gln Thr His
705 710 715 720
Leu Pro Thr Pro Arg Gly Pro Asp Arg Pro Glu Gly Ile Glu Glu Glu
725 730 735
Gly Gly Glu Arg Asp Arg Asp Arg Ser Ile Arg Leu Val Asn Gly Ser
740 745 750
Leu Ala Leu Ile Trp Asp Asp Leu Arg Ser Leu Cys Leu Phe Ser Tyr
755 760 765
His Arg Leu Arg Asp Leu Leu Leu Ile Val Thr Arg Ile Val Glu Leu
770 775 780
Leu Gly Arg Arg Gly Trp Glu Ala Leu Lys Tyr Trp Trp Asn Leu Leu
785 790 795 800
Gln Tyr Trp Ser Gln Glu Leu Lys Asn Ser Ala Val Ser Leu Leu Asn
805 810 815
Ala Thr Ala Ile Ala Val Ala Glu Gly Thr Asp Arg Val Ile Glu Val
820 825 830
Val Gln Gly Ala Cys Arg Ala Ile Arg His Ile Pro Arg Arg Ile Arg
835 840 845
Gln Gly Leu Glu Arg Ile Leu Leu
850 855
<210> 3
<211> 1533
<212> DNA
<213> 水泡性口炎病毒
<400> 3
atgaagtgtc tgctgtacct ggcgttcctg tttatcgggg tgaactgcaa gttcactatc 60
gtgtttccgc acaaccaaaa gggcaactgg aaaaacgtgc cttcaaatta ccattattgc 120
cccagcagct cggacctgaa ctggcacaat gacctcattg gaaccgcgct gcaggtgaag 180
atgccaaaga gccacaaggc tatccaggct gacggatgga tgtgccacgc gtcaaaatgg 240
gtgactacct gcgatttccg ctggtacgga ccaaaataca tcacgcacag catcagatca 300
ttcaccccgt cagtggaaca atgcaaagaa tccatcgaac agactaagca gggaacctgg 360
ctgaaccctg gatttccgcc gcagtcgtgt gggtacgcaa ccgtgaccga tgcagaggcc 420
gtgatcgtgc aagtcacgcc gcatcacgtg cttgtggacg agtacaccgg agaatgggtc 480
gattcccagt tcatcaacgg caagtgctcc aactacattt gcccaaccgt gcacaacagc 540
actacttggc acagcgacta caaagtgaag ggtctgtgtg attccaacct gatctccatg 600
gatatcactt tcttctcgga agacggcgaa ctgtcctcac tgggcaaaga aggaactggg 660
tttcgctcaa attacttcgc ctacgaaact ggaggaaaag cctgcaagat gcagtactgc 720
aagcactggg gcgtgagact acccagcggt gtctggttcg agatggccga taaggacctg 780
tttgcagcag cgagattccc ggaatgccct gagggatcga gcatctccgc tccaagccaa 840
acttcagtgg acgtgagcct gatccaggac gtggaacgga ttctcgacta ctcgctgtgc 900
caggagacct ggtcgaagat cagagcggga ctgcccatct caccggtgga cctgtcctac 960
ctggcgccaa agaatccggg cactggaccg gcgttcacca tcatcaacgg caccctcaaa 1020
tacttcgaga cgcggtacat ccgggtggac atcgcagctc cgatcctctc ccggatggtg 1080
ggaatgatct cggggactac taccgaacgc gagctctggg acgactgggc accttacgag 1140
gatgtcgaga tcggacctaa cggagtgctc cggacctcct ccgggtacaa gttccctctg 1200
tacatgatcg gccatggcat gctggactcg gatctgcatc tgtcgtccaa agcacaggtg 1260
tttgaacacc cacacattca agacgccgcc agccagctgc cggacgatga gtcgctgttc 1320
ttcggagaca cgggcttgtc aaagaatccc atcgagctgg tggaaggatg gttttcatcc 1380
tggaaaagca gcatcgcttc attcttcttc atcattggcc tgatcatcgg cctatttcta 1440
gtcctgcggg tgggaattca tctgtgcatc aagctcaagc acactaagaa gcggcaaatc 1500
