CN110950935A - 一种人乳头瘤病毒51型l1蛋白的突变体 - Google Patents

一种人乳头瘤病毒51型l1蛋白的突变体 Download PDF

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CN110950935A
CN110950935A CN201910914458.0A CN201910914458A CN110950935A CN 110950935 A CN110950935 A CN 110950935A CN 201910914458 A CN201910914458 A CN 201910914458A CN 110950935 A CN110950935 A CN 110950935A
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李少伟
王大宁
陈洁
顾颖
张军
夏宁邵
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Xiamen Innovax Biotech Co Ltd
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Abstract

本发明涉及一种突变的HPV51 L1蛋白(或其变体)，其编码序列和制备方法，以及包含其的病毒样颗粒，所述蛋白(或其变体)和病毒样颗粒能够诱发抗至少两个型别的HPV(例如，HPV51和HPV69，或者HPV51，HPV69和HPV26)的中和抗体，从而可用于预防所述至少两个型别的HPV感染以及由所述感染所导致的疾病例如宫颈癌和尖锐湿疣。本发明还涉及上述蛋白和病毒样颗粒用于制备药物组合物或疫苗的用途，所述药物组合物或疫苗可用于预防所述至少两个型别的HPV感染以及由所述感染所导致的疾病例如宫颈癌和尖锐湿疣。

Description

一种人乳头瘤病毒51型L1蛋白的突变体
技术领域
本发明涉及分子病毒学和免疫学领域。具体地，本发明涉及一种突变的HPV51 L1蛋白(或其变体)，其编码序列和制备方法，以及包含其的病毒样颗粒，所述蛋白(或其变体)和病毒样颗粒能够诱发抗至少两个型别的HPV(例如，HPV51和HPV69，或者HPV51，HPV69和HPV26)的中和抗体，从而可用于预防所述至少两个型别的HPV感染以及由所述感染所导致的疾病例如宫颈癌和尖锐湿疣。本发明还涉及上述蛋白和病毒样颗粒用于制备药物组合物或疫苗的用途，所述药物组合物或疫苗可用于预防所述至少两个型别的HPV感染以及由所述感染所导致的疾病例如宫颈癌和尖锐湿疣。
背景技术
人乳头瘤病毒(Human Papillomavirus，HPV))主要引起皮肤，粘膜的疣状病变。根据其与肿瘤发生的关系，HPV可分为高危型与低危型，其中高危型的HPV感染被证实是诱发包括女性宫颈癌在内的生殖器癌症主要原因；低危型则主要引起尖锐湿疣。预防与控制HPV感染的最有效方式是HPV疫苗，特别是能引起宫颈癌的高危型HPV疫苗。
HPV的主要衣壳蛋白L1具有自组装为空心病毒样颗粒(Virus-Like Particle,VLP)的特性。HPV VLP是由72个主要衣壳蛋白L1的五聚体相互作用构成的二十面体立体对称结构(Doorbar,J.and P.H.Gallimore.1987.J Virol,61(9):2793-9)。HPV VLP结构与天然HPV高度相似，保留了天然病毒的绝大多数中和表位，可诱导高滴度的中和抗体(Kirnbauer，R.，F.Booy，et al.1992 Proc Natl Acad Sci USA 89(24):12180-4)。
现有的研究发现，HPV VLP主要诱导针对同型HPV的中和抗体，产生针对同型HPV的保护性免疫，仅在一些同源性高的型别之间存在较低的交叉保护(Sara L.Bissett,GiadaMattiuzzo,et al.2014 Vaccine.32:6548-6555)。因此，现有的HPV疫苗的保护范围非常有限。通常，一个型别的HPV VLP只能用于预防该型别的HPV感染。在这种情况下，如果要扩大HPV疫苗的保护范围，只能在疫苗中增加更多型别的HPV VLP型别。目前已上市的HPV疫苗，包括Merck公司的
Figure BDA0002215675900000021
(其为针对HPV16、18、6和11的四价疫苗)和
Figure BDA0002215675900000022
(其为针对HPV6、11、16、18、31、33、45、52和58的九价疫苗)和GSK公司的
Figure BDA0002215675900000023
(其为针对HPV16和18的二价疫苗)，均是通过混合单独型别的HPV VLP制备而成的。然而，这种方案将导致HPV疫苗的生产成本大大提高，并且可能因为免疫剂量的增加而导致潜在的安全性问题。
因此，本领域仍然需要开发能够诱导针对多个型别的HPV的保护性中和抗体的HPV病毒样颗粒，以更经济、有效地预防多个型别的HPV感染和由此导致的疾病例如宫颈癌和尖锐湿疣。
发明内容
本发明至少部分基于发明人的下述出人意料的发现：将人乳头瘤病毒(HPV)51型L1蛋白中的特定区段置换为第二型别的HPV(例如HPV69)L1蛋白的相应区段后，所获得的突变的HPV51 L1蛋白能够诱导机体产生针对HPV51和第二型别的HPV(例如HPV69)的高滴度中和抗体，其保护效果与混合的HPV51 VLP和第二型别的HPV VLP相当，并且针对HPV51的保护效果与单独的HPV51 VLP相当，且针对第二型别的HPV(例如HPV69)的保护效果与单独的第二型别的HPV VLP相当。
此外，在上述置换的基础上，还可以将HPV51 L1蛋白中的另一个特定区段进一步置换为第三型别的HPV(例如HPV26)L1蛋白的相应区段，由此所获得的含有双置换的突变的HPV51 L1蛋白能诱导机体产生针对HPV51、第二型别的HPV(例如HPV69)和第三型别的HPV(例如HPV26)的高滴度中和抗体，其保护效果可与混合的HPV51 VLP、第二型别的HPV VLP和第三型别的HPV VLP相当。
因此，在一个方面，本发明提供了一种突变的HPV51 L1蛋白或其变体，其中，所述突变的HPV51L1蛋白与野生型HPV51 L1蛋白相比，具有下述突变：
(1)N端截短了0-15个氨基酸，例如N端截短了0、1、2、3、4、5、6、7、8、9、10、11、12、13、14或15个氨基酸；以及(2)(a)、(2)(b)、(2)(c)或(2)(d)中所定义的突变：
(2)(a)位于野生型HPV51 L1蛋白第52-60位的氨基酸残基被替换为第二型别的野生型HPV L1蛋白的相应位置的氨基酸残基；
(2)(b)位于野生型HPV51 L1蛋白第125-147位的氨基酸残基被替换为第二型别的野生型HPV的L1蛋白的相应位置的氨基酸残基；
(2)(c)位于野生型HPV51 L1蛋白第170-181位的氨基酸残基被替换为第二型别的野生型HPV的L1蛋白的相应位置的氨基酸残基；和
(2)(d)位于野生型HPV51 L1蛋白第259-289位的氨基酸残基被替换为第二型别的野生型HPV的L1蛋白的相应位置的氨基酸残基；
并且，所述变体与所述突变的HPV51 L1蛋白相异仅在于一个或几个(例如，1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个、15个、16或17个)氨基酸的置换(优选保守置换)、添加或缺失，且保留了所述突变的HPV51 L1蛋白的功能，即，能够诱导针对至少两个型别的HPV(例如，HPV51和HPV69)的中和抗体。
在某些实施方案中，所述突变的HPV51 L1蛋白具有(1)和(2)(a)中所定义的突变，并且任选地，还具有(3)(b)中所定义的突变突变。
在某些实施方案中，所述突变的HPV51 L1蛋白具有(1)和(2)(b)中所定义的突变，并且任选地，还具有(3)(c)中所定义的突变。
在某些实施方案中，所述突变的HPV51 L1蛋白具有(1)和(2)(c)中所定义的突变，并且任选地，还具有(3)(a)或(3)(b)中所定义的突变。
在某些实施方案中，所述突变的HPV51 L1蛋白具有(1)和(2)(d)中所定义的突变，并且任选地，还具有(3)(b)所定义的突变。
所述的(3)(a)、(3)(b)或(3)(c)中所定义的突变如下：
(3)(a)位于野生型HPV51L1蛋白第51-60位的氨基酸残基被替换为第三型别的野生型HPV L1蛋白的相应位置的氨基酸残基；
(3)(b)位于野生型HPV51L1蛋白第114-146位的氨基酸残基被替换为第三型别的野生型HPV L1蛋白的相应位置的氨基酸残基；
(3)(c)位于野生型HPV51L1蛋白第173-181位的氨基酸残基被替换为第三型别的野生型HPV L1蛋白的相应位置的氨基酸残基。
在某些实施方案中，所述突变的HPV51 L1蛋白与野生型HPV51 L1蛋白相比，N端截短了9个氨基酸。
在某些实施方案中，所述第二型别的野生型HPV为HPV69。在某些实施方案中，(2)(a)中所述的相应位置的氨基酸残基为野生型HPV69 L1蛋白第52-60位的氨基酸残基。在某些实施方案中，(2)(b)中所述的相应位置的氨基酸残基为野生型HPV69 L1蛋白第125-147位的氨基酸残基。在某些实施方案中，(2)(c)中所述的相应位置的氨基酸残基为野生型HPV69 L1蛋白第170-183位的氨基酸残基。在某些实施方案中，(2)(d)中所述的相应位置的氨基酸残基为野生型HPV69 L1蛋白第261-291位的氨基酸残基。
在某些实施方案中，所述第三型别的野生型HPV为HPV26。在某些实施方案中，(3)(a)中所述的相应位置的氨基酸残基为野生型HPV26 L1蛋白第51-60位的氨基酸残基。在某些实施方案中，(3)(b)中所述的相应位置的氨基酸残基为野生型HPV26 L1蛋白第114-146位的氨基酸残基。在某些实施方案中，(3)(c)中所述的相应位置的氨基酸残基为野生型HPV26 L1蛋白第173-181位的氨基酸残基。
在某些实施方案中，所述野生型HPV51 L1蛋白具有如SEQ ID NO:1所示的氨基酸序列。
在某些实施方案中，所述野生型HPV69 L1蛋白具有如SEQ ID NO:2所示的氨基酸序列。
在某些实施方案中，所述野生型HPV26 L1蛋白具有如SEQ ID NO:22所示的氨基酸序列。
在某些优选的实施方案中，所述野生型HPV69L1蛋白第52-60位的氨基酸残基的序列如SEQ ID NO:17所示。
在某些优选的实施方案中，所述野生型HPV69 L1蛋白第125-147位的氨基酸残基的序列如SEQ ID NO:18所示。
在某些优选的实施方案中，所述野生型HPV69L1蛋白第170-183位的氨基酸残基的序列如SEQ ID NO:19所示。
在某些优选的实施方案中，所述野生型HPV69 L1蛋白第261-291位的氨基酸残基的序列如SEQ ID NO:20所示。
在某些实施方案中，所述野生型HPV69 L1蛋白第350-362位的氨基酸残基的序列如SEQ ID NO:21所示。
在某些优选的实施方案中，所述野生型HPV26L1蛋白第51-60位的氨基酸残基的序列如SEQ ID NO:56所示。
在某些优选的实施方案中，所述野生型HPV26L1蛋白第114-146位的氨基酸残基的序列如SEQ ID NO:57所示。
在某些实施方案中，所述野生型HPV26 L1蛋白第173-181位的氨基酸残基的序列如SEQ ID NO:58所示。
在某些实施方案中，所述野生型HPV26 L1蛋白第259-289位的氨基酸残基的序列如SEQ ID NO:59所示。
在某些实施方案中，所述野生型HPV26 L1蛋白第348-360位的氨基酸残基的序列如SEQ ID NO:60所示。
在某些实施方案中，所述突变的HPV51 L1蛋白具有SEQ ID NO:4、5、6或7所示的氨基酸序列。
在某些实施方案中，所述突变的HPV51 L1蛋白具有SEQ ID NO:23、27、28、41或45所示的氨基酸序列。
在另一个方面，本发明提供了一种分离的核酸，其编码如上所述的突变的HPV51L1蛋白或其变体。在另一个方面，本发明提供了一种载体，其包含所述分离的核酸。在某些实施方案中，本发明的分离的核酸具有SEQ ID NO:12、13、14或15所示的核苷酸序列。
在某些实施方案中，本发明的分离的核酸具有SEQ ID NO:32、36、37、49或53所示的核苷酸序列。
可用于插入目的多核苷酸的载体是本领域公知的，包括但不限于克隆载体和表达载体。在一个实施方案中，载体是例如质粒，粘粒，噬菌体等等。
在另一个方面，本发明还涉及包含上述分离的核酸或载体的宿主细胞。此类宿主细胞包括但不限于，原核细胞例如大肠杆菌细胞，以及真核细胞例如酵母细胞，昆虫细胞，植物细胞和动物细胞(如哺乳动物细胞，例如小鼠细胞、人细胞等)。本发明的宿主细胞还可以是细胞系，例如293T细胞。
在另一个方面，本发明涉及一种HPV病毒样颗粒，其中该病毒样颗粒含有本发明的突变的HPV51 L1蛋白或其变体，或者由本发明的突变的HPV51 L1蛋白或其变体组成或形成。
在某些优选的实施方案中，本发明的HPV病毒样颗粒包含突变的HPV51L1蛋白，其与野生型HPV51 L1蛋白相比，N端截短了0-15个氨基酸，例如0、1、2、3、4、5、6、7、8、9、10、11、12、13、14或15个氨基酸，并且位于野生型HPV51 L1蛋白第52-60位的氨基酸残基被替换为野生型HPV69 L1蛋白第52-60位的氨基酸残基。
在某些优选的实施方案中，本发明的HPV病毒样颗粒包含突变的HPV51L1蛋白，其与野生型HPV51 L1蛋白相比，N端截短了0-15个氨基酸，例如0、1、2、3、4、5、6、7、8、9、10、11、12、13、14或15个氨基酸，并且位于野生型HPV51 L1蛋白第125-147位的氨基酸残基被替换为野生型HPV69 L1蛋白第125-147位的氨基酸残基。
在某些优选的实施方案中，本发明的HPV病毒样颗粒包含突变的HPV51L1蛋白，其与野生型HPV51 L1蛋白相比，N端截短了0-15个氨基酸，例如0、1、2、3、4、5、6、7、8、9、10、11、12、13、14或15个氨基酸，并且位于野生型HPV51 L1蛋白第170-181位的氨基酸残基被替换为野生型HPV69 L1蛋白第170-183位的氨基酸残基。
在某些优选的实施方案中，本发明的HPV病毒样颗粒包含突变的HPV51L1蛋白，其与野生型HPV51 L1蛋白相比，N端截短了0-15个氨基酸，例如0、1、2、3、4、5、6、7、8、9、10、11、12、13、14或15个氨基酸，并且位于野生型HPV51 L1蛋白第259-289位的氨基酸残基被替换为野生型HPV69 L1蛋白第261-291位的氨基酸残基。
在某些实施方案中，本发明的HPV病毒样颗粒包含突变的HPV51L1蛋白，其与野生型HPV51 L1蛋白相比，N端截短了0-15个氨基酸，例如0、1、2、3、4、5、6、7、8、9、10、11、12、13、14或15个氨基酸，并且位于野生型HPV51 L1蛋白第52-60位的氨基酸残基被替换为野生型HPV69 L1蛋白第52-60位的氨基酸残基，并且位于野生型HPV51 L1蛋白第114-146位的氨基酸残基被替换为野生型HPV26 L1蛋白第114-146位的氨基酸残基。
在某些实施方案中，本发明的HPV病毒样颗粒包含突变的HPV51L1蛋白，其与野生型HPV51 L1蛋白相比，N端截短了0-15个氨基酸，例如0、1、2、3、4、5、6、7、8、9、10、11、12、13、14或15个氨基酸，并且位于野生型HPV51 L1蛋白第125-147位的氨基酸残基被替换为野生型HPV69 L1蛋白第125-147位的氨基酸残基，并且位于野生型HPV51 L1蛋白第173-181位的氨基酸残基被替换为野生型HPV26 L1蛋白第173-181位的氨基酸残基。
在某些实施方案中，本发明的HPV病毒样颗粒包含突变的HPV51L1蛋白，其与野生型HPV51 L1蛋白相比，N端截短了0-15个氨基酸，例如0、1、2、3、4、5、6、7、8、9、10、11、12、13、14或15个氨基酸，并且位于野生型HPV51 L1蛋白第170-181位的氨基酸残基被替换为野生型HPV69 L1蛋白第170-183位的氨基酸残基，并且位于野生型HPV51 L1蛋白第51-60位的氨基酸残基被替换为野生型HPV26 L1蛋白第51-60位的氨基酸残基。
在某些实施方案中，本发明的HPV病毒样颗粒包含突变的HPV51L1蛋白，其与野生型HPV51 L1蛋白相比，N端截短了0-15个氨基酸，例如0、1、2、3、4、5、6、7、8、9、10、11、12、13、14或15个氨基酸，并且位于野生型HPV51 L1蛋白第170-181位的氨基酸残基被替换为野生型HPV69 L1蛋白第170-183位的氨基酸残基，并且位于野生型HPV51 L1蛋白第114-146位的氨基酸残基被替换为野生型HPV26 L1蛋白第114-146位的氨基酸残基。
在某些实施方案中，本发明的HPV病毒样颗粒包含突变的HPV51L1蛋白，其与野生型HPV51 L1蛋白相比，N端截短了0-15个氨基酸，例如0、1、2、3、4、5、6、7、8、9、10、11、12、13、14或15个氨基酸，并且位于野生型HPV51 L1蛋白第259-289位的氨基酸残基被替换为野生型HPV69 L1蛋白第261-291位的氨基酸残基，并且位于野生型HPV51 L1蛋白第114-146位的氨基酸残基被替换为野生型HPV26 L1蛋白第114-146位的氨基酸残基。
在某些实施方案中，本发明的HPV病毒样颗粒包含突变的HPV51L1蛋白，其与野生型HPV51 L1蛋白相比，N端截短了9个氨基酸，并且位于野生型HPV51 L1蛋白第52-60位的氨基酸残基被替换为野生型HPV69 L1蛋白第52-60位的氨基酸残基。
在某些实施方案中，本发明的HPV病毒样颗粒包含突变的HPV51L1蛋白，其与野生型HPV51 L1蛋白相比，N端截短了9个氨基酸，并且位于野生型HPV51 L1蛋白第125-147位的氨基酸残基被替换为野生型HPV69 L1蛋白第125-147位的氨基酸残基。
在某些实施方案中，本发明的HPV病毒样颗粒包含突变的HPV51L1蛋白，其与野生型HPV51 L1蛋白相比，N端截短了9个氨基酸，并且位于野生型HPV51 L1蛋白第170-181位的氨基酸残基被替换为野生型HPV69 L1蛋白第170-183位的氨基酸残基。
在某些实施方案中，本发明的HPV病毒样颗粒包含突变的HPV51L1蛋白，其与野生型HPV51 L1蛋白相比，N端截短了9个氨基酸，并且位于野生型HPV51 L1蛋白第259-289位的氨基酸残基被替换为野生型HPV69 L1蛋白第261-291位的氨基酸残基。
在某些实施方案中，本发明的HPV病毒样颗粒包含突变的HPV51L1蛋白，其与野生型HPV51 L1蛋白相比，N端截短了9个氨基酸，并且位于野生型HPV51 L1蛋白第52-60位的氨基酸残基被替换为野生型HPV69 L1蛋白第52-60位的氨基酸残基，并且位于野生型HPV51L1蛋白第114-146位的氨基酸残基被替换为野生型HPV26 L1蛋白第114-146位的氨基酸残基。
在某些实施方案中，本发明的HPV病毒样颗粒包含突变的HPV51L1蛋白，其与野生型HPV51 L1蛋白相比，N端截短了9个氨基酸，并且位于野生型HPV51 L1蛋白第125-147位的氨基酸残基被替换为野生型HPV69 L1蛋白第125-147位的氨基酸残基，并且位于野生型HPV51 L1蛋白第173-181位的氨基酸残基被替换为野生型HPV26 L1蛋白第173-181位的氨基酸残基。
在某些实施方案中，本发明的HPV病毒样颗粒包含突变的HPV51L1蛋白，其与野生型HPV51 L1蛋白相比，N端截短了9个氨基酸，并且位于野生型HPV51 L1蛋白第170-181位的氨基酸残基被替换为野生型HPV69 L1蛋白第170-183位的氨基酸残基，并且位于野生型HPV51 L1蛋白第51-60位的氨基酸残基被替换为野生型HPV26 L1蛋白第51-60位的氨基酸残基。
在某些实施方案中，本发明的HPV病毒样颗粒包含突变的HPV51L1蛋白，其与野生型HPV51 L1蛋白相比，N端截短了9个氨基酸，并且位于野生型HPV51 L1蛋白第170-181位的氨基酸残基被替换为野生型HPV69 L1蛋白第170-183位的氨基酸残基，并且位于野生型HPV51 L1蛋白第114-146位的氨基酸残基被替换为野生型HPV26 L1蛋白第114-146位的氨基酸残基。
在某些实施方案中，本发明的HPV病毒样颗粒包含突变的HPV51L1蛋白，其与野生型HPV51 L1蛋白相比，N端截短了9个氨基酸，并且位于野生型HPV51 L1蛋白第259-289位的氨基酸残基被替换为野生型HPV69 L1蛋白第261-291位的氨基酸残基，并且位于野生型HPV51 L1蛋白第114-146位的氨基酸残基被替换为野生型HPV26 L1蛋白第114-146位的氨基酸残基。
在某些实施方案中，本发明的HPV病毒样颗粒包含突变的HPV51 L1蛋白，其具有SEQ ID NO:4、5、6或7所示的序列。
在某些实施方案中，本发明的HPV病毒样颗粒包含突变的HPV51 L1蛋白，其具有SEQ ID NO:23、27、28、41或45所示的序列。
在另一个方面，本发明还涉及包含上述突变的HPV51 L1蛋白或其变体，或上述分离的核酸或载体或宿主细胞或HPV病毒样颗粒的组合物。在某些优选的实施方案中，所述组合物包含本发明的突变的HPV51 L1蛋白或其变体。在某些优选的实施方案中，所述组合物包含本发明的HPV病毒样颗粒。
