CN110055228B - 用于乙肝病毒感染的重组巨细胞病毒与应用 - Google Patents

用于乙肝病毒感染的重组巨细胞病毒与应用 Download PDF

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CN110055228B
CN110055228B CN201910306571.0A CN201910306571A CN110055228B CN 110055228 B CN110055228 B CN 110055228B CN 201910306571 A CN201910306571 A CN 201910306571A CN 110055228 B CN110055228 B CN 110055228B
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刘嘉
黄红明
米尔科·特里林
杨东亮
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Tongji Medical College of Huazhong University of Science and Technology
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Abstract

本发明提供了用于乙肝病毒感染的重组巨细胞病毒，所述重组巨细胞病毒能表达乙型肝炎病毒表面抗原，所述重组巨细胞病毒通过细菌人工染色体诱变产生，所述乙型肝炎病毒表面抗原的氨基酸序列如序列表SEQ ID NO：1所示。该重组巨细胞病毒可表达HBV表面抗原的完整复制及缺陷型复制；在HBV小鼠复制模型中证实了表达HBV表面抗原的重组巨细胞病毒载体乙肝疫苗抗HBV的免疫功效；初步阐明了表达HBV表面抗原的重组巨细胞病毒载体乙肝疫苗抗HBV的免疫功效的免疫机制。为寻找治愈乙肝的治疗性药物提供了新的理论与实践基础，在临床应用上有重要意义。