tacactgata tcgagatgaa tcgcctgggc aag 1533
<210> 4
<211> 511
<212> PRT
<213> 水泡性口炎病毒
<400> 4
Met Lys Cys Leu Leu Tyr Leu Ala Phe Leu Phe Ile Gly Val Asn Cys
1 5 10 15
Lys Phe Thr Ile Val Phe Pro His Asn Gln Lys Gly Asn Trp Lys Asn
20 25 30
Val Pro Ser Asn Tyr His Tyr Cys Pro Ser Ser Ser Asp Leu Asn Trp
35 40 45
His Asn Asp Leu Ile Gly Thr Ala Leu Gln Val Lys Met Pro Lys Ser
50 55 60
His Lys Ala Ile Gln Ala Asp Gly Trp Met Cys His Ala Ser Lys Trp
65 70 75 80
Val Thr Thr Cys Asp Phe Arg Trp Tyr Gly Pro Lys Tyr Ile Thr His
85 90 95
Ser Ile Arg Ser Phe Thr Pro Ser Val Glu Gln Cys Lys Glu Ser Ile
100 105 110
Glu Gln Thr Lys Gln Gly Thr Trp Leu Asn Pro Gly Phe Pro Pro Gln
115 120 125
Ser Cys Gly Tyr Ala Thr Val Thr Asp Ala Glu Ala Val Ile Val Gln
130 135 140
Val Thr Pro His His Val Leu Val Asp Glu Tyr Thr Gly Glu Trp Val
145 150 155 160
Asp Ser Gln Phe Ile Asn Gly Lys Cys Ser Asn Tyr Ile Cys Pro Thr
165 170 175
Val His Asn Ser Thr Thr Trp His Ser Asp Tyr Lys Val Lys Gly Leu
180 185 190
Cys Asp Ser Asn Leu Ile Ser Met Asp Ile Thr Phe Phe Ser Glu Asp
195 200 205
Gly Glu Leu Ser Ser Leu Gly Lys Glu Gly Thr Gly Phe Arg Ser Asn
210 215 220
Tyr Phe Ala Tyr Glu Thr Gly Gly Lys Ala Cys Lys Met Gln Tyr Cys
225 230 235 240
Lys His Trp Gly Val Arg Leu Pro Ser Gly Val Trp Phe Glu Met Ala
245 250 255
Asp Lys Asp Leu Phe Ala Ala Ala Arg Phe Pro Glu Cys Pro Glu Gly
260 265 270
Ser Ser Ile Ser Ala Pro Ser Gln Thr Ser Val Asp Val Ser Leu Ile
275 280 285
Gln Asp Val Glu Arg Ile Leu Asp Tyr Ser Leu Cys Gln Glu Thr Trp
290 295 300
Ser Lys Ile Arg Ala Gly Leu Pro Ile Ser Pro Val Asp Leu Ser Tyr
305 310 315 320
Leu Ala Pro Lys Asn Pro Gly Thr Gly Pro Ala Phe Thr Ile Ile Asn
325 330 335
Gly Thr Leu Lys Tyr Phe Glu Thr Arg Tyr Ile Arg Val Asp Ile Ala
340 345 350
Ala Pro Ile Leu Ser Arg Met Val Gly Met Ile Ser Gly Thr Thr Thr
355 360 365
Glu Arg Glu Leu Trp Asp Asp Trp Ala Pro Tyr Glu Asp Val Glu Ile
370 375 380
Gly Pro Asn Gly Val Leu Arg Thr Ser Ser Gly Tyr Lys Phe Pro Leu
385 390 395 400
Tyr Met Ile Gly His Gly Met Leu Asp Ser Asp Leu His Leu Ser Ser
405 410 415
Lys Ala Gln Val Phe Glu His Pro His Ile Gln Asp Ala Ala Ser Gln
420 425 430
Leu Pro Asp Asp Glu Ser Leu Phe Phe Gly Asp Thr Gly Leu Ser Lys
435 440 445
Asn Pro Ile Glu Leu Val Glu Gly Trp Phe Ser Ser Trp Lys Ser Ser
450 455 460
Ile Ala Ser Phe Phe Phe Ile Ile Gly Leu Ile Ile Gly Leu Phe Leu
465 470 475 480
Val Leu Arg Val Gly Ile His Leu Cys Ile Lys Leu Lys His Thr Lys
485 490 495