在另一个方面，本发明还涉及一种药物组合物或疫苗，其包含本发明的HPV病毒样颗粒，任选地还包含药学可接受的载体和/或赋形剂。本发明的药物组合物或疫苗可以用于预防HPV感染或由HPV感染所导致的疾病例如宫颈癌和尖锐湿疣。
在某些实施方案中，所述HPV病毒样颗粒以预防HPV感染或由HPV感染导致的疾病的有效量存在。在某些实施方案中，所述HPV感染是一个或多个型别的HPV感染(例如，由HPV51感染、HPV69感染和HPV26感染组成的组中的至少一种感染)。在某些实施方案中，所述由HPV感染所导致的疾病选自宫颈癌、尖锐湿疣及其组合。
本发明的药物组合物或疫苗可通过本领域公知的方法进行施用，例如但不限于通过口服或者注射进行施用。在本发明中，特别优选的施用方式是注射。
在某些优选的实施方案中，本发明的药物组合物或疫苗以单位剂量形式进行施用。例如但不意欲限定本发明，每单位剂量中包含的HPV病毒样颗粒的量为5μg－80μg，优选20μg－40μg。
在另一个方面，本发明涉及一种制备如上所述的突变的HPV51 L1蛋白或其变体的方法，其包括，在宿主细胞中表达所述突变的HPV51 L1蛋白或其变体，然后从所述宿主细胞的培养物中回收所述突变的HPV51 L1蛋白或其变体。
在某些优选的实施方案中，所述宿主细胞为大肠杆菌。
在某些优选的实施方案中，所述方法包括步骤：在大肠杆菌中表达所述突变的HPV51 L1蛋白或其变体，然后从所述大肠杆菌的裂解上清中纯化得到所述突变的HPV51 L1蛋白或其变体。在某些优选的实施方案中，通过色谱法(例如，阳离子交换色谱，羟基磷灰石色谱和/或疏水相互作用色谱)，从所述大肠杆菌的裂解上清中回收所述突变的HPV51 L1蛋白或其变体。
在另一个方面，本发明涉及一种制备疫苗的方法，其包括将本发明的HPV病毒样颗粒与药学可接受的载体和/或赋形剂混合。
在另一个方面，本发明涉及一种预防HPV感染或由HPV感染所导致的疾病的方法，其包括将预防有效量的根据本发明的HPV病毒样颗粒或药物组合物或疫苗施用给受试者。在一个优选的实施方案中，所述HPV感染是一个或多个型别的HPV感染(例如，HPV51感染、HPV69感染和/或HPV26感染)。在另一个优选的实施方案中，所述由HPV感染所导致的疾病包括但不限于，宫颈癌和尖锐湿疣。在另一个优选的实施方案中，所述受试者是哺乳动物，例如人。
在另一个方面，还涉及本发明的突变的HPV51 L1蛋白或其变体或HPV病毒样颗粒在制备药物组合物或疫苗中的用途，所述药物组合物或疫苗用于预防HPV感染或由HPV感染所导致的疾病。在一个优选的实施方案中，所述HPV感染是一个或多个型别的HPV感染(例如，HPV51感染、HPV69感染和/或HPV26感染)。在另一个优选的实施方案中，所述由HPV感染所导致的疾病包括但不限于，宫颈癌和尖锐湿疣。
在另一个方面，本发明还涉及本发明的突变的HPV51 L1蛋白或其变体或HPV病毒样颗粒，其用于预防HPV感染或由HPV感染所导致的疾病。在一个优选的实施方案中，所述HPV感染是一个或多个型别的HPV感染(例如，HPV51感染、HPV69感染和/或HPV26感染)。在另一个优选的实施方案中，所述由HPV感染所导致的疾病包括但不限于，宫颈癌和尖锐湿疣。
本发明中相关术语的说明及解释
在本发明中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且，本文中所用的细胞培养、分子遗传学、核酸化学、免疫学实验室操作步骤均为相应领域内广泛使用的常规步骤。同时，为了更好地理解本发明，下面提供相关术语的定义和解释。
根据本发明，术语“第二型别的野生型HPV”是指，不同于HPV51的另一型别的野生型HPV。在本发明中，第二型别的野生型HPV优选为野生型HPV69。
根据本发明，术语“第三型别的野生型HPV”是指，不同于HPV51，且不同于第二型别的野生型HPV的另一型别的野生型HPV。在本发明中，第三型别的野生型HPV优选为野生型HPV26。
根据本发明，表述“相应位置”是指，当对序列进行最优比对时，即当序列进行比对以获得最高百分数同一性时，进行比较的序列中的等同位置。根据本发明，术语“野生型HPV51 L1蛋白”是指，天然存在于人乳头瘤病毒51型(HPV51)中的主要衣壳蛋白L1。野生型HPV51 L1蛋白的序列是本领域公知的，并且可参见各种公共数据库(例如NCBI数据库登录号ACV88631.1、ALJ32930.1、CRH69903.1和AJS10540.1等)。
在本发明中，当提及野生型HPV51 L1蛋白的氨基酸序列时，参照SEQ ID NO：1所示的序列来进行描述。例如，表述“野生型HPV51 L1蛋白的第52-60位氨基酸残基”是指，SEQID NO：1所示的多肽的第52-60位氨基酸残基。然而，本领域技术人员理解，野生型HPV51可包括多种分离株，并且各种分离株的L1蛋白的氨基酸序列之间可能存在着差异。进一步，本领域技术人员理解，尽管可能存在着序列差异，但是HPV51的不同分离株的L1蛋白在氨基酸序列上具有极高的同一性(通常高于95％，例如高于96％，高于97％，高于98％，或高于99％)，并且具有实质上相同的生物学功能。因此，在本发明中，术语“野生型HPV51 L1蛋白”不仅包括SEQ ID NO:1所示的蛋白，而且应包括各种HPV51分离株的L1蛋白(例如ACV88631.1、ALJ32930.1、CRH69903.1和AJS10540.1所示的HPV51 L1蛋白)。并且，当描述野生型HPV51 L1蛋白的序列片段时，其不仅包括SEQ ID NO：1的序列片段，还包括各种HPV51分离株的L1蛋白中的相应序列片段。例如，表述“野生型HPV51 L1蛋白的第52-60位氨基酸残基”包括，SEQ ID NO：1的第52-60位氨基酸残基，以及各种HPV51分离株的L1蛋白中的相应片段。
根据本发明，术语“野生型HPV69 L1蛋白”是指，天然存在于人乳头瘤病毒69型(HPV69)中的主要衣壳蛋白L1。野生型HPV69L1蛋白的序列是本领域公知的，并且可参见各种公共数据库(例如NCBI数据库登录号AHV83654.1、ALJ32844.1和ALJ32828.1等)。
在本发明中，当提及野生型HPV69 L1蛋白的氨基酸序列时，参照SEQ ID NO：2所示的序列来进行描述。例如，表述“野生型HPV69 L1蛋白的第52-60位氨基酸残基”是指，SEQID NO：2所示的多肽的第52-60位氨基酸残基；表述“野生型HPV69 L1蛋白的第170-183位氨基酸残基”是指，SEQ ID NO：2所示的多肽的第170-183位氨基酸残基。然而，本领域技术人员理解，野生型HPV69可包括多种分离株，并且各种分离株的L1蛋白的氨基酸序列之间可能存在着差异。进一步，本领域技术人员理解，尽管可能存在着序列差异，但是HPV69的不同分离株的L1蛋白在氨基酸序列上具有极高的同一性(通常高于95％，例如高于96％，高于97％，高于98％，或高于99％)，并且具有实质上相同的生物学功能。因此，在本发明中，术语“野生型HPV69 L1蛋白”不仅包括SEQ ID NO:2所示的蛋白，而且应包括各种HPV69分离株的L1蛋白(例如AHV83654.1、ALJ32844.1和ALJ32828.1等所示的HPV69 L1蛋白)。并且，当描述野生型HPV69 L1蛋白的序列片段时，其不仅包括SEQ ID NO：2的序列片段，还包括各种HPV69分离株的L1蛋白中的相应序列片段。例如，表述“野生型HPV69 L1蛋白的第52-60位氨基酸残基”包括，SEQ ID NO：2的第52-60位氨基酸残基，以及各种HPV69分离株的L1蛋白中的相应片段。
根据本发明，术语“野生型HPV26 L1蛋白”是指，天然存在于人乳头瘤病毒26型(HPV26)中的主要衣壳蛋白L1。野生型HPV26L1蛋白的序列是本领域公知的，并且可参见各种公共数据库(例如NCBI数据库登录号NP041787.1、AHY96046.1和AHY96053.1等)。
在本发明中，当提及野生型HPV26 L1蛋白的氨基酸序列时，参照SEQ ID NO：22所示的序列来进行描述。例如，表述“野生型HPV26 L1蛋白的第51-60位氨基酸残基”是指，SEQID NO：22所示的多肽的第51-60位氨基酸残基；表述“野生型HPV26 L1蛋白的第173-181位氨基酸残基”是指，SEQ ID NO：22所示的多肽的第173-181位氨基酸残基。然而，本领域技术人员理解，野生型HPV26可包括多种分离株，并且各种分离株的L1蛋白的氨基酸序列之间可能存在着差异。进一步，本领域技术人员理解，尽管可能存在着序列差异，但是HPV26的不同分离株的L1蛋白在氨基酸序列上具有极高的同一性(通常高于95％，例如高于96％，高于97％，高于98％，或高于99％)，并且具有实质上相同的生物学功能。因此，在本发明中，术语“野生型HPV26 L1蛋白”不仅包括SEQ ID NO:22所示的蛋白，而且应包括各种HPV26分离株的L1蛋白(例如NP041787.1、AHY96046.1和AHY96053.1等所示的HPV26 L1蛋白)。并且，当描述野生型HPV26 L1蛋白的序列片段时，其不仅包括SEQ ID NO：22的序列片段，还包括各种HPV26分离株的L1蛋白中的相应序列片段。例如，表述“野生型HPV26 L1蛋白的第51-60位氨基酸残基”包括，SEQ ID NO：22的第51-60位氨基酸残基，以及各种HPV26分离株的L1蛋白中的相应片段。
根据本发明，表述“相应序列片段”或“相应片段”是指，当对序列进行最优比对时，即当序列进行比对以获得最高百分数同一性时，进行比较的序列中位于等同位置的片段。
根据本发明，表述“N端截短了X个氨基酸”是指，用起始密码子(用于起始蛋白质翻译)编码的甲硫氨酸残基置换蛋白质N末端的第1－X位氨基酸残基。例如，N端截短了9个氨基酸的HPV51 L1蛋白是指，用起始密码子编码的甲硫氨酸残基置换野生型HPV51 L1蛋白N末端的第1－9位氨基酸残基所获得的蛋白质。
根据本发明，术语“变体”是指这样的蛋白，其氨基酸序列与本发明的突变的HPV51L1蛋白(如SEQ ID NO：5或6所示的蛋白)的氨基酸序列相比，具有一个或几个(例如，1个、2个、3个、4个、5个或6个)氨基酸的置换(优选保守置换)、添加或缺失，或者具有至少90％，95％，96％，97％，98％，或99％的同一性，并且其保留了所述突变的HPV51 L1蛋白的功能。在本发明中，术语“突变的HPV51 L1蛋白的功能”是指：能够诱导机体产生针对至少两个型别的HPV(例如，HPV51和HPV69)的中和抗体。术语“同一性”是对核苷酸序列或氨基酸序列的相似性的量度。通常将序列排列起来，以获得最大限度的匹配。“同一性”本身具有本领域公知的意义并且可用公开的算法(例如BLAST)来计算。
根据本发明，术语“同一性”用于指两个多肽之间或两个核酸之间序列的匹配情况。当两个进行比较的序列中的某个位置都被相同的碱基或氨基酸单体亚单元占据时(例如，两个DNA分子的每一个中的某个位置都被腺嘌呤占据，或两个多肽的每一个中的某个位置都被赖氨酸占据)，那么各分子在该位置上是同一的。两个序列之间的“百分数同一性”是由这两个序列共有的匹配位置数目除以进行比较的位置数目×100的函数。例如，如果两个序列的10个位置中有6个匹配，那么这两个序列具有60％的同一性。例如，DNA序列CTGACT和CAGGTT共有50％的同一性(总共6个位置中有3个位置匹配)。通常，在将两个序列比对以产生最大同一性时进行比较。这样的比对可通过使用，例如，可通过计算机程序例如Align程序(DNAstar,Inc)方便地进行的Needleman等人(1970)J.Mol.Biol.48：443-453的方法来实现。还可使用已整合入ALIGN程序(版本2.0)的E.Meyers和W.Miller(Comput.ApplBiosci.，4:11-17(1988))的算法，使用PAM120权重残基表(weight residue table)、12的缺口长度罚分和4的缺口罚分来测定两个氨基酸序列之间的百分数同一性。此外，可使用已整合入GCG软件包(可在www.gcg.com上获得)的GAP程序中的Needleman和Wunsch(J MoIBiol.48:444-453(1970))算法，使用Blossum 62矩阵或PAM250矩阵以及16、14、12、10、8、6或4的缺口权重(gap weight)和1、2、3、4、5或6的长度权重来测定两个氨基酸序列之间的百分数同一性。
如本文中使用的，术语“保守置换”意指不会不利地影响或改变包含氨基酸序列的蛋白/多肽的必要特性的氨基酸置换。例如，可通过本领域内已知的标准技术例如定点诱变和PCR介导的诱变引入保守置换。保守氨基酸置换包括用具有相似侧链的氨基酸残基替代氨基酸残基的置换，例如用在物理学上或功能上与相应的氨基酸残基相似(例如具有相似大小、形状、电荷、化学性质，包括形成共价键或氢键的能力等)的残基进行的置换。已在本领域内定义了具有相似侧链的氨基酸残基的家族。这些家族包括具有碱性侧链(例如，赖氨酸、精氨酸和组氨酸)、酸性侧链(例如天冬氨酸、谷氨酸)、不带电荷的极性侧链(例如甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)、非极性侧链(例如丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸)、β分支侧链(例如，苏氨酸、缬氨酸、异亮氨酸)和芳香族侧链(例如，酪氨酸、苯丙氨酸、色氨酸、组氨酸)的氨基酸。因此，保守置换通常是指，用来自相同侧链家族的另一个氨基酸残基替代相应的氨基酸残基。鉴定氨基酸保守置换的方法在本领域内是熟知的(参见，例如，Brummell等人，Biochem.32:1180-1187(1993)；Kobayashi等人Protein Eng.12(10):879-884(1999)；和Burks等人Proc.Natl Acad.Set USA 94:412-417(1997)，其通过引用并入本文)。
根据本发明，术语“大肠杆菌表达系统”是指由大肠杆菌(菌株)与载体组成的表达系统，其中大肠杆菌(菌株)来源于市场上可得到的菌株，例如但不限于：ER2566，BL21(DE3)，B834(DE3)，BLR(DE3)。
根据本发明，术语“载体(vector)”是指，可将多核苷酸插入其中的一种核酸运载工具。当载体能使插入的多核苷酸所编码的蛋白获得表达时，载体称为表达载体。载体可以通过转化，转导或者转染导入宿主细胞，使其携带的遗传物质元件在宿主细胞中获得表达。载体是本领域技术人员公知的，包括但不限于：质粒；噬菌体；柯斯质粒等等。
根据本发明，术语“药学可接受的载体和/或赋形剂”是指在药理学和/或生理学上与受试者和活性成分相容的载体和/或赋形剂，其是本领域公知的(参见例如Remington'sPharmaceutical Sciences.Edited by Gennaro AR,19th ed.Pennsylvania:MackPublishing Company,1995)，并且包括但不限于：pH调节剂，表面活性剂，佐剂，离子强度增强剂。例如，pH调节剂包括但不限于磷酸盐缓冲液；表面活性剂包括但不限于阳离子，阴离子或者非离子型表面活性剂，例如Tween-80；佐剂包括但不限于铝佐剂(例如氢氧化铝)，弗氏佐剂(例如完全弗氏佐剂)；离子强度增强剂包括但不限于氯化钠。
根据本发明，术语“有效量”是指能够有效实现预期目的的量。例如，预防疾病(例如HPV感染)有效量是指，能够有效预防，阻止，或延迟疾病(例如HPV感染)的发生的量。测定这样的有效量在本领域技术人员的能力范围之内。
根据本发明，术语“色谱层析”包括但不限于：离子交换色谱(例如阳离子交换色谱)、疏水相互作用色谱、吸附层析法(例如羟基磷灰石色谱)、凝胶过滤(凝胶排阻)层析、亲和层析法。
根据本发明，术语“裂解上清”是指通过下述步骤所产生的溶液：将宿主细胞(例如大肠杆菌)在裂解液中破碎，然后将含有经破碎的宿主细胞的裂解液中的不溶物去除。各种裂解液是本领域技术人员公知的，包括但不限于Tris缓冲液，磷酸盐缓冲液，HEPES缓冲液，MOPS缓冲液等等。此外，可通过本领域技术人员熟知的各种方法来实现宿主细胞的破碎，包括但不限于匀浆器破碎、均质机破碎、超声波处理、研磨、高压挤压、溶菌酶处理等等。去除裂解液中的不溶物的方法也是本领域技术人员公知的，包括但不限于过滤和离心。
发明的有益效果
研究表明，虽然HPV51和其他型别的HPV(例如HPV69和/或HPV26)之间存在一定的交叉保护，但是这种交叉保护的能力很低，通常低于自身型别的VLP的保护水平的百分之一，甚至低于千分之一。因此，对于接种了HPV51疫苗的受试者来说，其感染其他型别的HPV(例如HPV69和/或HPV26)的风险依然很高。
本发明提供了一种突变的HPV51 L1蛋白以及由其形成的HPV病毒样颗粒。本发明的HPV病毒样颗粒能够在HPV51和其他型别的HPV(例如HPV69和/或HPV26)之间提供显著的交叉保护能力。特别地，在同等免疫剂量下，本发明的HPV病毒样颗粒能够诱发机体产生针对至少两个型别的HPV(例如，HPV51和HPV69，或者HPV51、HPV69和HPV26)的高滴度中和抗体，并且其效果与多个型别的HPV VLP的混合物(例如，HPV51 VLP和HPV69 VLP的混合物，或者HPV51 VLP、HPV69 VLP和HPV26 VLP的混合物)相当。因此，本发明的HPV病毒样颗粒能够用于同时预防至少两个型别的HPV(例如HPV51和HPV69，或者HPV51、HPV69和HPV26)的感染以及与此相关的疾病，具有显著的有利技术效果。这在扩大HPV疫苗的保护范围和降低HPV疫苗的生产成本等方面具有特别显著的优势。
下面将结合附图和实施例对本发明的实施方案进行详细描述，但是本领域技术人员将理解，下列附图和实施例仅用于说明本发明，而不是对本发明的范围的限定。根据附图和优选实施方案的下列详细描述，本发明的各种目的和有利方面对于本领域技术人员来说将变得显然。
附图说明
图1A显示了实施例1中经纯化的突变蛋白的SDS聚丙烯酰胺凝胶电泳的结果。泳道1：蛋白分子量标记；泳道2:HPV51N9(N端截短9个氨基酸的HPV51 L1蛋白)；泳道3:HPV69N0(全长的HPV69L1蛋白)；泳道4:H51N9-69T1(即SEQ ID NO：4所示的突变蛋白)；泳道5:H51N9-69T2(即SEQ ID NO：5所示的突变蛋白)；泳道6:H51N9-69T3(即SEQ ID NO：6所示的突变蛋白)；泳道7:H51N9-69T4(即SEQ ID NO：7所示的突变蛋白)；泳道8:H51N9-69T5(即SEQ ID NO：8所示的突变蛋白)。结果显示，经过色谱纯化后，突变蛋白H51N9-69T1、H51N9-69T2、H51N9-69T3、H51N9-69T4和H51N9-69T5的纯度达到90％左右。
图1B-1D显示了实施例1中经纯化的突变蛋白H51N9-69T2-26S1、H51N9-69T2-26S3、H51N9-69T2-26S4、H51N9-69T2-26S5、H51N9-69T3-26S1、H51N9-69T3-26S2、H51N9-69T3-26S4、H51N9-69T3-26S5、H51N9-69T4-26S1、H51N9-69T4-26S2、H51N9-69T4-26S3、H51N9-69T4-26S5的SDS聚丙烯酰胺凝胶电泳的结果。电泳结果显示，经过色谱纯化后，突变蛋白纯度均较高，纯度在80-90％左右。
图2A显示了用HPV L1广谱抗体4B3检测实施例1中制备的H51N9-69T1、H51N9-69T2、H51N9-69T3、H51N9-69T4和H51N9-69T5的蛋白质免疫印迹检测的结果。泳道1：蛋白分子量标记；泳道2:HPV51N9(N端截短9个氨基酸的HPV51 L1蛋白)；泳道3:HPV69N0(全长的HPV69 L1蛋白)；泳道4:H51N9-69T1；泳道5:H51N9-69T2；泳道6:H51N9-69T3；泳道7:H51N9-69T4；泳道8:H51N9-69T5。结果显示，突变蛋白H51N9-69T1、H51N9-69T2、H51N9-69T3、H51N9-69T4和H51N9-69T5能够被广谱抗体4B3特异性识别。
图2B-2D显示了用HPV L1广谱抗体4B3检测实施例1中制备的突变蛋白H51N9-69T2-26S1、H51N9-69T2-26S3、H51N9-69T2-26S4、H51N9-69S2-26T5、H51N9-69T3-26S1、H51N9-69T3-26S2、H51N9-69T3-26S4、H51N9-69T3-26S5、H51N9-69T4-26S1、H51N9-69T4-26S2、H51N9-69T4-26S3、H51N9-69T4-26S5的蛋白质免疫印迹检测的结果。检测结果显示，经过色谱纯化后，突变蛋白能够被广谱抗体4B3特异性识别。
图3显示了包含蛋白H51N9-69T1 VLP、H51N9-69T2 VLP、H51N9-69T3 VLP、H51N9-69T4 VLP和H51N9-69T5 VLP的样品的分子筛层析分析的结果。结果显示，包含H51N9-69T1VLP、H51N9-69T2 VLP、H51N9-69T3 VLP、H51N9-69T4 VLP和H51N9-69T5 VLP的样品最先出现的蛋白峰均在13-14min左右，与HPV51N9 VLP相当，结果表明突变蛋白H51N9-69T1 VLP、H51N9-69T2 VLP、H51N9-69T3 VLP、H51N9-69T4 VLP和H51N9-69T5 VLP均可形成均一的VLP。