Description

用于乙肝病毒感染的重组巨细胞病毒与应用
技术领域
本发明涉及病毒学、免疫学和医学技术领域，特别涉及预防和治疗乙肝病毒感染的重组巨细胞病毒与应用。
背景技术
乙型肝炎病毒(HBV)感染是全球性的公共卫生问题，慢性HBV感染在我国尤为严重。虽然全球范围内推广实行婴儿和新生儿接种HBV预防性疫苗后已经大大减少了新发感染病例,但是慢性感染人群依然无法得到彻底治疗。预防性疫苗是控制HBV发病不可或缺的一部分，但是我们更需要新的药物或者治疗性疫苗治愈已经感染HBV的人群以减少HBV及其相关疾病所引起的死亡。
急性自限性HBV感染的患者体内会自发出现针对HBV核心(即核衣壳)、聚合酶和表面(即包膜)蛋白的多克隆和多特异性辅助性T细胞以及细胞毒性的T细胞应答，而这些细胞应答在慢性HBV感染患者中出现功能障碍，反应很弱甚至检测不到。所以针对慢性HBV新的治疗性药物或者疫苗应该与特异性免疫应答特别是T细胞反应相结合，才能有效地治愈HBV。CMV作为载体的疫苗在联合特异性T细胞反应方面具有强大潜能，能够大幅度增强CD8+T细胞的免疫优势，可能实现在个体中建立保护性CD8+T细胞应答的目标。而HBV感染后特异性免疫激活与否决定着感染的最终结局，当机体免疫系统未能及时控制HBV感染时就会进展为慢性感染，此时CD8+T细胞存在功能耗竭，病毒特异性CD8+T细胞功能耗竭是HBV病毒持续复制的关键因素之一。
细菌人工染色体(Bacterial Artificial Chromsomes，BAC)，是一种基因诱变工具，具有转座效率高、负载容量大、宿主特异性差等特点。BAC用于维持和修饰大肠杆菌中不同来源的大序列。除基于RecA的穿梭诱变外，Red重组通常用于序列修饰。由于外源序列，如抗生素抗性基因以及frt-或loxP-位点在突变体BAC克隆中通常是不需要的，现有的一种技术允许无斑点生成点突变、缺失和插入较小的和更大的序列。该方法采用序列复制，其在第一次重组步骤中插入靶序列，并通过体内I-SceI切割和第二次Red重组切除选择标记。为了在不使用额外质粒的情况下进行方便和高效的诱变，产生了具有染色体编码的可诱导的Red-和I-SceI-表达的大肠杆菌菌株。
发明内容
本发明的第一个目的在于提供一种用于乙肝病毒感染的重组巨细胞病毒。
用于乙肝病毒感染的重组巨细胞病毒，所述重组巨细胞病毒能表达乙型肝炎病毒表面抗原，所述重组巨细胞病毒通过细菌人工染色体诱变产生，所述乙型肝炎病毒表面抗原的氨基酸序列如序列表SEQ ID NO：1所示。
进一步地，所述细菌人工染色体诱变将在启动子的控制下的乙型肝炎病毒表面抗原基因替换为巨细胞病毒中的m157或m27基因座。
进一步地，所述启动子为真核EF1启动子。
本发明还有另一个目的在于提供上述制备预防乙肝病毒感染的疫苗中的应用。
本发明的还有一个目的在于提供上述重组巨细胞病毒在制备治疗慢性乙肝病毒感染的疫苗中的应用。
本发明的有益效果在于：构建了可表达HBV表面抗原的完整复制及复制缺陷型小鼠巨细胞病毒载体乙肝疫苗；并在HBV小鼠复制模型中证实了表达HBV表面抗原的重组巨细胞病毒载体乙肝疫苗打破慢性HBV耐受、抗HBV复制的免疫功效；初步阐明了表达HBV表面抗原的重组巨细胞病毒载体乙肝疫苗抗HBV的免疫功效的免疫机制。该发现为寻找治愈乙肝的治疗性药物提供了新的理论与实践基础，在临床应用上有重要意义。
附图说明
图1为重组MCMVΔm157p-HBsAg的构建过程。
图2为重组MCMVΔm27p-HBsAg的构建过程。
图3为实验二的研究过程示意图。
图4-1和图4-2为实验二中HBsAg的含量值及百分比。
图5-1和图5-2为实验二中HBeAg的含量值及百分比。
图6为肝脏组织中HBsAg和HBcAg的表达量的组织切片图。
图7-1和图7-2为CD8+T细胞免疫检测肝脏中HBc和HBs含量结果。
图8为实验三的研究过程示意图。
图9-1和图9-2为实验三中小鼠血清中HBV抗原水平示意图。
图10为实验四的研究过程示意图。
图11-1和图11-2为实验四中小鼠血清HBV抗原水平示意图。
具体实施方式
为了更好的理解本发明，下面将结合实施例和附图来做进一步说明。
实验一、重组巨细胞病毒的构建：应用BAC(Bacterial Artificial Chromosome，细菌人工染色体)诱变以产生重组巨细胞病毒(MCMV)，在真核EF1启动子的控制下插入如上目的基因sHBsAg替换其中的m157或者m27基因座以表达HBV表面抗原。如图1和图2所示，分别构建出可表达乙肝表面抗原(HBsAg)的重组MCMV(Δm157p-HBsAg)和可表达HBsAg但存在复制缺陷的重组MCMV(Δm27p-HBsAg)。及不能表达HBV抗原的重组MCMV(Δm157p)。其中，HBsAg的氨基酸序列如序列表SEQ ID NO：1所示。在C57/BL6小鼠体内分别验证Δm157p-HBsAg、Δm157p-HBsAg及Δm157p抗HBV功效。
实验二、表达HBsAg的重组MCMV抗肝内HBV复制作用的研究：按照图3所示，用重组的表达HBsAg的MCMV分别于第1天和第3周感染小鼠，以腹腔注射PBS和部分野生型MCMV的小鼠作为对照组，定期检测血清中乙肝表面抗体滴度，6周后给予高压水尾静脉注射HBV质粒(pSM2)构建急性乙肝感染模型,于高压尾注射后1、4、7、9天用ELISA方法检测小鼠血清中HBV抗原滴度，外周血液样本检测血清HBsAg、HBeAg、HBV-DNA结果分别如图4-1、图4-2、图5-1、图5-2所示，可以发现Δm157-MCMV-HBsAg和Δm27-MCMV-HBsAg免疫过的小鼠可以迅速清除转染HBV质粒后血清中的HBV抗原以及HBV-DNA，可以迅速清除转染HBV质粒后肝脏中的HBsAg和HBcAg，且其血清中HBsAb滴度显著高于腹腔注射PBS和部分野生型MCMV的对照组小鼠。
抗原清除后处死小鼠，分离肝、脾浸润淋巴细胞，用流式细胞术检测小鼠肝、脾浸润淋巴细胞的HBV特异性T细胞应答。运用免疫组化方法检测分离的肝脏组织中HBsAg和HBcAg的表达量。结果如图6所示，Δm157-MCMV-HBsAg和Δm27-MCMV-HBsAg免疫过的小鼠可以迅速清除转染HBV质粒后肝脏中的HBV抗原；如图7-1、图7-2所示，肝脏中HBsAg特异性CD8+T细胞免疫应答显著增强。
实验三、建立免疫耐受的HBV复制模型中表达HBsAg的重组MCMV抗HBV作用的研究：如图8所示，先给予高压水注射HBV质粒(pAAV1.2)制造乙肝慢性持续复制模型，1周后用重组MCMV感染小鼠，以腹腔注射PBS和部分野生型MCMV的小鼠作为对照组，定期用ELISA方法检测血清中乙肝抗原及抗体滴度，将其降低HBV抗原的速度与对照组比较，差异明显时处死小鼠，分离肝、脾浸润淋巴细胞，用流式细胞术检测小鼠肝、脾浸润淋巴细胞的HBV特异性T细胞应答,运用免疫组化方法检测分离的肝脏组织中HBsAg和HBcAg的表达量。如图9-1、图9-2所示，Δm27-MCMV-HBsAg接种的小鼠血清中的HBsAg水平以及HBV-DNA水平显著降低。
实验四、如图10所示，先给予高压水注射HBV质粒(pAAV1.2)制造乙肝慢性持续复制模型，1周后用重组MCMV感染小鼠，以腹腔注射PBS和部分野生型MCMV的小鼠作为对照组，定期用ELISA方法检测血清中乙肝抗原及抗体滴度，于9周时高压水注射HBV质粒(pSM2)，继续观察血清中乙肝抗原及抗体滴度的变化。结果如图11-1、图11-2所示，Δm157-MCMV-HBsAg和Δm27-MCMV-HBsAg免疫过的小鼠可以迅速清除转染HBV质粒后血清中的HBV抗原。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为本发明专利范围的限制。对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变性和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
序列表
<110> 华中科技大学同济医学院附属协和医院
<120> 用于乙肝病毒感染的重组巨细胞病毒与应用
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<170> SIPOSequenceListing 1.0
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<213> 乙肝病毒(Hepatitis B virus)
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Leu Gly Gln Asn Ser Gln Ser Pro Thr Ser Asn His Ser Pro Thr Ser
    50                  55                  60
Cys Pro Pro Thr Cys Pro Gly Tyr Arg Trp Met Cys Leu Arg Arg Phe
65                  70                  75                  80
Ile Ile Phe Leu Phe Ile Leu Leu Leu Cys Leu Ile Phe Leu Leu Val
                85                  90                  95
Leu Leu Asp Tyr Gln Gly Met Leu Pro Val Cys Pro Leu Ile Pro Gly
            100                 105                 110
Ser Ser Thr Thr Ser Ala Gly Pro Cys Arg Thr Cys Thr Thr Thr Ala
        115                 120                 125
Gln Gly Thr Ser Met Tyr Pro Ser Cys Cys Cys Thr Lys Pro Ser Asp
    130                 135                 140
Gly Asn Cys Thr Cys Ile Pro Ile Pro Ser Ser Trp Ala Phe Gly Lys
145                 150                 155                 160
Phe Leu Trp Glu Trp Ala Ser Ala Arg Phe Ser Trp Leu Ser Leu Leu
                165                 170                 175
Val Pro Phe Val Gln Trp Phe Ala Gly Leu Ser Pro Thr Val Trp Leu
            180                 185                 190
Ser Val Ile Trp Met Met Trp Tyr Trp Gly Pro Ser Leu Tyr Arg Ile
        195                 200                 205
Leu Ser Pro Phe Leu Pro Leu Leu Pro Ile Phe Phe Cys Leu Trp Val
    210                 215                 220
Tyr Ile
225