Lys Arg Gln Ile Tyr Thr Asp Ile Glu Met Asn Arg Leu Gly Lys
500 505 510
<210> 5
<211> 4307
<212> DNA
<213> 1型人类免疫缺陷病毒
<400> 5
atgggtgcga gagcgtcagt attaagcggg ggagaattag atcgatggga aaaaattcgg 60
ttaaggccag ggggaaagaa aaaatataaa ttaaaacata tagtatgggc aagcagggag 120
ctagaacgat tcgcagttaa tcctggcctg ttagaaacat cagaaggctg tagacaaata 180
ctgggacagc tacaaccatc ccttcagaca ggatcagaag aacttagatc attatataat 240
acagtagcaa ccctctattg tgtgcatcaa aggatagaga taaaagacac caaggaagct 300
ttagacaaga tagaggaaga gcaaaacaaa agtaagaaaa aagcacagca agcagcagct 360
gacacaggac acagcaatca ggtcagccaa aattacccta tagtgcagaa catccagggg 420
caaatggtac atcaggccat atcacctaga actttaaatg catgggtaaa agtagtagaa 480
gagaaggctt tcagcccaga agtgataccc atgttttcag cattatcaga aggagccacc 540
ccacaagatt taaacaccat gctaaacaca gtggggggac atcaagcagc catgcaaatg 600
ttaaaagaga ccatcaatga ggaagctgca gaatgggata gagtgcatcc agtgcatgca 660
gggcctattg caccaggcca gatgagagaa ccaaggggaa gtgacatagc aggaactact 720
agtacccttc aggaacaaat aggatggatg acacataatc cacctatccc agtaggagaa 780
atctataaaa gatggataat cctgggatta aataaaatag taagaatgta tagccctacc 840
agcattctgg acataagaca aggaccaaag gaacccttta gagactatgt agaccgattc 900
tataaaactc taagagccga gcaagcttca caagaggtaa aaaattggat gacagaaacc 960
ttgttggtcc aaaatgcgaa cccagattgt aagactattt taaaagcatt gggaccagga 1020
gcgacactag aagaaatgat gacagcatgt cagggagtgg ggggacccgg ccataaagca 1080
agagttttgg ctgaagcaat gagccaagta acaaatccag ctaccataat gatacagaaa 1140
ggcaatttta ggaaccaaag aaagactgtt aagtgtttca attgtggcaa agaagggcac 1200
atagccaaaa attgcagggc ccctaggaaa aagggctgtt ggaaatgtgg aaaggaagga 1260
caccaaatga aagattgtac tgagagacag gctaattttt tagggaagat ctggccttcc 1320
cacaagggaa ggccagggaa ttttcttcag agcagaccag agccaacagc cccaccagaa 1380
gagagcttca ggtttgggga agagacaaca actccctctc agaagcagga gccgatagac 1440
aaggaactgt atcctttagc ttccctcaga tcactctttg gcagcgaccc ctcgtcacaa 1500
taaagatagg ggggcaatta aaggaagctc tattagatac aggagcagat gatacagtat 1560
tagaagaaat gaatttgcca ggaagatgga aaccaaaaat gataggggga attggaggtt 1620
ttatcaaagt aagacagtat gatcagatac tcatagaaat ctgcggacat aaagctatag 1680
gtacagtatt agtaggacct acacctgtca acataattgg aagaaatctg ttgactcaga 1740
ttggctgcac tttaaatttt cccattagtc ctattgagac tgtaccagta aaattaaagc 1800
caggaatgga tggcccaaaa gttaaacaat ggccattgac agaagaaaaa ataaaagcat 1860
tagtagaaat ttgtacagaa atggaaaagg aaggaaaaat ttcaaaaatt gggcctgaaa 1920
atccatacaa tactccagta tttgccataa agaaaaaaga cagtactaaa tggagaaaat 1980