图4显示了突变的H51N9-69T1-26S2 VLP、H51N9-69T1-26S3 VLP、H51N9-69T1-26S4 VLP、H51N9-69T1-26S5VLP、H51N9-69T2-26S1 VLP、H51N9-69T2-26S3 VLP、H51N9-69T2-26S4 VLP、H51N9-69T2-26S5 VLP、H51N9-69T3-26S1 VLP、H51N9-69T3-26S2 VLP、H51N9-69T3-26S4 VLP、H51N9-69T3-26S5 VLP、H51N9-69T4-26S1 VLP、H51N9-69T4-26S2VLP、H51N9-69T4-26S3 VLP和H51N9-69T4-26S5 VLP的样品的分子筛层析分析的结果。结果显示这些突变VLP最先出现的蛋白峰均在13-14min左右，与HPV51N9 VLP相当，结果表明突变蛋白突变蛋白H51N9-69T1-26S2、H51N9-69T1-26S3、、H51N9-69T2-26S1、H51N9-69T2-26S3、H51N9-69T2-26S4、H51N9-69T2-26S5、H51N9-69T3-26S1、H51N9-69T3-26S2、H51N9-69T3-26S4、H51N9-69T3-26S5、H51N9-69T4-26S1、H51N9-69T4-26S2、H51N9-69T4-26S3、H51N9-69T4-26S5均可形成均一的VLP，而H51N9-69T1-26S4和H51N9-69T1-26S5形成的VLP大小不均一。
图5显示了突变的H51N9-69T1 VLP、H51N9-69T2 VLP、H51N9-69T3 VLP和H51N9-69T4 VLP的沉降速率分析的结果。结果显示，H51N9-69T1 VLP、H51N9-69T2 VLP、H51N9-69T3 VLP和H51N9-69T4 VLP的沉降系数分别为148S、135S、117S、131S。这表明，制备的突变蛋白H51N9-69T1 VLP、H51N9-69T2 VLP、H51N9-69T3 VLP和H51N9-69T4 VLP均能够组装成大小、形态与野生型VLP(HPV51N9 VLP，123S)相似的病毒样颗粒。
图6显示了突变的H51N9-69T1-26S2 VLP、H51N9-69T1-26S3 VLP、H51N9-69T1-26S4 VLP、H51N9-69T1-26S5VLP、H51N9-69T2-26S1 VLP、H51N9-69T2-26S3 VLP、H51N9-69T2-26S4 VLP、H51N9-69T2-26S5 VLP、H51N9-69T3-26S1 VLP、H51N9-69T3-26S2 VLP、H51N9-69T3-26S4 VLP、H51N9-69T3-26S5 VLP、H51N9-69T4-26S1 VLP、H51N9-69T4-26S2VLP、H51N9-69T4-26S3 VLP和H51N9-69T4-26S5 VLP的沉降速率分析的结果。结果显示，H51N9-69T1-26S2 VLP、H51N9-69T1-26S3 VLP、H51N9-69T1-26S4 VLP、H51N9-69T1-26S5VLP、H51N9-69T2-26S1 VLP、H51N9-69T2-26S3 VLP、H51N9-69T2-26S4 VLP、H51N9-69T2-26S5 VLP、H51N9-69T3-26S1 VLP、H51N9-69T3-26S2VLP、H51N9-69T3-26S4 VLP、H51N9-69T3-26S5 VLP、H51N9-69T4-26S1 VLP、H51N9-69T4-26S2 VLP、H51N9-69T4-26S3VLP和H51N9-69T4-26S5 VLP的沉降系数分别为148S、130S、131S、130S、135S、140S、135S、144S、133S、131S、161S、140S、137S、132S、126S和48S，其中H51N9-69T1-26S3 VLP、H51N9-69T1-26S4 VLP、H51N9-69T1-26S5VLP、H51N9-69T2-26TS3 VLP、H51N9-69T3-26S1 VLP、H51N9-69T3-26S5 VLP的均一性较差，存在两种不同大小的VLP。
图7显示了各种VLP样品的透射电镜观察结果(放大倍数为100,000倍，Bar＝0.1μm)。其中：A为HPV51N9 VLP的透射电镜观察结果；B为H51N9-69T1 VLP的透射电镜观察结果；C为H51N9-69T2 VLP的透射电镜观察结果；D为H51N9-69T3 VLP的透射电镜观察结果；E为H51N9-69T4 VLP的透射电镜观察结果；F为H51N9-69T5 VLP的透射电镜观察结果；G为HPV69N0 VLP的透射电镜观察结果。结果显示，H51N9-69T1 VLP、H51N9-69T2 VLP、H51N9-69T3 VLP、H51N9-69T4 VLP和H51N9-69T5 VLP与HPV51N9 VLP类似，都能够组装成半径为25nm左右的VLP。
图8显示了各种VLP样品的透射电镜观察结果(放大倍数为100,000倍，Bar＝0.1μm)。其中：A为H51N9-69T1-26S2 VLP、H51N9-69T1-26S3 VLP、H51N9-69T1-26S4 VLP、H51N9-69T1-26S5VLP的透射电镜观察结果，B为H51N9-69T2-26S1 VLP、H51N9-69T2-26S3 VLP、H51N9-69T2-26S4 VLP、H51N9-69T2-26S5 VLP的透射电镜观察结果，C为H51N9-69T3-26S1VLP、H51N9-69T3-26S2 VLP、H51N9-69T3-26S4 VLP、H51N9-69T3-26S5 VLP的透射电镜观察结果，D为H51N9-69T4-26S1 VLP、H51N9-69T4-26S2 VLP、H51N9-69T4-26S3 VLP、H51N9-69T4-26S5 VLP的透射电镜观察结果。电镜结果显示除H51N9-69T1-26S4蛋白外，其余突变蛋白均形成半径为25nm左右的VLP。
图9显示了HPV26N0 VLP性质鉴定结果。其中A为HPV26N0 VLP分子筛检测结果；B为HPV26N0 VLP沉降速率分析结果；C为HPV26N0 VLP透射电镜观察结果。
图10A-图10B显示了用H51N9-69T1 VLP、H51N9-69T2 VLP、H51N9-69T3 VLP、H51N9-69T4 VLP和H51N9-69T5 VLP免疫小鼠后小鼠血清中的中和抗体滴度的评价结果。图10A：铝佐剂组1(免疫剂量为5.0μg，使用铝佐剂)；图10B：铝佐剂组2(免疫剂量为1μg，使用铝佐剂)。结果显示，H51N9-69T1 VLP、H51N9-69T2 VLP、H51N9-69T3 VLP和H51N9-69T4 VLP能诱导小鼠产生高滴度的针对HPV51的中和抗体，其保护效果与同剂量的单独的HPV51N9VLP、混合的HPV51/HPV69 VLP相当，且显著优于同剂量的单独的HPV69N0 VLP；H51N9-69T1VLP、H51N9-69T2 VLP、H51N9-69T3 VLP和H51N9-69T4 VLP也能诱导小鼠产生较高滴度的针对HPV69的中和抗体，其保护效果与同剂量的单独的HPV69N0 VLP、混合的HPV51/HPV69 VLP相当，但显著优于同剂量的单独的HPV51N9 VLP。这表明，H51N9-69T1 VLP、H51N9-69T2VLP、H51N9-69T3 VLP和H51N9-69T4 VLP对HPV51和HPV69具有良好的交叉免疫原性和交叉保护性。
图11A-图11B显示了用H51N9-69T1-26S2 VLP、H51N9-69T1-26S3 VLP、H51N9-69T1-26S4 VLP、H51N9-69T1-26S5VLP、H51N9-69T3-26S1 VLP、H51N9-69T3-26S2 VLP、H51N9-69T3-26S4 VLP和H51N9-69T3-26S5 VLP免疫小鼠后小鼠血清中的中和抗体滴度的评价结果。图11A：铝佐剂组1(免疫剂量为5.0μg，使用铝佐剂)；图11B：铝佐剂组2(免疫剂量为1μg，使用铝佐剂)。结果显示，H51N9-69T1-26S2 VLP、H51N9-69T3-26S1 VLP和H51N9-69T3-26S2 VLP能诱导小鼠产生高滴度的针对HPV51的中和抗体，其保护效果与同剂量的单独的HPV51N9 VLP、混合的HPV51/HPV69/HPV26 VLP相当，且显著优于同剂量的单独的HPV69N0 VLP和单独的HPV26N0 VLP；H51N9-69T1-26S2 VLP、H51N9-69T3-26S1 VLP和H51N9-69T3-26S2 VLP也能诱导小鼠产生较高滴度的针对HPV69的中和抗体，其保护效果与同剂量的单独的HPV69N0 VLP、混合的HPV51/HPV69/HPV26 VLP相当，且显著优于同剂量的单独的HPV51N9 VLP。H51N9-69T1-26S2 VLP、H51N9-69T3-26S1 VLP和H51N9-69T3-26S2VLP也能诱导小鼠产生较高滴度的针对HPV26的中和抗体，其保护效果与同剂量的单独的HPV26N0 VLP、混合的HPV51/HPV69/HPV26 VLP相当，且显著优于同剂量的单独的HPV51N9VLP。这表明，H51N9-69T1-26S2 VLP、H51N9-69T3-26S1 VLP和H51N9-69T3-26S2 VLP对HPV51、HPV69和HPV26具有良好的交叉免疫原性和交叉保护性。
图12A-图12B显示了用H51N9-69T2-26S1 VLP、H51N9-69T2-26S3 VLP、H51N9-69T2-26S4 VLP、H51N9-69T2-26S5 VLP、H51N9-69T4-26S1 VLP、H51N9-69T4-26S2 VLP、H51N9-69T4-26S3 VLP和H51N9-69T4-26S5 VLP免疫小鼠后小鼠血清中的中和抗体滴度的评价结果。图12A：铝佐剂组1(免疫剂量为5.0μg，使用铝佐剂)；图12B：铝佐剂组2(免疫剂量为1μg，使用铝佐剂)。结果显示，H51N9-69T2-26T3 VLP和H51N9-69T4-26T2 VLP能诱导小鼠产生高滴度的针对HPV51的中和抗体，其保护效果与同剂量的单独的HPV51N9 VLP、混合的HPV51/HPV69/HPV26 VLP相当，且显著优于同剂量的单独的HPV69N0 VLP和单独的HPV26N0VLP；H51N9-69T2-26T3 VLP和H51N9-69T4-26T2 VLP也能诱导小鼠产生较高滴度的针对HPV69的中和抗体，其保护效果与同剂量的单独的HPV69N0 VLP、混合的HPV51/HPV69/HPV26VLP相当，且显著优于同剂量的单独的HPV51N9 VLP。H51N9-69T2-26T3 VLP和H51N9-69T4-26T2 VLP也能诱导小鼠产生较高滴度的针对HPV26的中和抗体，其保护效果与同剂量的单独的HPV26N0 VLP、混合的HPV51/HPV69/HPV26 VLP相当，且显著优于同剂量的单独的HPV51N9 VLP。这表明，H51N9-69T2-26T3 VLP和H51N9-69T4-26T2 VLP对HPV51、HPV69和HPV26具有良好的交叉免疫原性和交叉保护性。
序列信息
本发明涉及的部分序列的信息提供于下面的表1中。
表1：序列的描述
Figure BDA0002215675900000241
Figure BDA0002215675900000251
Figure BDA0002215675900000261
序列1(SEQ ID NO:1)：
MALWRTNDSKVYLPPAPVSRIVNTEEYITRTGIYYYAGSSRLITLGHPYFPLPKTSTRAAIPKVSAFQYRVFRVQLPDPNKFGLPDPNLYNPDTDRLVWGCVGVEVGRGQPLGVGLSGHPLFNKYDDTENSRIANGNAQQDVRDNTSVDNKQTQLCIIGCAPPIGEHWGIGTTCKNTPVPPGDCPPLELVSSVIQDGDMIDTGFGAMDFAALQATKSDVPLDISQSVCKYPDYLKMSADTYGNSMFFHLRREQIFARHYYNKLGSVGEDIPTDYYIKGSGNGRDPIESYIYSATPSGSMITSDSQIFNKPYWLHRAQGHNNGICWNNQLFITCVDTTRSTNLTISTATAAVSPTFTPSNFKQYIRHGEEYELQFIFQLCKITLTTEVMAYLHTMDPTILEQWNFGLTLPPSASLEDAYRFVRNAATSCQKDTPPQAKPDPLAKYKFWDVDLKERFSLDLDQFALGRKFLLQVGVQRKPRPGLKRPASSASSSSSSSAKRKRVKK.
序列2(SEQ ID NO:2)：
MALWRTSDSKVYLPPTPVSRVVSTDEYVTRTGIYYYAGSSRLLTLGHPYFPIPKSGSTAEIPKVSAYQYRVFRVHLPDPNKFGLPDPQLYNPETERLVWACVGVEVGRGQPLGVGLSGHPLFNKLDDTENSHLATANADTDNRDNVCVDNKQTQLCIIGCTPPLGEHWGVGTVCKNAQSQVQRGDCPPLELISSVIEDGDMIDTGFGAMDFTALQATKCDVPLDINQSICKYPDYLKMSADTYGNSMFFFLRREQLFARHFFNKAGTIGDPVPVSMYIKGAGQGREPPTTSIYSATPSGSMVTSDAQLFNKPYWLQRAQGHNNGICWGNQLFVTCVDTTRSTNLTISTVSAQSASATFKPSDYKQFIRHGEEYELQFIFQLCKITLTTDVMAYIHTMNSTILENWNFGLTLPPTASLEDAYRFIKNSATTCQRDAPAQPKEDPFSKLKFWDVDLKEKFSIDLDQFPLGRKFMLQAGIQRRPKLGTKRPASSLSASSSSTTRKKRKLTK.
序列3(SEQ ID NO:3)：
MKVYLPPAPVSRIVNTEEYITRTGIYYYAGSSRLITLGHPYFPLPKTSTRAAIPKVSAFQYRVFRVQLPDPNKFGLPDPNLYNPDTDRLVWGCVGVEVGRGQPLGVGLSGHPLFNKYDDTENSRIANGNAQQDVRDNTSVDNKQTQLCIIGCAPPIGEHWGIGTTCKNTPVPPGDCPPLELVSSVIQDGDMIDTGFGAMDFAALQATKSDVPLDISQSVCKYPDYLKMSADTYGNSMFFHLRREQIFARHYYNKLGSVGEDIPTDYYIKGSGNGRDPIESYIYSATPSGSMITSDSQIFNKPYWLHRAQGHNNGICWNNQLFITCVDTTRSTNLTISTATAAVSPTFTPSNFKQYIRHGEEYELQFIFQLCKITLTTEVMAYLHTMDPTILEQWNFGLTLPPSASLEDAYRFVRNAATSCQKDTPPQAKPDPLAKYKFWDVDLKERFSLDLDQFALGRKFLLQVGVQRKPRPGLKRPASSASSSSSSSAKRKRVKK
序列4(SEQ ID NO:4)：
MKVYLPPAPVSRIVNTEEYITRTGIYYYAGSSRLITLGHPYFPIPKSGSTAEIPKVSAFQYRVFRVQLPDPNKFGLPDPNLYNPDTDRLVWGCVGVEVGRGQPLGVGLSGHPLFNKYDDTENSRIANGNAQQDVRDNTSVDNKQTQLCIIGCAPPIGEHWGIGTTCKNTPVPPGDCPPLELVSSVIQDGDMIDTGFGAMDFAALQATKSDVPLDISQSVCKYPDYLKMSADTYGNSMFFHLRREQIFARHYYNKLGSVGEDIPTDYYIKGSGNGRDPIESYIYSATPSGSMITSDSQIFNKPYWLHRAQGHNNGICWNNQLFITCVDTTRSTNLTISTATAAVSPTFTPSNFKQYIRHGEEYELQFIFQLCKITLTTEVMAYLHTMDPTILEQWNFGLTLPPSASLEDAYRFVRNAATSCQKDTPPQAKPDPLAKYKFWDVDLKERFSLDLDQFALGRKFLLQVGVQRKPRPGLKRPASSASSSSSSSAKRKRVKK
序列5(SEQ ID NO:5)：
MKVYLPPAPVSRIVNTEEYITRTGIYYYAGSSRLITLGHPYFPLPKTSTRAAIPKVSAFQYRVFRVQLPDPNKFGLPDPNLYNPDTDRLVWGCVGVEVGRGQPLGVGLSGHPLFNKLDDTENSHLATANADTDNRDNVCVDNKQTQLCIIGCAPPIGEHWGIGTTCKNTPVPPGDCPPLELVSSVIQDGDMIDTGFGAMDFAALQATKSDVPLDISQSVCKYPDYLKMSADTYGNSMFFHLRREQIFARHYYNKLGSVGEDIPTDYYIKGSGNGRDPIESYIYSATPSGSMITSDSQIFNKPYWLHRAQGHNNGICWNNQLFITCVDTTRSTNLTISTATAAVSPTFTPSNFKQYIRHGEEYELQFIFQLCKITLTTEVMAYLHTMDPTILEQWNFGLTLPPSASLEDAYRFVRNAATSCQKDTPPQAKPDPLAKYKFWDVDLKERFSLDLDQFALGRKFLLQVGVQRKPRPGLKRPASSASSSSSSSAKRKRVKK
序列6(SEQ ID NO:6)：
MKVYLPPAPVSRIVNTEEYITRTGIYYYAGSSRLITLGHPYFPLPKTSTRAAIPKVSAFQYRVFRVQLPDPNKFGLPDPNLYNPDTDRLVWGCVGVEVGRGQPLGVGLSGHPLFNKYDDTENSRIANGNAQQDVRDNTSVDNKQTQLCIIGCAPPIGEHWGVGTVCKNAQSQVQRGDCPPLELVSSVIQDGDMIDTGFGAMDFAALQATKSDVPLDISQSVCKYPDYLKMSADTYGNSMFFHLRREQIFARHYYNKLGSVGEDIPTDYYIKGSGNGRDPIESYIYSATPSGSMITSDSQIFNKPYWLHRAQGHNNGICWNNQLFITCVDTTRSTNLTISTATAAVSPTFTPSNFKQYIRHGEEYELQFIFQLCKITLTTEVMAYLHTMDPTILEQWNFGLTLPPSASLEDAYRFVRNAATSCQKDTPPQAKPDPLAKYKFWDVDLKERFSLDLDQFALGRKFLLQVGVQRKPRPGLKRPASSASSSSSSSAKRKRVKK.
序列7(SEQ ID NO:7)：
MKVYLPPAPVSRIVNTEEYITRTGIYYYAGSSRLITLGHPYFPLPKTSTRAAIPKVSAFQYRVFRVQLPDPNKFGLPDPNLYNPDTDRLVWGCVGVEVGRGQPLGVGLSGHPLFNKYDDTENSRIANGNAQQDVRDNTSVDNKQTQLCI IGCAPPIGEHWGIGTTCKNTPVPPGDCPPLELVSSVIQDGDMIDTGFGAMDFAALQATKSDVPLDISQSVCKYPDYLKMSADTYGNSMFFHLRREQIFARHFFNKAGTIGDPVPVSMYIKGAGQGREPPTTSIYSATPSGSMITSDSQIFNKPYWLHRAQGHNNGICWNNQLFITCVDTTRSTNLTISTATAAVSPTFTPSNFKQYIRHGEEYELQFIFQLCKITLTTEVMAYLHTMDPTILEQWNFGLTLPPSASLEDAYRFVRNAATSCQKDTPPQAKPDPLAKYKFWDVDLKERFSLDLDQFALGRKFLLQVGVQRKPRPGLKRPASSASSSSSSSAKRKRVKK
序列8(SEQ ID NO:8)：
MKVYLPPAPVSRIVNTEEYITRTGIYYYAGSSRLITLGHPYFPLPKTSTRAAIPKVSAFQYRVFRVQLPDPNKFGLPDPNLYNPDTDRLVWGCVGVEVGRGQPLGVGLSGHPLFNKYDDTENSRIANGNAQQDVRDNTSVDNKQTQLCI IGCAPPIGEHWGIGTTCKNTPVPPGDCPPLELVSSVIQDGDMIDTGFGAMDFAALQATKSDVPLDISQSVCKYPDYLKMSADTYGNSMFFHLRREQIFARHYYNKLGSVGEDIPTDYYIKGSGNGRDPIESYIYSATPSGSMITSDSQIFNKPYWLHRAQGHNNGICWNNQLFITCVDTTRSTNLTISTASAQSASATFKPSDFKQYIRHGEEYELQFIFQLCKITLTTEVMAYLHTMDPTILEQWNFGLTLPPSASLEDAYRFVRNAATSCQKDTPPQAKPDPLAKYKFWDVDLKERFSLDLDQFALGRKFLLQVGVQRKPRPGLKRPASSASSSSSSSAKRKRVKK.