Claims (1)

1. 用于乙肝病毒感染的重组巨细胞病毒在制备治疗慢性乙肝病毒感染的疫苗中的应用，其特征在于，所述重组巨细胞病毒能表达乙型肝炎病毒表面抗原，所述重组巨细胞病毒通过细菌人工染色体诱变产生，所述乙型肝炎病毒表面抗原的氨基酸序列如序列表SEQ IDNO：1所示；
所述细菌人工染色体诱变为在启动子的控制下以乙型肝炎病毒表面抗原基因替换巨细胞病毒中的m157或m27基因座；
所述启动子为真核EF1启动子。
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US5561063A (en) * 1987-06-26 1996-10-01 Syntro Corporation Recombinant human cytomegalovirus containing foreign gene
CN108064304A (zh) * 2015-02-10 2018-05-22 俄勒冈健康与科学大学 可用于产生非典型cd8+ t细胞应答的方法和组合物

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Genbank accession number：AAC62953.1;Weinberger,K.M.,et al.;《Genbank》;19981006;全文 *
Induction of early murine cytomegalovirus infection by different reporter gene-associated recombinant viruses;U. Drebber, et al.;《Journal of Viral Hepatitis》;20061231;363-370 *
STAT2-Dependent Immune Responses Ensure Host Survival despite the Presence of a Potent Viral Antagonist;Vu Thuy Khanh Le-Trilling,et al.;《Journal of Virology》;20180731;第92卷(第14期);e00296-18 *
免疫机制相关的鼠巨细胞病毒基因研究进展;邓群蓉等;《中国妇幼保健》;20061231;第21卷;866-867 *

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