tagtagattt cagagaactt aataagagaa ctcaagattt ctgggaagtt caattaggaa 2040
taccacatcc tgcagggtta aaacagaaaa aatcagtaac agtactggat gtgggcgatg 2100
catatttttc agttccctta gataaagact tcaggaagta tactgcattt accataccta 2160
gtataaacaa tgagacacca gggattagat atcagtacaa tgtgcttcca cagggatgga 2220
aaggatcacc agcaatattc cagtgtagca tgacaaaaat cttagagcct tttagaaaac 2280
aaaatccaga catagtcatc tatcaataca tggatgattt gtatgtagga tctgacttag 2340
aaatagggca gcatagaaca aaaatagagg aactgagaca acatctgttg aggtggggat 2400
ttaccacacc agacaaaaaa catcagaaag aacctccatt cctttggatg ggttatgaac 2460
tccatcctga taaatggaca gtacagccta tagtgctgcc agaaaaggac agctggactg 2520
tcaatgacat acagaaatta gtgggaaaat tgaattgggc aagtcagatt tatgcaggga 2580
ttaaagtaag gcaattatgt aaacttctta ggggaaccaa agcactaaca gaagtagtac 2640
cactaacaga agaagcagag ctagaactgg cagaaaacag ggagattcta aaagaaccgg 2700
tacatggagt gtattatgac ccatcaaaag acttaatagc agaaatacag aagcaggggc 2760
aaggccaatg gacatatcaa atttatcaag agccatttaa aaatctgaaa acaggaaagt 2820
atgcaagaat gaagggtgcc cacactaatg atgtgaaaca attaacagag gcagtacaaa 2880
aaatagccac agaaagcata gtaatatggg gaaagactcc taaatttaaa ttacccatac 2940
aaaaggaaac atgggaagca tggtggacag agtattggca agccacctgg attcctgagt 3000
gggagtttgt caatacccct cccttagtga agttatggta ccagttagag aaagaaccca 3060
taataggagc agaaactttc tatgtagatg gggcagccaa tagggaaact aaattaggaa 3120
aagcaggata tgtaactgac agaggaagac aaaaagttgt ccccctaacg gacacaacaa 3180
atcagaagac tgagttacaa gcaattcatc tagctttgca ggattcggga ttagaagtaa 3240
acatagtgac agactcacaa tatgcattgg gaatcattca agcacaacca gataagagtg 3300
aatcagagtt agtcagtcaa ataatagagc agttaataaa aaaggaaaaa gtctacctgg 3360
catgggtacc agcacacaaa ggaattggag gaaatgaaca agtagataaa ttggtcagtg 3420
ctggaatcag gaaagtacta tttttagatg gaatagataa ggcccaagaa gaacatgaga 3480
aatatcacag taattggaga gcaatggcta gtgattttaa cctaccacct gtagtagcaa 3540
aagaaatagt agccagctgt gataaatgtc agctaaaagg ggaagccatg catggacaag 3600
tagactgtag cccaggaata tggcagctag attgtacaca tttagaagga aaagttatct 3660
tggtagcagt tcatgtagcc agtggatata tagaagcaga agtaattcca gcagagacag 3720
ggcaagaaac agcatacttc ctcttaaaat tagcaggaag atggccagta aaaacagtac 3780
atacagacaa tggcagcaat ttcaccagta ctacagttaa ggccgcctgt tggtgggcgg 3840
ggatcaagca ggaatttggc attccctaca atccccaaag tcaaggagta atagaatcta 3900
tgaataaaga attaaagaaa attataggac aggtaagaga tcaggctgaa catcttaaga 3960
cagcagtaca aatggcagta ttcatccaca attttaaaag aaaagggggg attggggggt 4020
acagtgcagg ggaaagaata gtagacataa tagcaacaga catacaaact aaagaattac 4080