序列9(SEQ ID NO:9)：
ATGGCCCTGTGGAGGACCAACGACAGCAAGGTGTACCTGCCCCCCGCCCCCGTGAGCAGGATCGTGAACACCGAGGAGTACATCACCAGGACCGGCATCTACTACTACGCCGGCAGCAGCAGGCTGATCACCCTGGGCCACCCCTACTTCCCCCTGCCCAAGACCAGCACCAGGGCCGCCATCCCCAAGGTGAGCGCCTTCCAGTACAGGGTGTTCAGGGTGCAGCTCCCCGACCCCAACAAGTTCGGCCTGCCCGACCCCAACCTGTACAACCCCGACACCGACAGGCTGGTGTGGGGCTGCGTGGGCGTGGAGGTGGGCAGGGGCCAGCCCCTGGGCGTGGGCCTGAGCGGCCACCCCCTGTTCAACAAGTACGACGACACCGAGAACAGCAGGATCGCCAACGGCAACGCCCAGCAGGACGTGAGGGACAACACCAGCGTGGACAACAAGCAGACCCAGCTGTGCATCATCGGCTGCGCCCCCCCCATCGGCGAGCACTGGGGCATCGGCACCACCTGCAAGAACACCCCCGTGCCCCCCGGCGACTGCCCCCCCCTGGAGCTGGTGAGCAGCGTGATCCAGGACGGCGACATGATCGACACCGGCTTCGGCGCCATGGACTTCGCCGCCCTGCAGGCCACCAAGAGCGACGTGCCCCTGGACATCAGCCAGAGCGTGTGCAAGTACCCCGACTACCTGAAGATGAGCGCCGACACCTACGGCAACAGCATGTTCTTCCACCTGAGGAGGGAGCAGATCTTCGCCAGGCACTACTACAACAAGCTGGGCAGCGTGGGCGAGGACATCCCCACCGACTACTACATCAAGGGCAGCGGCAACGGCAGGGACCCCATCGAGAGCTACATCTACAGCGCCACCCCCAGCGGCAGCATGATCACCAGCGACAGCCAGATCTTCAACAAGCCCTACTGGCTGCACAGGGCCCAGGGCCACAACAACGGCATCTGCTGGAACAACCAGCTGTTCATCACCTGCGTGGACACCACCAGGAGCACCAACCTGACCATCAGCACCGCCACCGCCGCCGTGAGCCCCACCTTCACCCCCAGCAACTTCAAGCAGTACATCAGGCACGGCGAGGAGTACGAGCTGCAGTTCATCTTCCAGCTGTGCAAGATCACCCTGACCACCGAGGTGATGGCCTACCTGCACACCATGGACCCCACCATCCTGGAGCAGTGGAACTTCGGCCTGACCCTGCCCCCCAGCGCCAGCCTGGAGGACGCCTACAGGTTCGTGAGGAACGCCGCCACCAGCTGCCAGAAGGACACCCCCCCCCAGGCCAAGCCCGACCCCCTGGCCAAGTACAAGTTCTGGGACGTGGACCTGAAGGAGAGGTTCAGCCTGGACCTGGACCAGTTCGCCCTGGGCAGGAAGTTCCTGCTGCAGGTGGGCGTGCAGAGGAAGCCCAGGCCCGGCCTGAAGAGGCCCGCTAGCAGCGCCAGCTCCAGCAGCTCCAGCAGCGCCAAGAGGAAGAGGGTGAAGAAGTAA
序列10(SEQ ID NO:10)：
ATGGCTCTGTGGCGTACCTCTGACTCTAAAGTTTACCTGCCGCCGACCCCGGTTTCTCGTGTTGTTTCTACCGACGAATACGTTACCCGTACCGGTATCTACTACTACGCTGGTTCTTCTCGTCTGCTGACCCTGGGTCACCCGTACTTCCCGATCCCGAAATCTGGTTCTACCGCTGAAATCCCGAAGGTCTCTGCTTACCAGTACCGGGTATTCCGTGTCCACCTGCCGGACCCGAACAAATTCGGTCTGCCGGACCCGCAGCTGTACAATCCAGAAACCGAACGTCTGGTTTGGGCTTGCGTTGGTGTCGAGGTCGGTCGTGGTCAGCCGCTGGGTGTCGGTCTGTCTGGTCACCCGCTGTTCAACAAACTGGACGACACCGAAAACTCTCACCTGGCTACCGCTAACGCTGACACCGACAACCGTGACAACGTTTGCGTTGACAACAAACAGACCCAGCTGTGCATCATCGGTTGCACCCCGCCGCTGGGTGAACACTGGGGTGTCGGTACCGTTTGCAAAAACGCTCAGTCTCAGGTTCAGCGTGGTGACTGCCCGCCGCTGGAACTGATCTCTTCTGTTATCGAAGACGGTGACATGATCGACACCGGTTTCGGTGCTATGGACTTCACCGCTCTGCAGGCTACCAAATGCGACGTTCCGCTGGACATCAACCAGTCTATCTGCAAATACCCCGACTACCTGAAAATGTCTGCTGACACCTACGGTAACTCTATGTTCTTCTTCCTGCGTCGTGAACAGCTGTTCGCTCGTCACTTCTTCAACAAAGCTGGTACCATCGGTGACCCTGTTCCGGTTTCTATGTACATCAAAGGTGCTGGTCAGGGTCGTGAACCGCCGACCACATCCATCTACTCTGCTACCCCGTCTGGTTCTATGGTTACATCCGACGCTCAGCTGTTCAACAAACCGTACTGGCTGCAGCGTGCTCAGGGTCACAACAACGGTATCTGCTGGGGTAACCAGCTGTTCGTTACCTGCGTTGACACCACCCGTTCTACCAACCTGACCATCTCTACCGTTTCTGCTCAGTCTGCTTCTGCTACCTTCAAACCGTCTGACTACAAACAATTTATCCGTCACGGTGAAGAATACGAACTGCAGTTCATCTTCCAGCTGTGCAAAATCACCCTGACCACCGACGTTATGGCTTACATCCACACCATGAACTCTACCATCCTGGAAAACTGGAACTTCGGTCTGACCCTGCCGCCGACCGCTTCTCTGGAAGACGCTTACCGTTTCATCAAAAACTCTGCTACCACCTGCCAGCGTGACGCTCCGGCTCAGCCGAAAGAAGACCCGTTCTCTAAACTGAAATTCTGGGACGTTGACCTGAAAGAAAAATTCTCTATCGACCTGGACCAGTTCCCGCTGGGTCGTAAATTCATGCTGCAGGCTGGTATCCAGCGTCGTCCGAAACTGGGTACCAAACGTCCGGCTTCTTCTCTGTCTGCTTCTTCTTCTTCTACCACCCGTAAAAAACGTAAACTGACCAAATAA
序列11(SEQ ID NO:11)：
ATGAAGGTGTACCTGCCCCCCGCCCCCGTGAGCAGGATCGTGAACACCGAGGAGTACATCACCAGGACCGGCATCTACTACTACGCCGGCAGCAGCAGGCTGATCACCCTGGGCCACCCCTACTTCCCCCTGCCCAAGACCAGCACCAGGGCCGCCATCCCCAAGGTGAGCGCCTTCCAGTACAGGGTGTTCAGGGTGCAGCTCCCCGACCCCAACAAGTTCGGCCTGCCCGACCCCAACCTGTACAACCCCGACACCGACAGGCTGGTGTGGGGCTGCGTGGGCGTGGAGGTGGGCAGGGGCCAGCCCCTGGGCGTGGGCCTGAGCGGCCACCCCCTGTTCAACAAGTACGACGACACCGAGAACAGCAGGATCGCCAACGGCAACGCCCAGCAGGACGTGAGGGACAACACCAGCGTGGACAACAAGCAGACCCAGCTGTGCATCATCGGCTGCGCCCCCCCCATCGGCGAGCACTGGGGCATCGGCACCACCTGCAAGAACACCCCCGTGCCCCCCGGCGACTGCCCCCCCCTGGAGCTGGTGAGCAGCGTGATCCAGGACGGCGACATGATCGACACCGGCTTCGGCGCCATGGACTTCGCCGCCCTGCAGGCCACCAAGAGCGACGTGCCCCTGGACATCAGCCAGAGCGTGTGCAAGTACCCCGACTACCTGAAGATGAGCGCCGACACCTACGGCAACAGCATGTTCTTCCACCTGAGGAGGGAGCAGATCTTCGCCAGGCACTACTACAACAAGCTGGGCAGCGTGGGCGAGGACATCCCCACCGACTACTACATCAAGGGCAGCGGCAACGGCAGGGACCCCATCGAGAGCTACATCTACAGCGCCACCCCCAGCGGCAGCATGATCACCAGCGACAGCCAGATCTTCAACAAGCCCTACTGGCTGCACAGGGCCCAGGGCCACAACAACGGCATCTGCTGGAACAACCAGCTGTTCATCACCTGCGTGGACACCACCAGGAGCACCAACCTGACCATCAGCACCGCCACCGCCGCCGTGAGCCCCACCTTCACCCCCAGCAACTTCAAGCAGTACATCAGGCACGGCGAGGAGTACGAGCTGCAGTTCATCTTCCAGCTGTGCAAGATCACCCTGACCACCGAGGTGATGGCCTACCTGCACACCATGGACCCCACCATCCTGGAGCAGTGGAACTTCGGCCTGACCCTGCCCCCCAGCGCCAGCCTGGAGGACGCCTACAGGTTCGTGAGGAACGCCGCCACCAGCTGCCAGAAGGACACCCCCCCCCAGGCCAAGCCCGACCCCCTGGCCAAGTACAAGTTCTGGGACGTGGACCTGAAGGAGAGGTTCAGCCTGGACCTGGACCAGTTCGCCCTGGGCAGGAAGTTCCTGCTGCAGGTGGGCGTGCAGAGGAAGCCCAGGCCCGGCCTGAAGAGGCCCGCTAGCAGCGCCAGCTCCAGCAGCTCCAGCAGCGCCAAGAGGAAGAGGGTGAAGAAGTAA
序列12(SEQ ID NO:12)：
ATGAAGGTGTACCTGCCCCCCGCCCCCGTGAGCAGGATCGTGAACACCGAGGAGTACATCACCAGGACCGGCATCTACTACTACGCCGGCAGCAGCAGGCTGATCACCCTGGGCCACCCCTACTTCCCGATCCCGAAATCTGGTTCTACCGCTGAAATCCCGAAGGTCTCTGCCTTCCAGTACAGGGTGTTCAGGGTGCAGCTCCCCGACCCCAACAAGTTCGGCCTGCCCGACCCCAACCTGTACAACCCCGACACCGACAGGCTGGTGTGGGGCTGCGTGGGCGTGGAGGTGGGCAGGGGCCAGCCCCTGGGCGTGGGCCTGAGCGGCCACCCCCTGTTCAACAAGTACGACGACACCGAGAACAGCAGGATCGCCAACGGCAACGCCCAGCAGGACGTGAGGGACAACACCAGCGTGGACAACAAGCAGACCCAGCTGTGCATCATCGGCTGCGCCCCCCCCATCGGCGAGCACTGGGGCATCGGCACCACCTGCAAGAACACCCCCGTGCCCCCCGGCGACTGCCCCCCCCTGGAGCTGGTGAGCAGCGTGATCCAGGACGGCGACATGATCGACACCGGCTTCGGCGCCATGGACTTCGCCGCCCTGCAGGCCACCAAGAGCGACGTGCCCCTGGACATCAGCCAGAGCGTGTGCAAGTACCCCGACTACCTGAAGATGAGCGCCGACACCTACGGCAACAGCATGTTCTTCCACCTGAGGAGGGAGCAGATCTTCGCCAGGCACTACTACAACAAGCTGGGCAGCGTGGGCGAGGACATCCCCACCGACTACTACATCAAGGGCAGCGGCAACGGCAGGGACCCCATCGAGAGCTACATCTACAGCGCCACCCCCAGCGGCAGCATGATCACCAGCGACAGCCAGATCTTCAACAAGCCCTACTGGCTGCACAGGGCCCAGGGCCACAACAACGGCATCTGCTGGAACAACCAGCTGTTCATCACCTGCGTGGACACCACCAGGAGCACCAACCTGACCATCAGCACCGCCACCGCCGCCGTGAGCCCCACCTTCACCCCCAGCAACTTCAAGCAGTACATCAGGCACGGCGAGGAGTACGAGCTGCAGTTCATCTTCCAGCTGTGCAAGATCACCCTGACCACCGAGGTGATGGCCTACCTGCACACCATGGACCCCACCATCCTGGAGCAGTGGAACTTCGGCCTGACCCTGCCCCCCAGCGCCAGCCTGGAGGACGCCTACAGGTTCGTGAGGAACGCCGCCACCAGCTGCCAGAAGGACACCCCCCCCCAGGCCAAGCCCGACCCCCTGGCCAAGTACAAGTTCTGGGACGTGGACCTGAAGGAGAGGTTCAGCCTGGACCTGGACCAGTTCGCCCTGGGCAGGAAGTTCCTGCTGCAGGTGGGCGTGCAGAGGAAGCCCAGGCCCGGCCTGAAGAGGCCCGCTAGCAGCGCCAGCTCCAGCAGCTCCAGCAGCGCCAAGAGGAAGAGGGTGAAGAAGTAA
序列13(SEQ ID NO:13)：
ATGAAGGTGTACCTGCCCCCCGCCCCCGTGAGCAGGATCGTGAACACCGAGGAGTACATCACCAGGACCGGCATCTACTACTACGCCGGCAGCAGCAGGCTGATCACCCTGGGCCACCCCTACTTCCCCCTGCCCAAGACCAGCACCAGGGCCGCCATCCCCAAGGTGAGCGCCTTCCAGTACAGGGTGTTCAGGGTGCAGCTCCCCGACCCCAACAAGTTCGGCCTGCCCGACCCCAACCTGTACAACCCCGACACCGACAGGCTGGTGTGGGGCTGCGTGGGCGTGGAGGTGGGTCGTGGTCAGCCGCTGGGTGTCGGTCTGTCTGGTCACCCGCTGTTCAACAAACTGGACGACACCGAAAACTCTCACCTGGCTACCGCTAACGCTGACACCGACAACCGTGACAACGTTTGCGTTGACAACAAGCAGACCCAGCTGTGCATCATCGGCTGCGCCCCCCCCATCGGCGAGCACTGGGGCATCGGCACCACCTGCAAGAACACCCCCGTGCCCCCCGGCGACTGCCCCCCCCTGGAGCTGGTGAGCAGCGTGATCCAGGACGGCGACATGATCGACACCGGCTTCGGCGCCATGGACTTCGCCGCCCTGCAGGCCACCAAGAGCGACGTGCCCCTGGACATCAGCCAGAGCGTGTGCAAGTACCCCGACTACCTGAAGATGAGCGCCGACACCTACGGCAACAGCATGTTCTTCCACCTGAGGAGGGAGCAGATCTTCGCCAGGCACTACTACAACAAGCTGGGCAGCGTGGGCGAGGACATCCCCACCGACTACTACATCAAGGGCAGCGGCAACGGCAGGGACCCCATCGAGAGCTACATCTACAGCGCCACCCCCAGCGGCAGCATGATCACCAGCGACAGCCAGATCTTCAACAAGCCCTACTGGCTGCACAGGGCCCAGGGCCACAACAACGGCATCTGCTGGAACAACCAGCTGTTCATCACCTGCGTGGACACCACCAGGAGCACCAACCTGACCATCAGCACCGCCACCGCCGCCGTGAGCCCCACCTTCACCCCCAGCAACTTCAAGCAGTACATCAGGCACGGCGAGGAGTACGAGCTGCAGTTCATCTTCCAGCTGTGCAAGATCACCCTGACCACCGAGGTGATGGCCTACCTGCACACCATGGACCCCACCATCCTGGAGCAGTGGAACTTCGGCCTGACCCTGCCCCCCAGCGCCAGCCTGGAGGACGCCTACAGGTTCGTGAGGAACGCCGCCACCAGCTGCCAGAAGGACACCCCCCCCCAGGCCAAGCCCGACCCCCTGGCCAAGTACAAGTTCTGGGACGTGGACCTGAAGGAGAGGTTCAGCCTGGACCTGGACCAGTTCGCCCTGGGCAGGAAGTTCCTGCTGCAGGTGGGCGTGCAGAGGAAGCCCAGGCCCGGCCTGAAGAGGCCCGCTAGCAGCGCCAGCTCCAGCAGCTCCAGCAGCGCCAAGAGGAAGAGGGTGAAGAAGTAA
序列14(SEQ ID NO:14)：
ATGAAGGTGTACCTGCCCCCCGCCCCCGTGAGCAGGATCGTGAACACCGAGGAGTACATCACCAGGACCGGCATCTACTACTACGCCGGCAGCAGCAGGCTGATCACCCTGGGCCACCCCTACTTCCCCCTGCCCAAGACCAGCACCAGGGCCGCCATCCCCAAGGTGAGCGCCTTCCAGTACAGGGTGTTCAGGGTGCAGCTCCCCGACCCCAACAAGTTCGGCCTGCCCGACCCCAACCTGTACAACCCCGACACCGACAGGCTGGTGTGGGGCTGCGTGGGCGTGGAGGTGGGCAGGGGCCAGCCCCTGGGCGTGGGCCTGAGCGGCCACCCCCTGTTCAACAAGTACGACGACACCGAGAACAGCAGGATCGCCAACGGCAACGCCCAGCAGGACGTGAGGGACAACACCAGCGTGGACAACAAGCAGACCCAGCTGTGCATCATCGGCTGCGCCCCCCCCATCGGCGAGCACTGGGGTGTCGGTACCGTTTGCAAAAACGCTCAGTCTCAGGTTCAGCGTGGTGACTGCCCGCCGCTGGAGCTGGTGAGCAGCGTGATCCAGGACGGCGACATGATCGACACCGGCTTCGGCGCCATGGACTTCGCCGCCCTGCAGGCCACCAAGAGCGACGTGCCCCTGGACATCAGCCAGAGCGTGTGCAAGTACCCCGACTACCTGAAGATGAGCGCCGACACCTACGGCAACAGCATGTTCTTCCACCTGAGGAGGGAGCAGATCTTCGCCAGGCACTACTACAACAAGCTGGGCAGCGTGGGCGAGGACATCCCCACCGACTACTACATCAAGGGCAGCGGCAACGGCAGGGACCCCATCGAGAGCTACATCTACAGCGCCACCCCCAGCGGCAGCATGATCACCAGCGACAGCCAGATCTTCAACAAGCCCTACTGGCTGCACAGGGCCCAGGGCCACAACAACGGCATCTGCTGGAACAACCAGCTGTTCATCACCTGCGTGGACACCACCAGGAGCACCAACCTGACCATCAGCACCGCCACCGCCGCCGTGAGCCCCACCTTCACCCCCAGCAACTTCAAGCAGTACATCAGGCACGGCGAGGAGTACGAGCTGCAGTTCATCTTCCAGCTGTGCAAGATCACCCTGACCACCGAGGTGATGGCCTACCTGCACACCATGGACCCCACCATCCTGGAGCAGTGGAACTTCGGCCTGACCCTGCCCCCCAGCGCCAGCCTGGAGGACGCCTACAGGTTCGTGAGGAACGCCGCCACCAGCTGCCAGAAGGACACCCCCCCCCAGGCCAAGCCCGACCCCCTGGCCAAGTACAAGTTCTGGGACGTGGACCTGAAGGAGAGGTTCAGCCTGGACCTGGACCAGTTCGCCCTGGGCAGGAAGTTCCTGCTGCAGGTGGGCGTGCAGAGGAAGCCCAGGCCCGGCCTGAAGAGGCCCGCTAGCAGCGCCAGCTCCAGCAGCTCCAGCAGCGCCAAGAGGAAGAGGGTGAAGAAGTAA
序列15(SEQ ID NO:15)：
ATGAAGGTGTACCTGCCCCCCGCCCCCGTGAGCAGGATCGTGAACACCGAGGAGTACATCACCAGGACCGGCATCTACTACTACGCCGGCAGCAGCAGGCTGATCACCCTGGGCCACCCCTACTTCCCCCTGCCCAAGACCAGCACCAGGGCCGCCATCCCCAAGGTGAGCGCCTTCCAGTACAGGGTGTTCAGGGTGCAGCTCCCCGACCCCAACAAGTTCGGCCTGCCCGACCCCAACCTGTACAACCCCGACACCGACAGGCTGGTGTGGGGCTGCGTGGGCGTGGAGGTGGGCAGGGGCCAGCCCCTGGGCGTGGGCCTGAGCGGCCACCCCCTGTTCAACAAGTACGACGACACCGAGAACAGCAGGATCGCCAACGGCAACGCCCAGCAGGACGTGAGGGACAACACCAGCGTGGACAACAAGCAGACCCAGCTGTGCATCATCGGCTGCGCCCCCCCCATCGGCGAGCACTGGGGCATCGGCACCACCTGCAAGAACACCCCCGTGCCCCCCGGCGACTGCCCCCCCCTGGAGCTGGTGAGCAGCGTGATCCAGGACGGCGACATGATCGACACCGGCTTCGGCGCCATGGACTTCGCCGCCCTGCAGGCCACCAAGAGCGACGTGCCCCTGGACATCAGCCAGAGCGTGTGCAAGTACCCCGACTACCTGAAGATGAGCGCCGACACCTACGGCAACAGCATGTTCTTCCACCTGAGGAGGGAGCAGATCTTCGCCAGGCACTTCTTCAACAAAGCTGGTACCATCGGTGACCCTGTTCCGGTTTCTATGTACATCAAAGGTGCTGGTCAGGGTCGTGAACCGCCGACCACATCCATCTACTCTGCCACCCCCAGCGGCAGCATGATCACCAGCGACAGCCAGATCTTCAACAAGCCCTACTGGCTGCACAGGGCCCAGGGCCACAACAACGGCATCTGCTGGAACAACCAGCTGTTCATCACCTGCGTGGACACCACCAGGAGCACCAACCTGACCATCAGCACCGCCACCGCCGCCGTGAGCCCCACCTTCACCCCCAGCAACTTCAAGCAGTACATCAGGCACGGCGAGGAGTACGAGCTGCAGTTCATCTTCCAGCTGTGCAAGATCACCCTGACCACCGAGGTGATGGCCTACCTGCACACCATGGACCCCACCATCCTGGAGCAGTGGAACTTCGGCCTGACCCTGCCCCCCAGCGCCAGCCTGGAGGACGCCTACAGGTTCGTGAGGAACGCCGCCACCAGCTGCCAGAAGGACACCCCCCCCCAGGCCAAGCCCGACCCCCTGGCCAAGTACAAGTTCTGGGACGTGGACCTGAAGGAGAGGTTCAGCCTGGACCTGGACCAGTTCGCCCTGGGCAGGAAGTTCCTGCTGCAGGTGGGCGTGCAGAGGAAGCCCAGGCCCGGCCTGAAGAGGCCCGCTAGCAGCGCCAGCTCCAGCAGCTCCAGCAGCGCCAAGAGGAAGAGGGTGAAGAAGTAA
序列16(SEQ ID NO:16)：
ATGAAGGTGTACCTGCCCCCCGCCCCCGTGAGCAGGATCGTGAACACCGAGGAGTACATCACCAGGACCGGCATCTACTACTACGCCGGCAGCAGCAGGCTGATCACCCTGGGCCACCCCTACTTCCCCCTGCCCAAGACCAGCACCAGGGCCGCCATCCCCAAGGTGAGCGCCTTCCAGTACAGGGTGTTCAGGGTGCAGCTCCCCGACCCCAACAAGTTCGGCCTGCCCGACCCCAACCTGTACAACCCCGACACCGACAGGCTGGTGTGGGGCTGCGTGGGCGTGGAGGTGGGCAGGGGCCAGCCCCTGGGCGTGGGCCTGAGCGGCCACCCCCTGTTCAACAAGTACGACGACACCGAGAACAGCAGGATCGCCAACGGCAACGCCCAGCAGGACGTGAGGGACAACACCAGCGTGGACAACAAGCAGACCCAGCTGTGCATCATCGGCTGCGCCCCCCCCATCGGCGAGCACTGGGGCATCGGCACCACCTGCAAGAACACCCCCGTGCCCCCCGGCGACTGCCCCCCCCTGGAGCTGGTGAGCAGCGTGATCCAGGACGGCGACATGATCGACACCGGCTTCGGCGCCATGGACTTCGCCGCCCTGCAGGCCACCAAGAGCGACGTGCCCCTGGACATCAGCCAGAGCGTGTGCAAGTACCCCGACTACCTGAAGATGAGCGCCGACACCTACGGCAACAGCATGTTCTTCCACCTGAGGAGGGAGCAGATCTTCGCCAGGCACTACTACAACAAGCTGGGCAGCGTGGGCGAGGACATCCCCACCGACTACTACATCAAGGGCAGCGGCAACGGCAGGGACCCCATCGAGAGCTACATCTACAGCGCCACCCCCAGCGGCAGCATGATCACCAGCGACAGCCAGATCTTCAACAAGCCCTACTGGCTGCACAGGGCCCAGGGCCACAACAACGGCATCTGCTGGAACAACCAGCTGTTCATCACCTGCGTGGACACCACCAGGAGCACCAACCTGACCATCAGCACCGCCTCTGCTCAGTCTGCTTCTGCTACCTTCAAACCGTCTGACTTCAAGCAGTACATCAGGCACGGCGAGGAGTACGAGCTGCAGTTCATCTTCCAGCTGTGCAAGATCACCCTGACCACCGAGGTGATGGCCTACCTGCACACCATGGACCCCACCATCCTGGAGCAGTGGAACTTCGGCCTGACCCTGCCCCCCAGCGCCAGCCTGGAGGACGCCTACAGGTTCGTGAGGAACGCCGCCACCAGCTGCCAGAAGGACACCCCCCCCCAGGCCAAGCCCGACCCCCTGGCCAAGTACAAGTTCTGGGACGTGGACCTGAAGGAGAGGTTCAGCCTGGACCTGGACCAGTTCGCCCTGGGCAGGAAGTTCCTGCTGCAGGTGGGCGTGCAGAGGAAGCCCAGGCCCGGCCTGAAGAGGCCCGCTAGCAGCGCCAGCTCCAGCAGCTCCAGCAGCGCCAAGAGGAAGAGGGTGAAGAAGTAA
序列17(SEQ ID NO:17)：
IPKSGSTAE
序列18(SEQ ID NO:18)：
LDDTENSHLATANADTDNRDNVC
序列19(SEQ ID NO:19)：
VGTVCKNAQSQVQR
序列20(SEQ ID NO:20)：
FFNKAGTIGDPVPVSMYIKGAGQGREPPTTS
序列21(SEQ ID NO:21)：
SAQSASATFKPSD
序列22(SEQ ID NO:22)：
MALWRTSDSKVYLPPTPVSRVVNTDEYVTRTGIYYYAGSSRLLTLGHPYFS IPKTGQKAEIPKVSAYQYRVFRVHLPDPNKFGLPDPQLYNPDTERLVWACVGVEVGRGQPLGIGLSGHPLFNKLDDTENSHLATVNADTDNRDNVSVDNKQTQLCI IGCTPPLGEHWGIGTICKNTQTQRGDCPPLELISSI IEDGDMIDTGFGAMDFTALQATKSDVPIDISQSTCKYPDYLKMSADTYGNSMFFFLRREQLFARHFYNKAGAVGDAIPTTLYIKGAESGREPPTSSIYSATPSGSMVTSDAQLFNKPYWLQRAQGHNNGICWGNQLFVTCVDTTRSTNLTISTLSAASASTPFKPSDYKQFIRHGEEYELQFIFQLCKITLTTDVMAYIHLMNASILEDWNFGLTLPPTASLEDAYRFIKNSATTCQRNAPPVPKEDPFQKFKFWDVDLKEKFSIDLDQFPLGRKFMLQAGIQRRPKLGTKRPLSSTSSSTKRKKRKLTK.
序列23(SEQ ID NO:23)：
MKVYLPPAPVSRIVNTEEYITRTGIYYYAGSSRLITLGHPYFPIPKSGSTAEIPKVSAFQYRVFRVQLPDPNKFGLPDPNLYNPDTDRLVWGCVGVEVGRGQPLGIGLSGHPLFNKLDDTENSHLATVNADTDNRDNVSVDNKQTQLCI IGCAPPIGEHWGIGTTCKNTPVPPGDCPPLELVSSVIQDGDMIDTGFGAMDFAALQATKSDVPLDISQSVCKYPDYLKMSADTYGNSMFFHLRREQIFARHYYNKLGSVGEDIPTDYYIKGSGNGRDPIESYIYSATPSGSMITSDSQIFNKPYWLHRAQGHNNGICWNNQLFITCVDTTRSTNLTISTATAAVSPTFTPSNFKQYIRHGEEYELQFIFQLCKITLTTEVMAYLHTMDPTILEQWNFGLTLPPSASLEDAYRFVRNAATSCQKDTPPQAKPDPLAKYKFWDVDLKERFSLDLDQFALGRKFLLQVGVQRKPRPGLKRPASSASSSSSSSAKRKRVKK
序列24(SEQ ID NO:24)：
MKVYLPPAPVSRIVNTEEYITRTGIYYYAGSSRLITLGHPYFPIPKSGSTAEIPKVSAFQYRVFRVQLPDPNKFGLPDPNLYNPDTDRLVWGCVGVEVGRGQPLGVGLSGHPLFNKYDDTENSRIANGNAQQDVRDNTSVDNKQTQLCI IGCAPPIGEHWGIGTICKNTQTQRGDCPPLELVSSVIQDGDMIDTGFGAMDFAALQATKSDVPLDISQSVCKYPDYLKMSADTYGNSMFFHLRREQIFARHYYNKLGSVGEDIPTDYYIKGSGNGRDPIESYIYSATPSGSMITSDSQIFNKPYWLHRAQGHNNGICWNNQLFITCVDTTRSTNLTISTATAAVSPTFTPSNFKQYIRHGEEYELQFIFQLCKITLTTEVMAYLHTMDPTILEQWNFGLTLPPSASLEDAYRFVRNAATSCQKDTPPQAKPDPLAKYKFWDVDLKERFSLDLDQFALGRKFLLQVGVQRKPRPGLKRPASSASSSSSSSAKRKRVKK
序列25(SEQ ID NO:25)：
MKVYLPPAPVSRIVNTEEYITRTGIYYYAGSSRLITLGHPYFPIPKSGSTAEIPKVSAFQYRVFRVQLPDPNKFGLPDPNLYNPDTDRLVWGCVGVEVGRGQPLGVGLSGHPLFNKYDDTENSRIANGNAQQDVRDNTSVDNKQTQLCI IGCAPPIGEHWGIGTTCKNTPVPPGDCPPLELVSSVIQDGDMIDTGFGAMDFAALQATKSDVPLDISQSVCKYPDYLKMSADTYGNSMFFHLRREQIFARHFYNKAGAVGDAIPTTLYIKGAESGREPPTSSIYSATPSGSMITSDSQIFNKPYWLHRAQGHNNGICWNNQLFITCVDTTRSTNLTISTATAAVSPTFTPSNFKQYIRHGEEYELQFIFQLCKITLTTEVMAYLHTMDPTILEQWNFGLTLPPSASLEDAYRFVRNAATSCQKDTPPQAKPDPLAKYKFWDVDLKERFSLDLDQFALGRKFLLQVGVQRKPRPGLKRPASSASSSSSSSAKRKRVKK
序列26(SEQ ID NO:26)：
MKVYLPPAPVSRIVNTEEYITRTGIYYYAGSSRLITLGHPYFPIPKSGSTAEIPKVSAFQYRVFRVQLPDPNKFGLPDPNLYNPDTDRLVWGCVGVEVGRGQPLGVGLSGHPLFNKYDDTENSRIANGNAQQDVRDNTSVDNKQTQLCI IGCAPPIGEHWGIGTTCKNTPVPPGDCPPLELVSSVIQDGDMIDTGFGAMDFAALQATKSDVPLDISQSVCKYPDYLKMSADTYGNSMFFHLRREQIFARHYYNKLGSVGEDIPTDYYIKGSGNGRDPIESYIYSATPSGSMITSDSQIFNKPYWLHRAQGHNNGICWNNQLFITCVDTTRSTNLTISTASAASASTPFKPSDFKQYIRHGEEYELQFIFQLCKITLTTEVMAYLHTMDPTILEQWNFGLTLPPSASLEDAYRFVRNAATSCQKDTPPQAKPDPLAKYKFWDVDLKERFSLDLDQFALGRKFLLQVGVQRKPRPGLKRPASSASSSSSSSAKRKRVKK
序列27(SEQ ID NO:27)：
MKVYLPPAPVSRIVNTEEYITRTGIYYYAGSSRLITLGHPYFSIPKTGQKAEIPKVSAFQYRVFRVQLPDPNKFGLPDPNLYNPDTDRLVWGCVGVEVGRGQPLGVGLSGHPLFNKYDDTENSRIANGNAQQDVRDNTSVDNKQTQLCI IGCAPPIGEHWGVGTVCKNAQSQVQRGDCPPLELVSSVIQDGDMIDTGFGAMDFAALQATKSDVPLDISQSVCKYPDYLKMSADTYGNSMFFHLRREQIFARHYYNKLGSVGEDIPTDYYIKGSGNGRDPIESYIYSATPSGSMITSDSQIFNKPYWLHRAQGHNNGICWNNQLFITCVDTTRSTNLTISTATAAVSPTFTPSNFKQYIRHGEEYELQFIFQLCKITLTTEVMAYLHTMDPTILEQWNFGLTLPPSASLEDAYRFVRNAATSCQKDTPPQAKPDPLAKYKFWDVDLKERFSLDLDQFALGRKFLLQVGVQRKPRPGLKRPASSASSSSSSSAKRKRVKK
序列28(SEQ ID NO:28)：
MKVYLPPAPVSRIVNTEEYITRTGIYYYAGSSRLITLGHPYFPLPKTSTRAAIPKVSAFQYRVFRVQLPDPNKFGLPDPNLYNPDTDRLVWGCVGVEVGRGQPLGIGLSGHPLFNKLDDTENSHLATVNADTDNRDNVSVDNKQTQLCI IGCAPPIGEHWGVGTVCKNAQSQVQRGDCPPLELVSSVIQDGDMIDTGFGAMDFAALQATKSDVPLDISQSVCKYPDYLKMSADTYGNSMFFHLRREQIFARHYYNKLGSVGEDIPTDYYIKGSGNGRDPIESYIYSATPSGSMITSDSQIFNKPYWLHRAQGHNNGICWNNQLFITCVDTTRSTNLTISTATAAVSPTFTPSNFKQYIRHGEEYELQFIFQLCKITLTTEVMAYLHTMDPTILEQWNFGLTLPPSASLEDAYRFVRNAATSCQKDTPPQAKPDPLAKYKFWDVDLKERFSLDLDQFALGRKFLLQVGVQRKPRPGLKRPASSASSSSSSSAKRKRVKK
序列29(SEQ ID NO:29)：
MKVYLPPAPVSRIVNTEEYITRTGIYYYAGSSRLITLGHPYFPLPKTSTRAAIPKVSAFQYRVFRVQLPDPNKFGLPDPNLYNPDTDRLVWGCVGVEVGRGQPLGVGLSGHPLFNKYDDTENSRIANGNAQQDVRDNTSVDNKQTQLCI IGCAPPIGEHWGVGTVCKNAQSQVQRGDCPPLELVSSVIQDGDMIDTGFGAMDFAALQATKSDVPLDISQSVCKYPDYLKMSADTYGNSMFFHLRREQIFARHFYNKAGAVGDAIPTTLYIKGAESGREPPTSS IYSATPSGSMITSDSQIFNKPYWLHRAQGHNNGICWNNQLFITCVDTTRSTNLTISTATAAVSPTFTPSNFKQYIRHGEEYELQFIFQLCKITLTTEVMAYLHTMDPTILEQWNFGLTLPPSASLEDAYRFVRNAATSCQKDTPPQAKPDPLAKYKFWDVDLKERFSLDLDQFALGRKFLLQVGVQRKPRPGLKRPASSASSSSSSSAKRKRVKK
序列30(SEQ ID NO:30)：
MKVYLPPAPVSRIVNTEEYITRTGIYYYAGSSRLITLGHPYFPLPKTSTRAAIPKVSAFQYRVFRVQLPDPNKFGLPDPNLYNPDTDRLVWGCVGVEVGRGQPLGVGLSGHPLFNKYDDTENSRIANGNAQQDVRDNTSVDNKQTQLCI IGCAPPIGEHWGVGTVCKNAQSQVQRGDCPPLELVSSVIQDGDMIDTGFGAMDFAALQATKSDVPLDISQSVCKYPDYLKMSADTYGNSMFFHLRREQIFARHYYNKLGSVGEDIPTDYYIKGSGNGRDPIESYIYSATPSGSMITSDSQIFNKPYWLHRAQGHNNGICWNNQLFITCVDTTRSTNLTISTASAASASTPFKPSDFKQYIRHGEEYELQFIFQLCKITLTTEVMAYLHTMDPTILEQWNFGLTLPPSASLEDAYRFVRNAATSCQKDTPPQAKPDPLAKYKFWDVDLKERFSLDLDQFALGRKFLLQVGVQRKPRPGLKRPASSASSSSSSSAKRKRVKK
序列31(SEQ ID NO:31)：
编码SEQ ID NO：22的DNA序列
ATGGCTCTGTGGCGTACCTCTGACTCTAAAGTTTACCTGCCGCCGACCCCGGTTTCTCGTGTTGTTAACACCGACGAATACGTTACCCGTACCGGTATCTACTACTACGCTGGTTCTTCTCGTCTGCTGACCCTGGGTCACCCGTACTTCTCTATCCCGAAAACCGGTCAGAAAGCTGAAATCCCGAAAGTTTCTGCTTACCAGTACCGTGTTTTCCGTGTTCACCTGCCGGACCCGAACAAATTCGGTCTGCCGGACCCGCAGCTGTACAACCCGGACACCGAACGTCTGGTTTGGGCTTGCGTTGGTGTTGAAGTTGGTCGTGGTCAGCCGCTGGGTATCGGTCTGTCTGGTCACCCGCTGTTCAACAAACTGGACGACACCGAAAACTCTCACCTGGCTACCGTTAACGCTGACACCGACAACCGTGACAACGTTTCTGTTGACAACAAACAGACCCAGCTGTGCATCATCGGTTGCACCCCGCCGCTGGGTGAACACTGGGGTATCGGTACCATCTGCAAAAACACCCAGACCCAGCGTGGTGACTGCCCGCCGCTGGAACTGATCTCTTCTATCATCGAAGACGGTGACATGATCGACACCGGTTTCGGTGCTATGGACTTCACCGCTCTGCAGGCTACCAAATCTGACGTTCCGATCGACATCTCTCAGTCTACCTGCAAATACCCGGACTACCTGAAAATGTCTGCTGACACCTACGGTAACTCTATGTTCTTCTTCCTGCGTCGTGAACAGCTGTTCGCTCGTCACTTCTACAACAAAGCTGGTGCTGTTGGTGACGCTATCCCGACCACCCTGTACATCAAAGGTGCTGAATCTGGTCGTGAACCGCCGACCTCTTCTATCTACTCTGCTACCCCGTCTGGTTCTATGGTTACCTCTGACGCTCAGCTGTTCAACAAACCGTACTGGCTGCAGCGTGCTCAGGGTCACAACAACGGTATCTGCTGGGGTAACCAGCTGTTCGTTACCTGCGTTGACACCACCCGTTCTACCAACCTGACCATCTCTACCCTGTCTGCTGCTTCTGCTTCTACCCCGTTCAAACCGTCTGACTACAAACAGTTCATCCGTCACGGTGAAGAATACGAACTGCAGTTCATCTTCCAGCTGTGCAAAATCACCCTGACCACCGACGTTATGGCTTACATCCACCTGATGAACGCTTCTATCCTGGAAGACTGGAACTTCGGTCTGACCCTGCCGCCGACCGCTTCTCTGGAAGACGCTTACCGTTTCATCAAAAACTCTGCTACCACCTGCCAGCGTAACGCTCCGCCGGTTCCGAAAGAAGACCCGTTCCAGAAATTCAAATTCTGGGACGTTGACCTGAAAGAAAAATTCTCTATCGACCTGGACCAGTTCCCGCTGGGTCGTAAATTCATGCTGCAGGCTGGTATCCAGCGTCGTCCGAAACTGGGTACCAAACGTCCGCTGTCTTCTACCTCTTCTTCTACCAAACGTAAAAAACGTAAACTGACCAAATAA
序列32(SEQ ID NO:32)：
编码SEQ ID NO：23的DNA序列
ATGAAGGTGTACCTGCCCCCCGCCCCCGTGAGCAGGATCGTGAACACCGAGGAGTACATCACCAGGACCGGCATCTACTACTACGCCGGCAGCAGCAGGCTGATCACCCTGGGCCACCCCTACTTCCCGATCCCGAAATCTGGTTCTACCGCTGAAATCCCGAAGGTCTCTGCCTTCCAGTACAGGGTGTTCAGGGTGCAGCTCCCCGACCCCAACAAGTTCGGCCTGCCCGACCCCAACCTGTACAACCCCGACACCGACAGGCTGGTGTGGGGCTGCGTGGGCGTGGAGGTGGGTCGTGGTCAGCCGCTGGGTATCGGTCTGTCTGGTCACCCGCTGTTCAACAAACTGGACGACACCGAAAACTCTCACCTGGCTACCGTTAACGCTGACACCGACAACCGTGACAACGTTTCTGTTGACAACAAGCAGACCCAGCTGTGCATCATCGGCTGCGCCCCCCCCATCGGCGAGCACTGGGGCATCGGCACCACCTGCAAGAACACCCCCGTGCCCCCCGGCGACTGCCCCCCCCTGGAGCTGGTGAGCAGCGTGATCCAGGACGGCGACATGATCGACACCGGCTTCGGCGCCATGGACTTCGCCGCCCTGCAGGCCACCAAGAGCGACGTGCCCCTGGACATCAGCCAGAGCGTGTGCAAGTACCCCGACTACCTGAAGATGAGCGCCGACACCTACGGCAACAGCATGTTCTTCCACCTGAGGAGGGAGCAGATCTTCGCCAGGCACTACTACAACAAGCTGGGCAGCGTGGGCGAGGACATCCCCACCGACTACTACATCAAGGGCAGCGGCAACGGCAGGGACCCCATCGAGAGCTACATCTACAGCGCCACCCCCAGCGGCAGCATGATCACCAGCGACAGCCAGATCTTCAACAAGCCCTACTGGCTGCACAGGGCCCAGGGCCACAACAACGGCATCTGCTGGAACAACCAGCTGTTCATCACCTGCGTGGACACCACCAGGAGCACCAACCTGACCATCAGCACCGCCACCGCCGCCGTGAGCCCCACCTTCACCCCCAGCAACTTCAAGCAGTACATCAGGCACGGCGAGGAGTACGAGCTGCAGTTCATCTTCCAGCTGTGCAAGATCACCCTGACCACCGAGGTGATGGCCTACCTGCACACCATGGACCCCACCATCCTGGAGCAGTGGAACTTCGGCCTGACCCTGCCCCCCAGCGCCAGCCTGGAGGACGCCTACAGGTTCGTGAGGAACGCCGCCACCAGCTGCCAGAAGGACACCCCCCCCCAGGCCAAGCCCGACCCCCTGGCCAAGTACAAGTTCTGGGACGTGGACCTGAAGGAGAGGTTCAGCCTGGACCTGGACCAGTTCGCCCTGGGCAGGAAGTTCCTGCTGCAGGTGGGCGTGCAGAGGAAGCCCAGGCCCGGCCTGAAGAGGCCCGCTAGCAGCGCCAGCTCCAGCAGCTCCAGCAGCGCCAAGAGGAAGAGGGTGAAGAAGTAA
序列33(SEQ ID NO:33)：
编码SEQ ID NO：24的DNA序列
ATGAAGGTGTACCTGCCCCCCGCCCCCGTGAGCAGGATCGTGAACACCGAGGAGTACATCACCAGGACCGGCATCTACTACTACGCCGGCAGCAGCAGGCTGATCACCCTGGGCCACCCCTACTTCCCGATCCCGAAATCTGGTTCTACCGCTGAAATCCCGAAGGTCTCTGCCTTCCAGTACAGGGTGTTCAGGGTGCAGCTCCCCGACCCCAACAAGTTCGGCCTGCCCGACCCCAACCTGTACAACCCCGACACCGACAGGCTGGTGTGGGGCTGCGTGGGCGTGGAGGTGGGCAGGGGCCAGCCCCTGGGCGTGGGCCTGAGCGGCCACCCCCTGTTCAACAAGTACGACGACACCGAGAACAGCAGGATCGCCAACGGCAACGCCCAGCAGGACGTGAGGGACAACACCAGCGTGGACAACAAGCAGACCCAGCTGTGCATCATCGGCTGCGCCCCCCCCATCGGCGAGCACTGGGGTATCGGTACCATCTGCAAAAACACCCAGACCCAGCGTGGTGACTGCCCGCCGCTGGAGCTGGTGAGCAGCGTGATCCAGGACGGCGACATGATCGACACCGGCTTCGGCGCCATGGACTTCGCCGCCCTGCAGGCCACCAAGAGCGACGTGCCCCTGGACATCAGCCAGAGCGTGTGCAAGTACCCCGACTACCTGAAGATGAGCGCCGACACCTACGGCAACAGCATGTTCTTCCACCTGAGGAGGGAGCAGATCTTCGCCAGGCACTACTACAACAAGCTGGGCAGCGTGGGCGAGGACATCCCCACCGACTACTACATCAAGGGCAGCGGCAACGGCAGGGACCCCATCGAGAGCTACATCTACAGCGCCACCCCCAGCGGCAGCATGATCACCAGCGACAGCCAGATCTTCAACAAGCCCTACTGGCTGCACAGGGCCCAGGGCCACAACAACGGCATCTGCTGGAACAACCAGCTGTTCATCACCTGCGTGGACACCACCAGGAGCACCAACCTGACCATCAGCACCGCCACCGCCGCCGTGAGCCCCACCTTCACCCCCAGCAACTTCAAGCAGTACATCAGGCACGGCGAGGAGTACGAGCTGCAGTTCATCTTCCAGCTGTGCAAGATCACCCTGACCACCGAGGTGATGGCCTACCTGCACACCATGGACCCCACCATCCTGGAGCAGTGGAACTTCGGCCTGACCCTGCCCCCCAGCGCCAGCCTGGAGGACGCCTACAGGTTCGTGAGGAACGCCGCCACCAGCTGCCAGAAGGACACCCCCCCCCAGGCCAAGCCCGACCCCCTGGCCAAGTACAAGTTCTGGGACGTGGACCTGAAGGAGAGGTTCAGCCTGGACCTGGACCAGTTCGCCCTGGGCAGGAAGTTCCTGCTGCAGGTGGGCGTGCAGAGGAAGCCCAGGCCCGGCCTGAAGAGGCCCGCTAGCAGCGCCAGCTCCAGCAGCTCCAGCAGCGCCAAGAGGAAGAGGGTGAAGAAGTAA
序列34(SEQ ID NO:34)：
编码SEQ ID NO：25的DNA序列