aaaaacaaat tacaaaaatt caaaattttc gggtttatta cagggacagc agagatccag 4140
tttggaaagg accagcaaag ctcctctgga aaggtgaagg ggcagtagta atacaagata 4200
atagtgacat aaaagtagtg ccaagaagaa aagcaaagat catcagggat tatggaaaac 4260
agatggcagg tgatgattgt gtggcaagta gacaggatga ggattaa 4307
<210> 6
<211> 348
<212> DNA
<213> 1型人类免疫缺陷病毒
<400> 6
atggcaggcc gctcagggga ctcggatgag gatctgctga aggcggtgcg gctcatcaaa 60
ttcctgtacc agagcaaccc gccaccgaac cccgaaggaa ctcgccaggc tcgcaggaac 120
cgccgcagac gctggcgcga acggcagcgc cagatccaca gcatcagcga acgcatcctg 180
tcaacttact tgggacggtc agcggaacct gtcccgctgc agctgccgcc gctggagcgc 240
ctgactctgg attgcaacga agactgcgga accagcggaa cccagggcgt gggaagccca 300
cagatcctgg tggaatcgcc taccatcttg gaaagcggcg cgaaagaa 348
<210> 7
<211> 116
<212> PRT
<213> 1型人类免疫缺陷病毒
<400> 7
Met Ala Gly Arg Ser Gly Asp Ser Asp Glu Asp Leu Leu Lys Ala Val
1 5 10 15
Arg Leu Ile Lys Phe Leu Tyr Gln Ser Asn Pro Pro Pro Asn Pro Glu
20 25 30
Gly Thr Arg Gln Ala Arg Arg Asn Arg Arg Arg Arg Trp Arg Glu Arg
35 40 45
Gln Arg Gln Ile His Ser Ile Ser Glu Arg Ile Leu Ser Thr Tyr Leu
50 55 60
Gly Arg Ser Ala Glu Pro Val Pro Leu Gln Leu Pro Pro Leu Glu Arg
65 70 75 80
Leu Thr Leu Asp Cys Asn Glu Asp Cys Gly Thr Ser Gly Thr Gln Gly
85 90 95
Val Gly Ser Pro Gln Ile Leu Val Glu Ser Pro Thr Ile Leu Glu Ser
100 105 110
Gly Ala Lys Glu
115
<210> 8
<211> 19
<212> DNA
<213> 大肠杆菌 (Escherichia coli)
<400> 8
tccctatcag tgatagaga 19
<210> 9
<211> 624
<212> DNA
<213> 大肠杆菌 (Escherichia coli)
<400> 9
atgtcgcgcc tggacaaaag caaagtgatt aactcagcgc tggaactgtt gaatgaggtg 60
ggaattgaag gactcactac tcgcaagctg gcacagaagc tgggcgtcga gcagccaacg 120
ctgtactggc atgtgaagaa taaacgggcg ctcctagacg cgcttgccat cgaaatgctg 180
gaccgccatc acacccactt ttgccccctg gagggcgaat cctggcaaga ttttctgcgg 240
aacaatgcaa agtcgttccg gtgcgctctg ctgtcccacc gcgatggcgc aaaagtgcac 300
ctgggcactc ggcccaccga gaaacaatac gaaaccctgg aaaaccaact ggctttcctt 360
tgccaacagg gattttcact ggagaatgcc ctgtacgcac tatccgcggt cggccacttt 420
accctgggat gcgtcctcga agatcaggag caccaagtcg ccaaggagga aagagaaact 480
cctaccactg actcaatgcc tccgctcctg agacaagcca tcgagctgtt cgaccaccag 540
ggtgctgaac ctgcatttct gttcgggctt gaactgatta tctgcggcct ggagaaacag 600
ttgaagtgcg agtcgggatc ctag 624
<210> 10
<211> 207
<212> PRT
<213> 大肠杆菌 (Escherichia coli)
<400> 10
Met Ser Arg Leu Asp Lys Ser Lys Val Ile Asn Ser Ala Leu Glu Leu
1 5 10 15
Leu Asn Glu Val Gly Ile Glu Gly Leu Thr Thr Arg Lys Leu Ala Gln
20 25 30
Lys Leu Gly Val Glu Gln Pro Thr Leu Tyr Trp His Val Lys Asn Lys