ATGAAGGTGTACCTGCCCCCCGCCCCCGTGAGCAGGATCGTGAACACCGAGGAGTACATCACCAGGACCGGCATCTACTACTACGCCGGCAGCAGCAGGCTGATCACCCTGGGCCACCCCTACTTCCCGATCCCGAAATCTGGTTCTACCGCTGAAATCCCGAAGGTCTCTGCCTTCCAGTACAGGGTGTTCAGGGTGCAGCTCCCCGACCCCAACAAGTTCGGCCTGCCCGACCCCAACCTGTACAACCCCGACACCGACAGGCTGGTGTGGGGCTGCGTGGGCGTGGAGGTGGGCAGGGGCCAGCCCCTGGGCGTGGGCCTGAGCGGCCACCCCCTGTTCAACAAGTACGACGACACCGAGAACAGCAGGATCGCCAACGGCAACGCCCAGCAGGACGTGAGGGACAACACCAGCGTGGACAACAAGCAGACCCAGCTGTGCATCATCGGCTGCGCCCCCCCCATCGGCGAGCACTGGGGCATCGGCACCACCTGCAAGAACACCCCCGTGCCCCCCGGCGACTGCCCCCCCCTGGAGCTGGTGAGCAGCGTGATCCAGGACGGCGACATGATCGACACCGGCTTCGGCGCCATGGACTTCGCCGCCCTGCAGGCCACCAAGAGCGACGTGCCCCTGGACATCAGCCAGAGCGTGTGCAAGTACCCCGACTACCTGAAGATGAGCGCCGACACCTACGGCAACAGCATGTTCTTCCACCTGAGGAGGGAGCAGATCTTCGCCAGGCACTTCTACAACAAAGCTGGTGCTGTTGGTGACGCTATCCCGACCACCCTGTACATCAAAGGTGCTGAATCTGGTCGTGAACCGCCGACCTCTTCTATCTACTCTGCCACCCCCAGCGGCAGCATGATCACCAGCGACAGCCAGATCTTCAACAAGCCCTACTGGCTGCACAGGGCCCAGGGCCACAACAACGGCATCTGCTGGAACAACCAGCTGTTCATCACCTGCGTGGACACCACCAGGAGCACCAACCTGACCATCAGCACCGCCACCGCCGCCGTGAGCCCCACCTTCACCCCCAGCAACTTCAAGCAGTACATCAGGCACGGCGAGGAGTACGAGCTGCAGTTCATCTTCCAGCTGTGCAAGATCACCCTGACCACCGAGGTGATGGCCTACCTGCACACCATGGACCCCACCATCCTGGAGCAGTGGAACTTCGGCCTGACCCTGCCCCCCAGCGCCAGCCTGGAGGACGCCTACAGGTTCGTGAGGAACGCCGCCACCAGCTGCCAGAAGGACACCCCCCCCCAGGCCAAGCCCGACCCCCTGGCCAAGTACAAGTTCTGGGACGTGGACCTGAAGGAGAGGTTCAGCCTGGACCTGGACCAGTTCGCCCTGGGCAGGAAGTTCCTGCTGCAGGTGGGCGTGCAGAGGAAGCCCAGGCCCGGCCTGAAGAGGCCCGCTAGCAGCGCCAGCTCCAGCAGCTCCAGCAGCGCCAAGAGGAAGAGGGTGAAGAAGTAA
序列35(SEQ ID NO:35)：
编码SEQ ID NO：26的DNA序列
ATGAAGGTGTACCTGCCCCCCGCCCCCGTGAGCAGGATCGTGAACACCGAGGAGTACATCACCAGGACCGGCATCTACTACTACGCCGGCAGCAGCAGGCTGATCACCCTGGGCCACCCCTACTTCCCGATCCCGAAATCTGGTTCTACCGCTGAAATCCCGAAGGTCTCTGCCTTCCAGTACAGGGTGTTCAGGGTGCAGCTCCCCGACCCCAACAAGTTCGGCCTGCCCGACCCCAACCTGTACAACCCCGACACCGACAGGCTGGTGTGGGGCTGCGTGGGCGTGGAGGTGGGCAGGGGCCAGCCCCTGGGCGTGGGCCTGAGCGGCCACCCCCTGTTCAACAAGTACGACGACACCGAGAACAGCAGGATCGCCAACGGCAACGCCCAGCAGGACGTGAGGGACAACACCAGCGTGGACAACAAGCAGACCCAGCTGTGCATCATCGGCTGCGCCCCCCCCATCGGCGAGCACTGGGGCATCGGCACCACCTGCAAGAACACCCCCGTGCCCCCCGGCGACTGCCCCCCCCTGGAGCTGGTGAGCAGCGTGATCCAGGACGGCGACATGATCGACACCGGCTTCGGCGCCATGGACTTCGCCGCCCTGCAGGCCACCAAGAGCGACGTGCCCCTGGACATCAGCCAGAGCGTGTGCAAGTACCCCGACTACCTGAAGATGAGCGCCGACACCTACGGCAACAGCATGTTCTTCCACCTGAGGAGGGAGCAGATCTTCGCCAGGCACTACTACAACAAGCTGGGCAGCGTGGGCGAGGACATCCCCACCGACTACTACATCAAGGGCAGCGGCAACGGCAGGGACCCCATCGAGAGCTACATCTACAGCGCCACCCCCAGCGGCAGCATGATCACCAGCGACAGCCAGATCTTCAACAAGCCCTACTGGCTGCACAGGGCCCAGGGCCACAACAACGGCATCTGCTGGAACAACCAGCTGTTCATCACCTGCGTGGACACCACCAGGAGCACCAACCTGACCATCAGCACCGCCTCTGCTGCTTCTGCTTCTACCCCGTTCAAACCGTCTGACTTCAAGCAGTACATCAGGCACGGCGAGGAGTACGAGCTGCAGTTCATCTTCCAGCTGTGCAAGATCACCCTGACCACCGAGGTGATGGCCTACCTGCACACCATGGACCCCACCATCCTGGAGCAGTGGAACTTCGGCCTGACCCTGCCCCCCAGCGCCAGCCTGGAGGACGCCTACAGGTTCGTGAGGAACGCCGCCACCAGCTGCCAGAAGGACACCCCCCCCCAGGCCAAGCCCGACCCCCTGGCCAAGTACAAGTTCTGGGACGTGGACCTGAAGGAGAGGTTCAGCCTGGACCTGGACCAGTTCGCCCTGGGCAGGAAGTTCCTGCTGCAGGTGGGCGTGCAGAGGAAGCCCAGGCCCGGCCTGAAGAGGCCCGCTAGCAGCGCCAGCTCCAGCAGCTCCAGCAGCGCCAAGAGGAAGAGGGTGAAGAAGTAA
序列36(SEQ ID NO:36)：
编码SEQ ID NO：27的DNA序列
ATGAAGGTGTACCTGCCCCCCGCCCCCGTGAGCAGGATCGTGAACACCGAGGAGTACATCACCAGGACCGGCATCTACTACTACGCCGGCAGCAGCAGGCTGATCACCCTGGGCCACCCCTACTTCTCTATCCCGAAAACCGGTCAGAAAGCTGAAATCCCGAAAGTTTCTGCCTTCCAGTACAGGGTGTTCAGGGTGCAGCTCCCCGACCCCAACAAGTTCGGCCTGCCCGACCCCAACCTGTACAACCCCGACACCGACAGGCTGGTGTGGGGCTGCGTGGGCGTGGAGGTGGGCAGGGGCCAGCCCCTGGGCGTGGGCCTGAGCGGCCACCCCCTGTTCAACAAGTACGACGACACCGAGAACAGCAGGATCGCCAACGGCAACGCCCAGCAGGACGTGAGGGACAACACCAGCGTGGACAACAAGCAGACCCAGCTGTGCATCATCGGCTGCGCCCCCCCCATCGGCGAGCACTGGGGTGTCGGTACCGTTTGCAAAAACGCTCAGTCTCAGGTTCAGCGTGGTGACTGCCCGCCGCTGGAGCTGGTGAGCAGCGTGATCCAGGACGGCGACATGATCGACACCGGCTTCGGCGCCATGGACTTCGCCGCCCTGCAGGCCACCAAGAGCGACGTGCCCCTGGACATCAGCCAGAGCGTGTGCAAGTACCCCGACTACCTGAAGATGAGCGCCGACACCTACGGCAACAGCATGTTCTTCCACCTGAGGAGGGAGCAGATCTTCGCCAGGCACTACTACAACAAGCTGGGCAGCGTGGGCGAGGACATCCCCACCGACTACTACATCAAGGGCAGCGGCAACGGCAGGGACCCCATCGAGAGCTACATCTACAGCGCCACCCCCAGCGGCAGCATGATCACCAGCGACAGCCAGATCTTCAACAAGCCCTACTGGCTGCACAGGGCCCAGGGCCACAACAACGGCATCTGCTGGAACAACCAGCTGTTCATCACCTGCGTGGACACCACCAGGAGCACCAACCTGACCATCAGCACCGCCACCGCCGCCGTGAGCCCCACCTTCACCCCCAGCAACTTCAAGCAGTACATCAGGCACGGCGAGGAGTACGAGCTGCAGTTCATCTTCCAGCTGTGCAAGATCACCCTGACCACCGAGGTGATGGCCTACCTGCACACCATGGACCCCACCATCCTGGAGCAGTGGAACTTCGGCCTGACCCTGCCCCCCAGCGCCAGCCTGGAGGACGCCTACAGGTTCGTGAGGAACGCCGCCACCAGCTGCCAGAAGGACACCCCCCCCCAGGCCAAGCCCGACCCCCTGGCCAAGTACAAGTTCTGGGACGTGGACCTGAAGGAGAGGTTCAGCCTGGACCTGGACCAGTTCGCCCTGGGCAGGAAGTTCCTGCTGCAGGTGGGCGTGCAGAGGAAGCCCAGGCCCGGCCTGAAGAGGCCCGCTAGCAGCGCCAGCTCCAGCAGCTCCAGCAGCGCCAAGAGGAAGAGGGTGAAGAAGTAA
序列37(SEQ ID NO:37)：
编码SEQ ID NO：28的DNA序列
ATGAAGGTGTACCTGCCCCCCGCCCCCGTGAGCAGGATCGTGAACACCGAGGAGTACATCACCAGGACCGGCATCTACTACTACGCCGGCAGCAGCAGGCTGATCACCCTGGGCCACCCCTACTTCCCCCTGCCCAAGACCAGCACCAGGGCCGCCATCCCCAAGGTGAGCGCCTTCCAGTACAGGGTGTTCAGGGTGCAGCTCCCCGACCCCAACAAGTTCGGCCTGCCCGACCCCAACCTGTACAACCCCGACACCGACAGGCTGGTGTGGGGCTGCGTGGGCGTGGAGGTGGGTCGTGGTCAGCCGCTGGGTATCGGTCTGTCTGGTCACCCGCTGTTCAACAAACTGGACGACACCGAAAACTCTCACCTGGCTACCGTTAACGCTGACACCGACAACCGTGACAACGTTTCTGTTGACAACAAGCAGACCCAGCTGTGCATCATCGGCTGCGCCCCCCCCATCGGCGAGCACTGGGGTGTCGGTACCGTTTGCAAAAACGCTCAGTCTCAGGTTCAGCGTGGTGACTGCCCGCCGCTGGAGCTGGTGAGCAGCGTGATCCAGGACGGCGACATGATCGACACCGGCTTCGGCGCCATGGACTTCGCCGCCCTGCAGGCCACCAAGAGCGACGTGCCCCTGGACATCAGCCAGAGCGTGTGCAAGTACCCCGACTACCTGAAGATGAGCGCCGACACCTACGGCAACAGCATGTTCTTCCACCTGAGGAGGGAGCAGATCTTCGCCAGGCACTACTACAACAAGCTGGGCAGCGTGGGCGAGGACATCCCCACCGACTACTACATCAAGGGCAGCGGCAACGGCAGGGACCCCATCGAGAGCTACATCTACAGCGCCACCCCCAGCGGCAGCATGATCACCAGCGACAGCCAGATCTTCAACAAGCCCTACTGGCTGCACAGGGCCCAGGGCCACAACAACGGCATCTGCTGGAACAACCAGCTGTTCATCACCTGCGTGGACACCACCAGGAGCACCAACCTGACCATCAGCACCGCCACCGCCGCCGTGAGCCCCACCTTCACCCCCAGCAACTTCAAGCAGTACATCAGGCACGGCGAGGAGTACGAGCTGCAGTTCATCTTCCAGCTGTGCAAGATCACCCTGACCACCGAGGTGATGGCCTACCTGCACACCATGGACCCCACCATCCTGGAGCAGTGGAACTTCGGCCTGACCCTGCCCCCCAGCGCCAGCCTGGAGGACGCCTACAGGTTCGTGAGGAACGCCGCCACCAGCTGCCAGAAGGACACCCCCCCCCAGGCCAAGCCCGACCCCCTGGCCAAGTACAAGTTCTGGGACGTGGACCTGAAGGAGAGGTTCAGCCTGGACCTGGACCAGTTCGCCCTGGGCAGGAAGTTCCTGCTGCAGGTGGGCGTGCAGAGGAAGCCCAGGCCCGGCCTGAAGAGGCCCGCTAGCAGCGCCAGCTCCAGCAGCTCCAGCAGCGCCAAGAGGAAGAGGGTGAAGAAGTAA
序列38(SEQ ID NO:38)：
编码SEQ ID NO：29的DNA序列
ATGAAGGTGTACCTGCCCCCCGCCCCCGTGAGCAGGATCGTGAACACCGAGGAGTACATCACCAGGACCGGCATCTACTACTACGCCGGCAGCAGCAGGCTGATCACCCTGGGCCACCCCTACTTCCCCCTGCCCAAGACCAGCACCAGGGCCGCCATCCCCAAGGTGAGCGCCTTCCAGTACAGGGTGTTCAGGGTGCAGCTCCCCGACCCCAACAAGTTCGGCCTGCCCGACCCCAACCTGTACAACCCCGACACCGACAGGCTGGTGTGGGGCTGCGTGGGCGTGGAGGTGGGCAGGGGCCAGCCCCTGGGCGTGGGCCTGAGCGGCCACCCCCTGTTCAACAAGTACGACGACACCGAGAACAGCAGGATCGCCAACGGCAACGCCCAGCAGGACGTGAGGGACAACACCAGCGTGGACAACAAGCAGACCCAGCTGTGCATCATCGGCTGCGCCCCCCCCATCGGCGAGCACTGGGGTGTCGGTACCGTTTGCAAAAACGCTCAGTCTCAGGTTCAGCGTGGTGACTGCCCGCCGCTGGAGCTGGTGAGCAGCGTGATCCAGGACGGCGACATGATCGACACCGGCTTCGGCGCCATGGACTTCGCCGCCCTGCAGGCCACCAAGAGCGACGTGCCCCTGGACATCAGCCAGAGCGTGTGCAAGTACCCCGACTACCTGAAGATGAGCGCCGACACCTACGGCAACAGCATGTTCTTCCACCTGAGGAGGGAGCAGATCTTCGCCAGGCACTTCTACAACAAAGCTGGTGCTGTTGGTGACGCTATCCCGACCACCCTGTACATCAAAGGTGCTGAATCTGGTCGTGAACCGCCGACCTCTTCTATCTACTCTGCCACCCCCAGCGGCAGCATGATCACCAGCGACAGCCAGATCTTCAACAAGCCCTACTGGCTGCACAGGGCCCAGGGCCACAACAACGGCATCTGCTGGAACAACCAGCTGTTCATCACCTGCGTGGACACCACCAGGAGCACCAACCTGACCATCAGCACCGCCACCGCCGCCGTGAGCCCCACCTTCACCCCCAGCAACTTCAAGCAGTACATCAGGCACGGCGAGGAGTACGAGCTGCAGTTCATCTTCCAGCTGTGCAAGATCACCCTGACCACCGAGGTGATGGCCTACCTGCACACCATGGACCCCACCATCCTGGAGCAGTGGAACTTCGGCCTGACCCTGCCCCCCAGCGCCAGCCTGGAGGACGCCTACAGGTTCGTGAGGAACGCCGCCACCAGCTGCCAGAAGGACACCCCCCCCCAGGCCAAGCCCGACCCCCTGGCCAAGTACAAGTTCTGGGACGTGGACCTGAAGGAGAGGTTCAGCCTGGACCTGGACCAGTTCGCCCTGGGCAGGAAGTTCCTGCTGCAGGTGGGCGTGCAGAGGAAGCCCAGGCCCGGCCTGAAGAGGCCCGCTAGCAGCGCCAGCTCCAGCAGCTCCAGCAGCGCCAAGAGGAAGAGGGTGAAGAAGTAA
序列39(SEQ ID NO:39)：
编码SEQ ID NO：30的DNA序列
ATGAAGGTGTACCTGCCCCCCGCCCCCGTGAGCAGGATCGTGAACACCGAGGAGTACATCACCAGGACCGGCATCTACTACTACGCCGGCAGCAGCAGGCTGATCACCCTGGGCCACCCCTACTTCCCCCTGCCCAAGACCAGCACCAGGGCCGCCATCCCCAAGGTGAGCGCCTTCCAGTACAGGGTGTTCAGGGTGCAGCTCCCCGACCCCAACAAGTTCGGCCTGCCCGACCCCAACCTGTACAACCCCGACACCGACAGGCTGGTGTGGGGCTGCGTGGGCGTGGAGGTGGGCAGGGGCCAGCCCCTGGGCGTGGGCCTGAGCGGCCACCCCCTGTTCAACAAGTACGACGACACCGAGAACAGCAGGATCGCCAACGGCAACGCCCAGCAGGACGTGAGGGACAACACCAGCGTGGACAACAAGCAGACCCAGCTGTGCATCATCGGCTGCGCCCCCCCCATCGGCGAGCACTGGGGTGTCGGTACCGTTTGCAAAAACGCTCAGTCTCAGGTTCAGCGTGGTGACTGCCCGCCGCTGGAGCTGGTGAGCAGCGTGATCCAGGACGGCGACATGATCGACACCGGCTTCGGCGCCATGGACTTCGCCGCCCTGCAGGCCACCAAGAGCGACGTGCCCCTGGACATCAGCCAGAGCGTGTGCAAGTACCCCGACTACCTGAAGATGAGCGCCGACACCTACGGCAACAGCATGTTCTTCCACCTGAGGAGGGAGCAGATCTTCGCCAGGCACTACTACAACAAGCTGGGCAGCGTGGGCGAGGACATCCCCACCGACTACTACATCAAGGGCAGCGGCAACGGCAGGGACCCCATCGAGAGCTACATCTACAGCGCCACCCCCAGCGGCAGCATGATCACCAGCGACAGCCAGATCTTCAACAAGCCCTACTGGCTGCACAGGGCCCAGGGCCACAACAACGGCATCTGCTGGAACAACCAGCTGTTCATCACCTGCGTGGACACCACCAGGAGCACCAACCTGACCATCAGCACCGCCTCTGCTGCTTCTGCTTCTACCCCGTTCAAACCGTCTGACTTCAAGCAGTACATCAGGCACGGCGAGGAGTACGAGCTGCAGTTCATCTTCCAGCTGTGCAAGATCACCCTGACCACCGAGGTGATGGCCTACCTGCACACCATGGACCCCACCATCCTGGAGCAGTGGAACTTCGGCCTGACCCTGCCCCCCAGCGCCAGCCTGGAGGACGCCTACAGGTTCGTGAGGAACGCCGCCACCAGCTGCCAGAAGGACACCCCCCCCCAGGCCAAGCCCGACCCCCTGGCCAAGTACAAGTTCTGGGACGTGGACCTGAAGGAGAGGTTCAGCCTGGACCTGGACCAGTTCGCCCTGGGCAGGAAGTTCCTGCTGCAGGTGGGCGTGCAGAGGAAGCCCAGGCCCGGCCTGAAGAGGCCCGCTAGCAGCGCCAGCTCCAGCAGCTCCAGCAGCGCCAAGAGGAAGAGGGTGAAGAAGTAA
序列40(SEQ ID NO:40)：
MKVYLPPAPVSRIVNTEEYITRTGIYYYAGSSRLITLGHPYFSIPKTGQKAEIPKVSAFQYRVFRVQLPDPNKFGLPDPNLYNPDTDRLVWGCVGVEVGRGQPLGVGLSGHPLFNKLDDTENSHLATANADTDNRDNVCVDNKQTQLCI IGCAPPIGEHWGIGTTCKNTPVPPGDCPPLELVSSVIQDGDMIDTGFGAMDFAALQATKSDVPLDISQSVCKYPDYLKMSADTYGNSMFFHLRREQIFARHYYNKLGSVGEDIPTDYYIKGSGNGRDPIESYIYSATPSGSMITSDSQIFNKPYWLHRAQGHNNGICWNNQLFITCVDTTRSTNLTISTATAAVSPTFTPSNFKQYIRHGEEYELQFIFQLCKITLTTEVMAYLHTMDPTILEQWNFGLTLPPSASLEDAYRFVRNAATSCQKDTPPQAKPDPLAKYKFWDVDLKERFSLDLDQFALGRKFLLQVGVQRKPRPGLKRPASSASSSSSSSAKRKRVKK
序列41(SEQ ID NO:41)：
MKVYLPPAPVSRIVNTEEYITRTGIYYYAGSSRLITLGHPYFPLPKTSTRAAIPKVSAFQYRVFRVQLPDPNKFGLPDPNLYNPDTDRLVWGCVGVEVGRGQPLGVGLSGHPLFNKLDDTENSHLATANADTDNRDNVCVDNKQTQLCI IGCAPPIGEHWGIGTICKNTQTQRGDCPPLELVSSVIQDGDMIDTGFGAMDFAALQATKSDVPLDISQSVCKYPDYLKMSADTYGNSMFFHLRREQIFARHYYNKLGSVGEDIPTDYYIKGSGNGRDPIESYIYSATPSGSMITSDSQIFNKPYWLHRAQGHNNGICWNNQLFITCVDTTRSTNLTISTATAAVSPTFTPSNFKQYIRHGEEYELQFIFQLCKITLTTEVMAYLHTMDPTILEQWNFGLTLPPSASLEDAYRFVRNAATSCQKDTPPQAKPDPLAKYKFWDVDLKERFSLDLDQFALGRKFLLQVGVQRKPRPGLKRPASSASSSSSSSAKRKRVKK
序列42(SEQ ID NO:42)：