35 40 45
Arg Ala Leu Leu Asp Ala Leu Ala Ile Glu Met Leu Asp Arg His His
50 55 60
Thr His Phe Cys Pro Leu Glu Gly Glu Ser Trp Gln Asp Phe Leu Arg
65 70 75 80
Asn Asn Ala Lys Ser Phe Arg Cys Ala Leu Leu Ser His Arg Asp Gly
85 90 95
Ala Lys Val His Leu Gly Thr Arg Pro Thr Glu Lys Gln Tyr Glu Thr
100 105 110
Leu Glu Asn Gln Leu Ala Phe Leu Cys Gln Gln Gly Phe Ser Leu Glu
115 120 125
Asn Ala Leu Tyr Ala Leu Ser Ala Val Gly His Phe Thr Leu Gly Cys
130 135 140
Val Leu Glu Asp Gln Glu His Gln Val Ala Lys Glu Glu Arg Glu Thr
145 150 155 160
Pro Thr Thr Asp Ser Met Pro Pro Leu Leu Arg Gln Ala Ile Glu Leu
165 170 175
Phe Asp His Gln Gly Ala Glu Pro Ala Phe Leu Phe Gly Leu Glu Leu
180 185 190
Ile Ile Cys Gly Leu Glu Lys Gln Leu Lys Cys Glu Ser Gly Ser
195 200 205
<210> 11
<211> 876
<212> DNA
<213> 杆状病毒
<400> 11
atgaacgagg acactccgcc gttttatttt atcaatacgc gcgacaactt tcgcgataac 60
atcgccgaac acgtattcga tatgttacta gaaagacatg gctcgtttga aaattatccc 120
attgtaaaca cggcattcat caacagcttg atcgttaacg ggtttaaata caatcaagtc 180
gatgaccacg ttgtgtgcga gtattgtgaa gcagaaataa aaaattggtc cgaagacgag 240
tgtattgaat atgcacacgt aaccttgtcg ccgtattgcg cctacgccaa taagattgct 300
gagcatgaat cgtttggcga caacattacc atcaacgctg tactggtaaa agaaggcaga 360
cccaagtgtg tgtacagatg catgtccaat ttacagtcgc gtatggatac gtttgttact 420
ttttggcctg ccgcattgcg tgacatgatt ataaacatcg cggaagcggg acttttttac 480
acgggtcgcg gagacgaaac tgtatgtttc ttttgcgatt gttgcgtacg tgattggcat 540
actaacgaag acgcctggca gcgacacgcc accgaaaacc cgcaatgcta ctttgtgctg 600
tcggtgaaag gtaaagaatt ttgtcaaaac gcaattactg ccactcacgt tgataaacgt 660
gacgatgacg acgacgacga tgataattta aacgagagcg tcgatgacat tgaggaaaaa 720
tacgaatgca aagtctgtct tgaacgccaa cgcgacgcag tgcttatgcc ttgtcggcat 780
ttttgtgttt gcgttcagtg ttattttggt ttagatcaaa agtgtccgac ctgtcgtcaa 840
gacgtcaccg atttcataaa aatatttgtg gtgtag 876
<210> 12
<211> 1521
<212> DNA
<213> 爱泼斯坦巴尔病毒
<400> 12
atgggagatc gtagcgaagt ccccggtccg gcacgccccg gacctccggg aattggcccc 60
gaaggccctc taggacagct cctgcgtcgg caccgcagtc cctccccgac ccgtggaggc 120
caagagcccc ggcgggtcag acgccgcgta ttagtccagc aggaagagga agtagtaagt 180
ggctcaccat cagggccccg gggagacagg tcagaggtcc caggcccagc ccgccctggc 240
ccgccgggta tcggacccga agggcccctg ggccagctgt tgcgccggca cagatcaccc 300
agccccaccc gcggcggtca ggaacctcgc cgggtcagac ggcgggtgct cgtacaacag 360
gaagaggaag ttgtttctgg atcgccctcg ggcccgcgcg gcgaccgctc agaggtgcct 420
ggaccagccc ggcctgggcc ccccggaatc ggacctgaag gaccgctggg tcagttacta 480
cgccggcacc ggtccccttc gccgactcgg ggcgggcagg aaccccggcg cgtgaggcgt 540
cgcgtcctgg tccagcagga ggaagaggtt gtcagcggca gcccatccgg gccgaggggg 600
gatcgttcgg aagtgcccgg cccagcacgc ccgggcccgc caggtattgg gcccgaaggt 660
ccgttaggtc agctgctccg gcggcatagg tcaccatccc cgactcgggg cggccaggaa 720
ccgcggagag tgcgccggag agtgctggtg caacaggagg aagaagtcgt gtccgggtcg 780
ccgtcaggtc ctcggggcga ccggtcagaa gtacctggac cggcccgccc cggaccgccg 840
ggcatcgggc cggaaggccc cctgggacag ctgctgcgga gacatagatc gccatccccc 900
accagaggcg gacaggaacc gcgccgcgtg cgccgccggg tgctggttca gcaagaagaa 960
gaggttgtgt cgggttcacc tagcggcccg agaggcgacc ggagcgaagt gccaggacca 1020
gcacgtccgg gccctccagg tatcggccca gaaggaccac tgggacaact gctgagacgc 1080
catcgctcgc cgagccctac gcgcggaggt caagaaccga gacgggtccg cagacgagtc 1140
ctcgttcaac aagaagaaga ggtcgtgtct ggaagcccgt ctggcccaag aggggacaga 1200
agcgaggtgc cgggaccggc gcggccgggg ccgccgggga tcgggcctga aggtccgctg 1260
gggcagctct tgcgcagaca ccgctcgccc agcccaaccc gcggtggaca agaaccccga 1320
cgggtgcggc ggcgcgtgct cgtgcaacaa gaagaagagg ttgtctcggg ctcgccatct 1380
ggcccgctca gaccaagacc gcgaccgccg gcccggtccc tccgcgaatg gctgctgcgc 1440
atcagagaca gattcgagcc gccaactgaa accacccagc ggcagtccat ctacattgag 1500
gaagaggaag atgaggatta g 1521
<210> 13
<211> 702
<212> DNA
<213> 智人(Homo sapiens)
<400> 13
atgagccagt caaatcggga actggtggtg gattttctga gctacaagct ctcgcaaaag 60
ggctactcat ggagccagtt ttcggatgtc gaagaaaacc ggaccgaggc tccagagggc 120
accgaatcgg agatggaaac tccgtcagca atcaacggaa atccatcatg gcacctggca 180
gatagcccgg cggtgaacgg agcaaccgga cattcaagct ccctggacgc cagagaagtg 240
attccgatgg cggcagtgaa gcaggcgcta cgcgaagcgg gagacgagtt cgagctgcgg 300
tacaggagag cttttagcga cctgactagc cagctccaca tcactccggg gaccgcctac 360
cagtcgtttg aacaggtggt gaacgagctg tttcgggatg gagtcaactg gggcagaatc 420
gtggccttct tttccttcgg cggtgcgctg tgcgtcgaat ccgtggacaa ggagatgcag 480
gtcctggtca gccggatcgc agcgtggatg gccacttatc tcaacgatca cctggagccg 540
tggattcaag agaatggggg ctgggacacc ttcgtggaac tgtatggaaa caacgcggca 600
gcagagtcga ggaagggcca agaacgcttt aatcggtggt tcctgactgg aatgacggtg 660
gcaggagtgg tgctactggg ctcgcttttc agccgcaaat aa 702
<210> 14
<211> 16
<212> PRT
<213> 水泡性口炎病毒
<400> 14
Met Leu Ser Tyr Leu Ile Phe Ala Leu Ala Val Ser Pro Ile Leu Gly
1 5 10 15
Claims (18)
1.一种双链核酸分子,其包含:
(a)包含env基因的第一核酸;以及
(b)包含gag-pol基因的第二核酸;
其中,所述第一核酸的编码序列和所述第二核酸的编码序列在所述双链核酸分子的相对链上,其中,所述env基因和所述gag-pol基因分别独立地与第一诱导型启动子和第二诱导型启动子可操作地相关联,所述第一启动子和所述第二启动子在它们之间具有小于95%的核苷酸序列同一性,并且其中,所述双链核酸分子包含1个或多个编码凋亡抑制剂的核苷酸序列。