MKVYLPPAPVSRIVNTEEYITRTGIYYYAGSSRLITLGHPYFPLPKTSTRAAIPKVSAFQYRVFRVQLPDPNKFGLPDPNLYNPDTDRLVWGCVGVEVGRGQPLGVGLSGHPLFNKLDDTENSHLATANADTDNRDNVCVDNKQTQLCI IGCAPPIGEHWGIGTTCKNTPVPPGDCPPLELVSSVIQDGDMIDTGFGAMDFAALQATKSDVPLDISQSVCKYPDYLKMSADTYGNSMFFHLRREQIFARHFYNKAGAVGDAIPTTLYIKGAESGREPPTSSIYSATPSGSMITSDSQIFNKPYWLHRAQGHNNGICWNNQLFITCVDTTRSTNLTISTATAAVSPTFTPSNFKQYIRHGEEYELQFIFQLCKITLTTEVMAYLHTMDPTILEQWNFGLTLPPSASLEDAYRFVRNAATSCQKDTPPQAKPDPLAKYKFWDVDLKERFSLDLDQFALGRKFLLQVGVQRKPRPGLKRPASSASSSSSSSAKRKRVKK
序列43(SEQ ID NO:43)：
MKVYLPPAPVSRIVNTEEYITRTGIYYYAGSSRLITLGHPYFPLPKTSTRAAIPKVSAFQYRVFRVQLPDPNKFGLPDPNLYNPDTDRLVWGCVGVEVGRGQPLGVGLSGHPLFNKLDDTENSHLATANADTDNRDNVCVDNKQTQLCI IGCAPPIGEHWGIGTTCKNTPVPPGDCPPLELVSSVIQDGDMIDTGFGAMDFAALQATKSDVPLDISQSVCKYPDYLKMSADTYGNSMFFHLRREQIFARHYYNKLGSVGEDIPTDYYIKGSGNGRDPIESYIYSATPSGSMITSDSQIFNKPYWLHRAQGHNNGICWNNQLFITCVDTTRSTNLTISTASAASASTPFKPSDFKQYIRHGEEYELQFIFQLCKITLTTEVMAYLHTMDPTILEQWNFGLTLPPSASLEDAYRFVRNAATSCQKDTPPQAKPDPLAKYKFWDVDLKERFSLDLDQFALGRKFLLQVGVQRKPRPGLKRPASSASSSSSSSAKRKRVKK
序列44(SEQ ID NO:44)：
MKVYLPPAPVSRIVNTEEYITRTGIYYYAGSSRLITLGHPYFSIPKTGQKAEIPKVSAFQYRVFRVQLPDPNKFGLPDPNLYNPDTDRLVWGCVGVEVGRGQPLGVGLSGHPLFNKYDDTENSRIANGNAQQDVRDNTSVDNKQTQLCI IGCAPPIGEHWGIGTTCKNTPVPPGDCPPLELVSSVIQDGDMIDTGFGAMDFAALQATKSDVPLDISQSVCKYPDYLKMSADTYGNSMFFHLRREQIFARHFFNKAGTIGDPVPVSMYIKGAGQGREPPTTSIYSATPSGSMITSDSQIFNKPYWLHRAQGHNNGICWNNQLFITCVDTTRSTNLTISTATAAVSPTFTPSNFKQYIRHGEEYELQFIFQLCKITLTTEVMAYLHTMDPTILEQWNFGLTLPPSASLEDAYRFVRNAATSCQKDTPPQAKPDPLAKYKFWDVDLKERFSLDLDQFALGRKFLLQVGVQRKPRPGLKRPASSASSSSSSSAKRKRVKK
序列45(SEQ ID NO:45)：
MKVYLPPAPVSRIVNTEEYITRTGIYYYAGSSRLITLGHPYFPLPKTSTRAAIPKVSAFQYRVFRVQLPDPNKFGLPDPNLYNPDTDRLVWGCVGVEVGRGQPLGIGLSGHPLFNKLDDTENSHLATVNADTDNRDNVSVDNKQTQLCI IGCAPPIGEHWGIGTTCKNTPVPPGDCPPLELVSSVIQDGDMIDTGFGAMDFAALQATKSDVPLDISQSVCKYPDYLKMSADTYGNSMFFHLRREQIFARHFFNKAGTIGDPVPVSMYIKGAGQGREPPTTSIYSATPSGSMITSDSQIFNKPYWLHRAQGHNNGICWNNQLFITCVDTTRSTNLTISTATAAVSPTFTPSNFKQYIRHGEEYELQFIFQLCKITLTTEVMAYLHTMDPTILEQWNFGLTLPPSASLEDAYRFVRNAATSCQKDTPPQAKPDPLAKYKFWDVDLKERFSLDLDQFALGRKFLLQVGVQRKPRPGLKRPASSASSSSSSSAKRKRVKK
序列46(SEQ ID NO:46)：
MKVYLPPAPVSRIVNTEEYITRTGIYYYAGSSRLITLGHPYFPLPKTSTRAAIPKVSAFQYRVFRVQLPDPNKFGLPDPNLYNPDTDRLVWGCVGVEVGRGQPLGVGLSGHPLFNKYDDTENSRIANGNAQQDVRDNTSVDNKQTQLCI IGCAPPIGEHWGIGTICKNTQTQRGDCPPLELVSSVIQDGDMIDTGFGAMDFAALQATKSDVPLDISQSVCKYPDYLKMSADTYGNSMFFHLRREQIFARHFFNKAGTIGDPVPVSMYIKGAGQGREPPTTSIYSATPSGSMITSDSQIFNKPYWLHRAQGHNNGICWNNQLFITCVDTTRSTNLTISTATAAVSPTFTPSNFKQYIRHGEEYELQFIFQLCKITLTTEVMAYLHTMDPTILEQWNFGLTLPPSASLEDAYRFVRNAATSCQKDTPPQAKPDPLAKYKFWDVDLKERFSLDLDQFALGRKFLLQVGVQRKPRPGLKRPASSASSSSSSSAKRKRVKK
序列47(SEQ ID NO:47)：
MKVYLPPAPVSRIVNTEEYITRTGIYYYAGSSRLITLGHPYFPLPKTSTRAAIPKVSAFQYRVFRVQLPDPNKFGLPDPNLYNPDTDRLVWGCVGVEVGRGQPLGVGLSGHPLFNKYDDTENSRIANGNAQQDVRDNTSVDNKQTQLCI IGCAPPIGEHWGIGTTCKNTPVPPGDCPPLELVSSVIQDGDMIDTGFGAMDFAALQATKSDVPLDISQSVCKYPDYLKMSADTYGNSMFFHLRREQIFARHFFNKAGTIGDPVPVSMYIKGAGQGREPPTTSIYSATPSGSMITSDSQIFNKPYWLHRAQGHNNGICWNNQLFITCVDTTRSTNLTISTASAASASTPFKPSDFKQYIRHGEEYELQFIFQLCKITLTTEVMAYLHTMDPTILEQWNFGLTLPPSASLEDAYRFVRNAATSCQKDTPPQAKPDPLAKYKFWDVDLKERFSLDLDQFALGRKFLLQVGVQRKPRPGLKRPASSASSSSSSSAKRKRVKK
序列48(SEQ ID NO:48)：
编码SEQ ID NO：40的DNA序列
ATGAAGGTGTACCTGCCCCCCGCCCCCGTGAGCAGGATCGTGAACACCGAGGAGTACATCACCAGGACCGGCATCTACTACTACGCCGGCAGCAGCAGGCTGATCACCCTGGGCCACCCCTACTTCTCTATCCCGAAAACCGGTCAGAAAGCTGAAATCCCGAAAGTTTCTGCCTTCCAGTACAGGGTGTTCAGGGTGCAGCTCCCCGACCCCAACAAGTTCGGCCTGCCCGACCCCAACCTGTACAACCCCGACACCGACAGGCTGGTGTGGGGCTGCGTGGGCGTGGAGGTGGGTCGTGGTCAGCCGCTGGGTGTCGGTCTGTCTGGTCACCCGCTGTTCAACAAACTGGACGACACCGAAAACTCTCACCTGGCTACCGCTAACGCTGACACCGACAACCGTGACAACGTTTGCGTTGACAACAAGCAGACCCAGCTGTGCATCATCGGCTGCGCCCCCCCCATCGGCGAGCACTGGGGCATCGGCACCACCTGCAAGAACACCCCCGTGCCCCCCGGCGACTGCCCCCCCCTGGAGCTGGTGAGCAGCGTGATCCAGGACGGCGACATGATCGACACCGGCTTCGGCGCCATGGACTTCGCCGCCCTGCAGGCCACCAAGAGCGACGTGCCCCTGGACATCAGCCAGAGCGTGTGCAAGTACCCCGACTACCTGAAGATGAGCGCCGACACCTACGGCAACAGCATGTTCTTCCACCTGAGGAGGGAGCAGATCTTCGCCAGGCACTACTACAACAAGCTGGGCAGCGTGGGCGAGGACATCCCCACCGACTACTACATCAAGGGCAGCGGCAACGGCAGGGACCCCATCGAGAGCTACATCTACAGCGCCACCCCCAGCGGCAGCATGATCACCAGCGACAGCCAGATCTTCAACAAGCCCTACTGGCTGCACAGGGCCCAGGGCCACAACAACGGCATCTGCTGGAACAACCAGCTGTTCATCACCTGCGTGGACACCACCAGGAGCACCAACCTGACCATCAGCACCGCCACCGCCGCCGTGAGCCCCACCTTCACCCCCAGCAACTTCAAGCAGTACATCAGGCACGGCGAGGAGTACGAGCTGCAGTTCATCTTCCAGCTGTGCAAGATCACCCTGACCACCGAGGTGATGGCCTACCTGCACACCATGGACCCCACCATCCTGGAGCAGTGGAACTTCGGCCTGACCCTGCCCCCCAGCGCCAGCCTGGAGGACGCCTACAGGTTCGTGAGGAACGCCGCCACCAGCTGCCAGAAGGACACCCCCCCCCAGGCCAAGCCCGACCCCCTGGCCAAGTACAAGTTCTGGGACGTGGACCTGAAGGAGAGGTTCAGCCTGGACCTGGACCAGTTCGCCCTGGGCAGGAAGTTCCTGCTGCAGGTGGGCGTGCAGAGGAAGCCCAGGCCCGGCCTGAAGAGGCCCGCTAGCAGCGCCAGCTCCAGCAGCTCCAGCAGCGCCAAGAGGAAGAGGGTGAAGAAGTAA
序列49(SEQ ID NO:49)：
编码SEQ ID NO：41的DNA序列
ATGAAGGTGTACCTGCCCCCCGCCCCCGTGAGCAGGATCGTGAACACCGAGGAGTACATCACCAGGACCGGCATCTACTACTACGCCGGCAGCAGCAGGCTGATCACCCTGGGCCACCCCTACTTCCCCCTGCCCAAGACCAGCACCAGGGCCGCCATCCCCAAGGTGAGCGCCTTCCAGTACAGGGTGTTCAGGGTGCAGCTCCCCGACCCCAACAAGTTCGGCCTGCCCGACCCCAACCTGTACAACCCCGACACCGACAGGCTGGTGTGGGGCTGCGTGGGCGTGGAGGTGGGTCGTGGTCAGCCGCTGGGTGTCGGTCTGTCTGGTCACCCGCTGTTCAACAAACTGGACGACACCGAAAACTCTCACCTGGCTACCGCTAACGCTGACACCGACAACCGTGACAACGTTTGCGTTGACAACAAGCAGACCCAGCTGTGCATCATCGGCTGCGCCCCCCCCATCGGCGAGCACTGGGGTATCGGTACCATCTGCAAAAACACCCAGACCCAGCGTGGTGACTGCCCGCCGCTGGAGCTGGTGAGCAGCGTGATCCAGGACGGCGACATGATCGACACCGGCTTCGGCGCCATGGACTTCGCCGCCCTGCAGGCCACCAAGAGCGACGTGCCCCTGGACATCAGCCAGAGCGTGTGCAAGTACCCCGACTACCTGAAGATGAGCGCCGACACCTACGGCAACAGCATGTTCTTCCACCTGAGGAGGGAGCAGATCTTCGCCAGGCACTACTACAACAAGCTGGGCAGCGTGGGCGAGGACATCCCCACCGACTACTACATCAAGGGCAGCGGCAACGGCAGGGACCCCATCGAGAGCTACATCTACAGCGCCACCCCCAGCGGCAGCATGATCACCAGCGACAGCCAGATCTTCAACAAGCCCTACTGGCTGCACAGGGCCCAGGGCCACAACAACGGCATCTGCTGGAACAACCAGCTGTTCATCACCTGCGTGGACACCACCAGGAGCACCAACCTGACCATCAGCACCGCCACCGCCGCCGTGAGCCCCACCTTCACCCCCAGCAACTTCAAGCAGTACATCAGGCACGGCGAGGAGTACGAGCTGCAGTTCATCTTCCAGCTGTGCAAGATCACCCTGACCACCGAGGTGATGGCCTACCTGCACACCATGGACCCCACCATCCTGGAGCAGTGGAACTTCGGCCTGACCCTGCCCCCCAGCGCCAGCCTGGAGGACGCCTACAGGTTCGTGAGGAACGCCGCCACCAGCTGCCAGAAGGACACCCCCCCCCAGGCCAAGCCCGACCCCCTGGCCAAGTACAAGTTCTGGGACGTGGACCTGAAGGAGAGGTTCAGCCTGGACCTGGACCAGTTCGCCCTGGGCAGGAAGTTCCTGCTGCAGGTGGGCGTGCAGAGGAAGCCCAGGCCCGGCCTGAAGAGGCCCGCTAGCAGCGCCAGCTCCAGCAGCTCCAGCAGCGCCAAGAGGAAGAGGGTGAAGAAGTAA
序列50(SEQ ID NO:50)：
编码SEQ ID NO：42的DNA序列
ATGAAGGTGTACCTGCCCCCCGCCCCCGTGAGCAGGATCGTGAACACCGAGGAGTACATCACCAGGACCGGCATCTACTACTACGCCGGCAGCAGCAGGCTGATCACCCTGGGCCACCCCTACTTCCCCCTGCCCAAGACCAGCACCAGGGCCGCCATCCCCAAGGTGAGCGCCTTCCAGTACAGGGTGTTCAGGGTGCAGCTCCCCGACCCCAACAAGTTCGGCCTGCCCGACCCCAACCTGTACAACCCCGACACCGACAGGCTGGTGTGGGGCTGCGTGGGCGTGGAGGTGGGTCGTGGTCAGCCGCTGGGTGTCGGTCTGTCTGGTCACCCGCTGTTCAACAAACTGGACGACACCGAAAACTCTCACCTGGCTACCGCTAACGCTGACACCGACAACCGTGACAACGTTTGCGTTGACAACAAGCAGACCCAGCTGTGCATCATCGGCTGCGCCCCCCCCATCGGCGAGCACTGGGGCATCGGCACCACCTGCAAGAACACCCCCGTGCCCCCCGGCGACTGCCCCCCCCTGGAGCTGGTGAGCAGCGTGATCCAGGACGGCGACATGATCGACACCGGCTTCGGCGCCATGGACTTCGCCGCCCTGCAGGCCACCAAGAGCGACGTGCCCCTGGACATCAGCCAGAGCGTGTGCAAGTACCCCGACTACCTGAAGATGAGCGCCGACACCTACGGCAACAGCATGTTCTTCCACCTGAGGAGGGAGCAGATCTTCGCCAGGCACTTCTACAACAAAGCTGGTGCTGTTGGTGACGCTATCCCGACCACCCTGTACATCAAAGGTGCTGAATCTGGTCGTGAACCGCCGACCTCTTCTATCTACTCTGCCACCCCCAGCGGCAGCATGATCACCAGCGACAGCCAGATCTTCAACAAGCCCTACTGGCTGCACAGGGCCCAGGGCCACAACAACGGCATCTGCTGGAACAACCAGCTGTTCATCACCTGCGTGGACACCACCAGGAGCACCAACCTGACCATCAGCACCGCCACCGCCGCCGTGAGCCCCACCTTCACCCCCAGCAACTTCAAGCAGTACATCAGGCACGGCGAGGAGTACGAGCTGCAGTTCATCTTCCAGCTGTGCAAGATCACCCTGACCACCGAGGTGATGGCCTACCTGCACACCATGGACCCCACCATCCTGGAGCAGTGGAACTTCGGCCTGACCCTGCCCCCCAGCGCCAGCCTGGAGGACGCCTACAGGTTCGTGAGGAACGCCGCCACCAGCTGCCAGAAGGACACCCCCCCCCAGGCCAAGCCCGACCCCCTGGCCAAGTACAAGTTCTGGGACGTGGACCTGAAGGAGAGGTTCAGCCTGGACCTGGACCAGTTCGCCCTGGGCAGGAAGTTCCTGCTGCAGGTGGGCGTGCAGAGGAAGCCCAGGCCCGGCCTGAAGAGGCCCGCTAGCAGCGCCAGCTCCAGCAGCTCCAGCAGCGCCAAGAGGAAGAGGGTGAAGAAGTAA
序列51(SEQ ID NO:51)：
编码SEQ ID NO：43的DNA序列
ATGAAGGTGTACCTGCCCCCCGCCCCCGTGAGCAGGATCGTGAACACCGAGGAGTACATCACCAGGACCGGCATCTACTACTACGCCGGCAGCAGCAGGCTGATCACCCTGGGCCACCCCTACTTCCCCCTGCCCAAGACCAGCACCAGGGCCGCCATCCCCAAGGTGAGCGCCTTCCAGTACAGGGTGTTCAGGGTGCAGCTCCCCGACCCCAACAAGTTCGGCCTGCCCGACCCCAACCTGTACAACCCCGACACCGACAGGCTGGTGTGGGGCTGCGTGGGCGTGGAGGTGGGTCGTGGTCAGCCGCTGGGTGTCGGTCTGTCTGGTCACCCGCTGTTCAACAAACTGGACGACACCGAAAACTCTCACCTGGCTACCGCTAACGCTGACACCGACAACCGTGACAACGTTTGCGTTGACAACAAGCAGACCCAGCTGTGCATCATCGGCTGCGCCCCCCCCATCGGCGAGCACTGGGGCATCGGCACCACCTGCAAGAACACCCCCGTGCCCCCCGGCGACTGCCCCCCCCTGGAGCTGGTGAGCAGCGTGATCCAGGACGGCGACATGATCGACACCGGCTTCGGCGCCATGGACTTCGCCGCCCTGCAGGCCACCAAGAGCGACGTGCCCCTGGACATCAGCCAGAGCGTGTGCAAGTACCCCGACTACCTGAAGATGAGCGCCGACACCTACGGCAACAGCATGTTCTTCCACCTGAGGAGGGAGCAGATCTTCGCCAGGCACTACTACAACAAGCTGGGCAGCGTGGGCGAGGACATCCCCACCGACTACTACATCAAGGGCAGCGGCAACGGCAGGGACCCCATCGAGAGCTACATCTACAGCGCCACCCCCAGCGGCAGCATGATCACCAGCGACAGCCAGATCTTCAACAAGCCCTACTGGCTGCACAGGGCCCAGGGCCACAACAACGGCATCTGCTGGAACAACCAGCTGTTCATCACCTGCGTGGACACCACCAGGAGCACCAACCTGACCATCAGCACCGCCTCTGCTGCTTCTGCTTCTACCCCGTTCAAACCGTCTGACTTCAAGCAGTACATCAGGCACGGCGAGGAGTACGAGCTGCAGTTCATCTTCCAGCTGTGCAAGATCACCCTGACCACCGAGGTGATGGCCTACCTGCACACCATGGACCCCACCATCCTGGAGCAGTGGAACTTCGGCCTGACCCTGCCCCCCAGCGCCAGCCTGGAGGACGCCTACAGGTTCGTGAGGAACGCCGCCACCAGCTGCCAGAAGGACACCCCCCCCCAGGCCAAGCCCGACCCCCTGGCCAAGTACAAGTTCTGGGACGTGGACCTGAAGGAGAGGTTCAGCCTGGACCTGGACCAGTTCGCCCTGGGCAGGAAGTTCCTGCTGCAGGTGGGCGTGCAGAGGAAGCCCAGGCCCGGCCTGAAGAGGCCCGCTAGCAGCGCCAGCTCCAGCAGCTCCAGCAGCGCCAAGAGGAAGAGGGTGAAGAAGTAA
序列52(SEQ ID NO:52)：
编码SEQ ID NO：44的DNA序列