2.根据权利要求1所述的双链核酸分子,其中,所述第一启动子和所述第二启动子之间的核苷酸序列同一性小于90%、85%、80%、70%或60%。
3.根据权利要求1或权利要求2所述的双链核酸分子,其中,所述env基因是VSV-G基因。
4.根据前述权利要求中任一项所述的双链核酸分子,其中,所述gag-pol基因来自HIV-1或其衍生物。
5.根据前述权利要求中任一项所述的双链核酸分子,其中,所述核酸分子另外包含rev基因。
6.根据前述权利要求中任一项所述的双链核酸分子,其中,所述核酸分子另外包含转基因。
7.根据前述权利要求中任一项所述的双链核酸分子,其中,所述核酸分子包含1个或2个编码凋亡抑制剂的核苷酸序列。
8.根据前述权利要求中任一项所述的双链核酸分子,其中,所述凋亡抑制剂选自由以下组成的组:鸡胚致死孤病毒GAM1、腺病毒E4 Orf6、腺病毒E1B 55K、腺病毒E1B 19K、粘液瘤病毒M11L、巨细胞病毒IE1、巨细胞病毒IE2、杆状病毒p35、杆状病毒IAP-1、疱疹病毒US3、松鼠猴疱疹病毒ORF16、单纯疱疹2LAT ORF 1、人XIAP、非洲猪瘟ASFV-5-HL(LMW-5-HL/A179L)、卡波西肉瘤病毒KSbcl2、痘苗病毒SPI-2、牛痘病毒CrmA、爱泼斯坦巴尔病毒BHRF1、爱泼斯坦巴尔病毒EBNA-5、爱泼斯坦巴尔病毒BZLF-1、乳头瘤病毒E6、人Aven、人BCL2和人BCL-XL。
9.根据权利要求7所述的双链核酸分子,其中,所述核酸分子包含编码凋亡抑制剂IAP1和EBNA5、IAP1和BCL-XL、或EBNA5和BCL-XL的核苷酸序列。
10.一种逆转录病毒载体,其包含根据前述权利要求中任一项所述的双链核酸分子,所述逆转录病毒载体更优选为慢病毒载体。
11.一种哺乳动物细胞,其包含根据权利要求1至9中任一项所述的双链核酸,优选地,其中所述双链核酸被稳定地整合到所述哺乳动物细胞的核基因组中。
12.一种逆转录病毒包装细胞,其包含根据权利要求1至9中任一项所述的双链核酸分子。
13.一种试剂盒,其包括:
(i)包含根据权利要求1至9中任一项所述的双链核酸的逆转录病毒包装载体,
以及以下一种或多种:
(ii)逆转录病毒转移载体,所述逆转录病毒转移载体包含转基因和逆转录病毒rev基因;
(iii)适于产生病毒颗粒的细胞系的细胞。
14.一种试剂盒,其包括:
(i)包含根据权利要求1至9中任一项所述的双链核酸的逆转录病毒包装载体,所述双链核酸还包含rev基因,
以及下述一种或多种:
(ii)包含转基因的逆转录病毒转移载体;
(iii)适于产生病毒颗粒的细胞系的细胞。
15.一种用于产生逆转录病毒包装细胞的方法,所述方法包括下述步骤:
(i)将根据权利要求1至9中任一项所述的双链核酸分子稳定地整合到哺乳动物细胞中,
由此产生表达逆转录病毒env基因和gag-pol基因以及可选的rev基因的哺乳动物细胞。
16.根据权利要求12所述的逆转录病毒包装细胞在逆转录病毒颗粒的生产中的用途。
17.一种用于产生逆转录病毒的方法,所述方法包括以下步骤:
(a)将包含5’和3’逆转录病毒LTR的逆转录病毒转移载体、逆转录病毒包装信号和逆转录病毒rev基因引入到根据权利要求12所述的逆转录病毒包装细胞中,其中,所述逆转录病毒包装细胞包含稳定地整合到所述逆转录病毒包装细胞的基因组中的逆转录病毒env基因和gag-pol基因;
(b)在一定条件下培养所述细胞,使得所述逆转录病毒由所述细胞组装和分泌;以及
(c)从上清液中收获包装的逆转录病毒。
18.一种用于产生逆转录病毒的方法,所述方法包括以下步骤:
(a)将包含转基因的逆转录病毒转移载体引入到根据权利要求12所述的逆转录病毒包装细胞中,其中,所述逆转录病毒包装细胞包含稳定地整合到所述逆转录病毒包装细胞的基因组中的逆转录病毒env基因、gag-pol基因和rev基因;
(b)在一定条件下培养所述细胞,使得所述逆转录病毒由所述细胞组装和分泌;以及
(c)从上清液中收获包装的逆转录病毒。
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CN110892064A (zh) | 2017-07-25 | 2020-03-17 | 牛津遗传学有限公司 | 腺病毒载体 |
KR20220047635A (ko) | 2019-08-23 | 2022-04-18 | 론자 워커스빌 아이엔씨. | 렌티바이러스 벡터의 생산을 위한 방법 및 작제물 |
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AU2018336042A1 (en) | 2020-04-23 |
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WO2019058108A1 (en) | 2019-03-28 |
JP7105875B2 (ja) | 2022-07-25 |
CN111108116B (zh) | 2024-03-26 |
SG11202001367QA (en) | 2020-04-29 |
US11667929B2 (en) | 2023-06-06 |
GB201715052D0 (en) | 2017-11-01 |
AU2018336042B2 (en) | 2022-03-10 |
US20200277629A1 (en) | 2020-09-03 |
CA3076270C (en) | 2023-08-22 |
EP3684790A1 (en) | 2020-07-29 |
KR102423444B1 (ko) | 2022-07-20 |
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