ATGAAGGTGTACCTGCCCCCCGCCCCCGTGAGCAGGATCGTGAACACCGAGGAGTACATCACCAGGACCGGCATCTACTACTACGCCGGCAGCAGCAGGCTGATCACCCTGGGCCACCCCTACTTCTCTATCCCGAAAACCGGTCAGAAAGCTGAAATCCCGAAAGTTTCTGCCTTCCAGTACAGGGTGTTCAGGGTGCAGCTCCCCGACCCCAACAAGTTCGGCCTGCCCGACCCCAACCTGTACAACCCCGACACCGACAGGCTGGTGTGGGGCTGCGTGGGCGTGGAGGTGGGCAGGGGCCAGCCCCTGGGCGTGGGCCTGAGCGGCCACCCCCTGTTCAACAAGTACGACGACACCGAGAACAGCAGGATCGCCAACGGCAACGCCCAGCAGGACGTGAGGGACAACACCAGCGTGGACAACAAGCAGACCCAGCTGTGCATCATCGGCTGCGCCCCCCCCATCGGCGAGCACTGGGGCATCGGCACCACCTGCAAGAACACCCCCGTGCCCCCCGGCGACTGCCCCCCCCTGGAGCTGGTGAGCAGCGTGATCCAGGACGGCGACATGATCGACACCGGCTTCGGCGCCATGGACTTCGCCGCCCTGCAGGCCACCAAGAGCGACGTGCCCCTGGACATCAGCCAGAGCGTGTGCAAGTACCCCGACTACCTGAAGATGAGCGCCGACACCTACGGCAACAGCATGTTCTTCCACCTGAGGAGGGAGCAGATCTTCGCCAGGCACTTCTTCAACAAAGCTGGTACCATCGGTGACCCTGTTCCGGTTTCTATGTACATCAAAGGTGCTGGTCAGGGTCGTGAACCGCCGACCACATCCATCTACTCTGCCACCCCCAGCGGCAGCATGATCACCAGCGACAGCCAGATCTTCAACAAGCCCTACTGGCTGCACAGGGCCCAGGGCCACAACAACGGCATCTGCTGGAACAACCAGCTGTTCATCACCTGCGTGGACACCACCAGGAGCACCAACCTGACCATCAGCACCGCCACCGCCGCCGTGAGCCCCACCTTCACCCCCAGCAACTTCAAGCAGTACATCAGGCACGGCGAGGAGTACGAGCTGCAGTTCATCTTCCAGCTGTGCAAGATCACCCTGACCACCGAGGTGATGGCCTACCTGCACACCATGGACCCCACCATCCTGGAGCAGTGGAACTTCGGCCTGACCCTGCCCCCCAGCGCCAGCCTGGAGGACGCCTACAGGTTCGTGAGGAACGCCGCCACCAGCTGCCAGAAGGACACCCCCCCCCAGGCCAAGCCCGACCCCCTGGCCAAGTACAAGTTCTGGGACGTGGACCTGAAGGAGAGGTTCAGCCTGGACCTGGACCAGTTCGCCCTGGGCAGGAAGTTCCTGCTGCAGGTGGGCGTGCAGAGGAAGCCCAGGCCCGGCCTGAAGAGGCCCGCTAGCAGCGCCAGCTCCAGCAGCTCCAGCAGCGCCAAGAGGAAGAGGGTGAAGAAGTAA
序列53(SEQ ID NO:53)：
编码SEQ ID NO：45的DNA序列
ATGAAGGTGTACCTGCCCCCCGCCCCCGTGAGCAGGATCGTGAACACCGAGGAGTACATCACCAGGACCGGCATCTACTACTACGCCGGCAGCAGCAGGCTGATCACCCTGGGCCACCCCTACTTCCCCCTGCCCAAGACCAGCACCAGGGCCGCCATCCCCAAGGTGAGCGCCTTCCAGTACAGGGTGTTCAGGGTGCAGCTCCCCGACCCCAACAAGTTCGGCCTGCCCGACCCCAACCTGTACAACCCCGACACCGACAGGCTGGTGTGGGGCTGCGTGGGCGTGGAGGTGGGTCGTGGTCAGCCGCTGGGTATCGGTCTGTCTGGTCACCCGCTGTTCAACAAACTGGACGACACCGAAAACTCTCACCTGGCTACCGTTAACGCTGACACCGACAACCGTGACAACGTTTCTGTTGACAACAAGCAGACCCAGCTGTGCATCATCGGCTGCGCCCCCCCCATCGGCGAGCACTGGGGCATCGGCACCACCTGCAAGAACACCCCCGTGCCCCCCGGCGACTGCCCCCCCCTGGAGCTGGTGAGCAGCGTGATCCAGGACGGCGACATGATCGACACCGGCTTCGGCGCCATGGACTTCGCCGCCCTGCAGGCCACCAAGAGCGACGTGCCCCTGGACATCAGCCAGAGCGTGTGCAAGTACCCCGACTACCTGAAGATGAGCGCCGACACCTACGGCAACAGCATGTTCTTCCACCTGAGGAGGGAGCAGATCTTCGCCAGGCACTTCTTCAACAAAGCTGGTACCATCGGTGACCCTGTTCCGGTTTCTATGTACATCAAAGGTGCTGGTCAGGGTCGTGAACCGCCGACCACATCCATCTACTCTGCCACCCCCAGCGGCAGCATGATCACCAGCGACAGCCAGATCTTCAACAAGCCCTACTGGCTGCACAGGGCCCAGGGCCACAACAACGGCATCTGCTGGAACAACCAGCTGTTCATCACCTGCGTGGACACCACCAGGAGCACCAACCTGACCATCAGCACCGCCACCGCCGCCGTGAGCCCCACCTTCACCCCCAGCAACTTCAAGCAGTACATCAGGCACGGCGAGGAGTACGAGCTGCAGTTCATCTTCCAGCTGTGCAAGATCACCCTGACCACCGAGGTGATGGCCTACCTGCACACCATGGACCCCACCATCCTGGAGCAGTGGAACTTCGGCCTGACCCTGCCCCCCAGCGCCAGCCTGGAGGACGCCTACAGGTTCGTGAGGAACGCCGCCACCAGCTGCCAGAAGGACACCCCCCCCCAGGCCAAGCCCGACCCCCTGGCCAAGTACAAGTTCTGGGACGTGGACCTGAAGGAGAGGTTCAGCCTGGACCTGGACCAGTTCGCCCTGGGCAGGAAGTTCCTGCTGCAGGTGGGCGTGCAGAGGAAGCCCAGGCCCGGCCTGAAGAGGCCCGCTAGCAGCGCCAGCTCCAGCAGCTCCAGCAGCGCCAAGAGGAAGAGGGTGAAGAAGTAA
序列54(SEQ ID NO:54)：
编码SEQ ID NO：46的DNA序列
ATGAAGGTGTACCTGCCCCCCGCCCCCGTGAGCAGGATCGTGAACACCGAGGAGTACATCACCAGGACCGGCATCTACTACTACGCCGGCAGCAGCAGGCTGATCACCCTGGGCCACCCCTACTTCCCCCTGCCCAAGACCAGCACCAGGGCCGCCATCCCCAAGGTGAGCGCCTTCCAGTACAGGGTGTTCAGGGTGCAGCTCCCCGACCCCAACAAGTTCGGCCTGCCCGACCCCAACCTGTACAACCCCGACACCGACAGGCTGGTGTGGGGCTGCGTGGGCGTGGAGGTGGGCAGGGGCCAGCCCCTGGGCGTGGGCCTGAGCGGCCACCCCCTGTTCAACAAGTACGACGACACCGAGAACAGCAGGATCGCCAACGGCAACGCCCAGCAGGACGTGAGGGACAACACCAGCGTGGACAACAAGCAGACCCAGCTGTGCATCATCGGCTGCGCCCCCCCCATCGGCGAGCACTGGGGTATCGGTACCATCTGCAAAAACACCCAGACCCAGCGTGGTGACTGCCCGCCGCTGGAGCTGGTGAGCAGCGTGATCCAGGACGGCGACATGATCGACACCGGCTTCGGCGCCATGGACTTCGCCGCCCTGCAGGCCACCAAGAGCGACGTGCCCCTGGACATCAGCCAGAGCGTGTGCAAGTACCCCGACTACCTGAAGATGAGCGCCGACACCTACGGCAACAGCATGTTCTTCCACCTGAGGAGGGAGCAGATCTTCGCCAGGCACTTCTTCAACAAAGCTGGTACCATCGGTGACCCTGTTCCGGTTTCTATGTACATCAAAGGTGCTGGTCAGGGTCGTGAACCGCCGACCACATCCATCTACTCTGCCACCCCCAGCGGCAGCATGATCACCAGCGACAGCCAGATCTTCAACAAGCCCTACTGGCTGCACAGGGCCCAGGGCCACAACAACGGCATCTGCTGGAACAACCAGCTGTTCATCACCTGCGTGGACACCACCAGGAGCACCAACCTGACCATCAGCACCGCCACCGCCGCCGTGAGCCCCACCTTCACCCCCAGCAACTTCAAGCAGTACATCAGGCACGGCGAGGAGTACGAGCTGCAGTTCATCTTCCAGCTGTGCAAGATCACCCTGACCACCGAGGTGATGGCCTACCTGCACACCATGGACCCCACCATCCTGGAGCAGTGGAACTTCGGCCTGACCCTGCCCCCCAGCGCCAGCCTGGAGGACGCCTACAGGTTCGTGAGGAACGCCGCCACCAGCTGCCAGAAGGACACCCCCCCCCAGGCCAAGCCCGACCCCCTGGCCAAGTACAAGTTCTGGGACGTGGACCTGAAGGAGAGGTTCAGCCTGGACCTGGACCAGTTCGCCCTGGGCAGGAAGTTCCTGCTGCAGGTGGGCGTGCAGAGGAAGCCCAGGCCCGGCCTGAAGAGGCCCGCTAGCAGCGCCAGCTCCAGCAGCTCCAGCAGCGCCAAGAGGAAGAGGGTGAAGAAGTAA
序列55(SEQ ID NO:55)：
编码SEQ ID NO：47的DNA序列
ATGAAGGTGTACCTGCCCCCCGCCCCCGTGAGCAGGATCGTGAACACCGAGGAGTACATCACCAGGACCGGCATCTACTACTACGCCGGCAGCAGCAGGCTGATCACCCTGGGCCACCCCTACTTCCCCCTGCCCAAGACCAGCACCAGGGCCGCCATCCCCAAGGTGAGCGCCTTCCAGTACAGGGTGTTCAGGGTGCAGCTCCCCGACCCCAACAAGTTCGGCCTGCCCGACCCCAACCTGTACAACCCCGACACCGACAGGCTGGTGTGGGGCTGCGTGGGCGTGGAGGTGGGCAGGGGCCAGCCCCTGGGCGTGGGCCTGAGCGGCCACCCCCTGTTCAACAAGTACGACGACACCGAGAACAGCAGGATCGCCAACGGCAACGCCCAGCAGGACGTGAGGGACAACACCAGCGTGGACAACAAGCAGACCCAGCTGTGCATCATCGGCTGCGCCCCCCCCATCGGCGAGCACTGGGGCATCGGCACCACCTGCAAGAACACCCCCGTGCCCCCCGGCGACTGCCCCCCCCTGGAGCTGGTGAGCAGCGTGATCCAGGACGGCGACATGATCGACACCGGCTTCGGCGCCATGGACTTCGCCGCCCTGCAGGCCACCAAGAGCGACGTGCCCCTGGACATCAGCCAGAGCGTGTGCAAGTACCCCGACTACCTGAAGATGAGCGCCGACACCTACGGCAACAGCATGTTCTTCCACCTGAGGAGGGAGCAGATCTTCGCCAGGCACTTCTTCAACAAAGCTGGTACCATCGGTGACCCTGTTCCGGTTTCTATGTACATCAAAGGTGCTGGTCAGGGTCGTGAACCGCCGACCACATCCATCTACTCTGCCACCCCCAGCGGCAGCATGATCACCAGCGACAGCCAGATCTTCAACAAGCCCTACTGGCTGCACAGGGCCCAGGGCCACAACAACGGCATCTGCTGGAACAACCAGCTGTTCATCACCTGCGTGGACACCACCAGGAGCACCAACCTGACCATCAGCACCGCCTCTGCTGCTTCTGCTTCTACCCCGTTCAAACCGTCTGACTTCAAGCAGTACATCAGGCACGGCGAGGAGTACGAGCTGCAGTTCATCTTCCAGCTGTGCAAGATCACCCTGACCACCGAGGTGATGGCCTACCTGCACACCATGGACCCCACCATCCTGGAGCAGTGGAACTTCGGCCTGACCCTGCCCCCCAGCGCCAGCCTGGAGGACGCCTACAGGTTCGTGAGGAACGCCGCCACCAGCTGCCAGAAGGACACCCCCCCCCAGGCCAAGCCCGACCCCCTGGCCAAGTACAAGTTCTGGGACGTGGACCTGAAGGAGAGGTTCAGCCTGGACCTGGACCAGTTCGCCCTGGGCAGGAAGTTCCTGCTGCAGGTGGGCGTGCAGAGGAAGCCCAGGCCCGGCCTGAAGAGGCCCGCTAGCAGCGCCAGCTCCAGCAGCTCCAGCAGCGCCAAGAGGAAGAGGGTGAAGAAGTAA
序列56(SEQ ID NO:56)：
SIPKTGQKAE
序列57(SEQ ID NO:57)：
IGLSGHPLFNKLDDTENSHLATVNADTDNRDNV
序列58(SEQ ID NO:58)：
ICKNTQTQR
序列59(SEQ ID NO:59)：
FYNKAGAVGDAIPTTLYIKGAESGREPPTSS
序列60(SEQ ID NO:60)：
SAASASTPFKPSD
具体实施方式
现参照下列意在举例说明本发明(而非限定本发明)的实施例来描述本发明。
除非特别指明，本发明中所使用的分子生物学实验方法和免疫检测法，基本上参照J.Sambrook等人，分子克隆：实验室手册，第2版，冷泉港实验室出版社，1989，以及F.M.Ausubel等人，精编分子生物学实验指南，第3版，John Wiley&Sons，Inc.，1995中所述的方法进行；限制性内切酶的使用依照产品制造商推荐的条件。本领域技术人员知晓，实施例以举例方式描述本发明，且不意欲限制本发明所要求保护的范围。
实施例1.突变的HPV51 L1蛋白的表达与纯化
表达载体的构建
采用Gibson装配(Gibson DG,Young L,Chuang RY,Venter JC,Hutchison CA,Smith HO.Enzymatic assembly of DNA molecules up to several hundredkilobases.Nat Methods.2009；6:343–5.doi:10.1038/nmeth.1318.)来构建编码突变的HPV51 L1蛋白的表达载体，所述突变的HPV51 L1蛋白含有来源于HPV69 L1的特定区段和/或来源于HPV26L1的特定区段。简言之，即首先采用PCR反应来获得包含突变的短片段和不包含突变的长片段，再采用Gibson装配体系将两片段连接成环。
使用的初始模板包括pTO-T7-HPV51N9C质粒(其编码N端截短了9氨基酸的HPV51L1蛋白；在表2中简写为51L1N9)、pTO-T7-HPV69N0C质粒(其编码全长的HPV69 L1蛋白；在表2中简写为69L1N0)和pTO-T7-HPV26N0C质粒(其编码全长的HPV26L1蛋白；在表2中简写为26L1N0)。用于各个PCR反应的模板、引物见表2，用于扩增短片段的PCR反应扩增条件设为：94℃变性10分钟，25个循环的“94℃变性50秒，指定温度退火一定时间，72℃延伸1分钟”，最后72℃延伸10分钟；用于扩增长片段的PCR反应扩增条件设为：94℃变性10分钟，25个循环的“94℃变性50秒，指定温度退火一定时间，72℃延伸7分30秒”，最后72℃延伸10分钟。退火温度和时间列于表2。所使用的PCR引物的序列列于表3。将PCR产物电泳后使用DNA回收试剂盒(BEYOTIME(碧云天)，货号：D0033)回收目的片段并测定浓度。按摩尔比2:1比例混合短片段和长片段，总体积3μL；与3μL 2X Gibson装配预混试剂(2X Gibson Assembly MasterMix，购自NEB，包含T5 exonuclease，Phusion DNA polymerase，Taq DNA ligase)混合，50℃反应1小时。
用装配后产物6μL转化40μL以氯化钙法制备的感受态大肠杆菌ER2566(购自新英格兰生物实验室公司)细菌。将转化的大肠杆菌涂布于含卡那霉素(终浓度25μg/mL，下同)的固体LB培养基(LB培养基成分：10g/L蛋白胨，5g/L酵母粉，10g/L氯化钠，下同)，并37℃静置培养10-12小时，直至单菌落清晰可辨。挑取单菌落至含4mL液体LB培养基(含卡那霉素)的试管，在37℃ 220转/分钟下振荡培养10小时，从中取1mL菌液于-70℃保存。从大肠杆菌中提取质粒，并利用T7引物对质粒中插入的目的片段的核苷酸序列进行测序。测序结果显示，所构建的各个质粒(表达载体)中插入的目的片段的核苷酸序列分别为SEQ ID NO：12、13、14、15、16、32、33、34、35、36、37、38、39、48、49、50、51、52、53、54、55，其编码的氨基酸序列为SEQ ID NO：4、5、6、7、8、23、24、25、26、27、28、29、30、40、41、42、43、44、45、46、47(所对应的蛋白分别命名为H51N9-69T1、H51N9-69T2、H51N9-69T3、H51N9-69T4、H51N9-69T5、H51N9-69T1-26S2、H51N9-69T1-26S3、H51N9-69T1-26S4、H51N9-69T1-26S5、H51N9-69T3-26S1、H51N9-69T3-26S2、H51N9-69T3-26S4、H51N9-69T3-26S5、H51N9-69T2-26T1、H51N9-69T2-26T3、H51N9-69T2-26T4、H51N9-69T2-26T5、H51N9-69T4-26T1、H51N9-69T4-26T2、H51N9-69T4-26T3、H51N9-69T4-26T5)。
突变蛋白H51N9-69T1与HPV51N9的区别在于：位于野生型HPV51 L1蛋白第52-60位的氨基酸残基被替换为野生型HPV69 L1蛋白第52-60位的氨基酸残基。突变蛋白H51N9-69T2与HPV51N9的区别在于：位于野生型HPV51 L1蛋白第125-147位的氨基酸残基被替换为野生型HPV69 L1蛋白第125-147位的氨基酸残基。突变蛋白H51N9-69T3与HPV51N9的区别在于：位于野生型HPV51 L1蛋白第170-181位的氨基酸残基被替换为野生型HPV69 L1蛋白第170-183位的氨基酸残基。突变蛋白H51N9-69T4与HPV51N9的区别在于：位于野生型HPV51L1蛋白第259-289位的氨基酸残基被替换为野生型HPV69 L1蛋白第261-291位的氨基酸残基。突变蛋白H51N9-69T5与HPV51N9的区别在于：位于野生型HPV51 L1蛋白第348-359位的氨基酸残基被替换为野生型HPV69 L1蛋白第350-362位的氨基酸残基。
突变蛋白H51N9-69T1-26S2与HPV51N9的区别在于：位于野生型HPV51 L1蛋白第52-60位的氨基酸残基被替换为野生型HPV69 L1蛋白第52-60位的氨基酸残基，并且位于野生型HPV51 L1蛋白第114-146位的氨基酸残基被替换为野生型HPV26 L1蛋白第114-146位的氨基酸残基。
突变蛋白H51N9-69T1-26S3与HPV51N9的区别在于：位于野生型HPV51 L1蛋白第52-60位的氨基酸残基被替换为野生型HPV69 L1蛋白第52-60位的氨基酸残基，并且位于野生型HPV51 L1蛋白第173-181位的氨基酸残基被替换为野生型HPV26 L1蛋白第173-181位的氨基酸残基。
突变蛋白H51N9-69T1-26S4与HPV51N9的区别在于：位于野生型HPV51 L1蛋白第52-60位的氨基酸残基被替换为野生型HPV69 L1蛋白第52-60位的氨基酸残基，并且位于野生型HPV51 L1蛋白第259-289位的氨基酸残基被替换为野生型HPV26 L1蛋白第259-289位的氨基酸残基。
突变蛋白H51N9-69T1-26S5与HPV51N9的区别在于：位于野生型HPV51 L1蛋白第52-60位的氨基酸残基被替换为野生型HPV69 L1蛋白第52-60位的氨基酸残基，并且位于野生型HPV51 L1蛋白第348-359位的氨基酸残基被替换为野生型HPV26 L1蛋白第348-360位的氨基酸残基。
突变蛋白H51N9-69T3-26S1与HPV51N9的区别在于：位于野生型HPV51 L1蛋白第170-181位的氨基酸残基被替换为野生型HPV69 L1蛋白第170-183位的氨基酸残基，并且位于野生型HPV51 L1蛋白第51-60位的氨基酸残基被替换为野生型HPV26 L1蛋白第51-60位的氨基酸残基。
突变蛋白H51N9-69T3-26S2与HPV51N9的区别在于：位于野生型HPV51 L1蛋白第170-181位的氨基酸残基被替换为野生型HPV69 L1蛋白第170-183位的氨基酸残基，并且位于野生型HPV51 L1蛋白第114-146位的氨基酸残基被替换为野生型HPV26 L1蛋白第114-146位的氨基酸残基。
突变蛋白H51N9-69T3-26S4与HPV51N9的区别在于：位于野生型HPV51 L1蛋白第170-181位的氨基酸残基被替换为野生型HPV69 L1蛋白第170-183位的氨基酸残基，并且位于野生型HPV51 L1蛋白第259-289位的氨基酸残基被替换为野生型HPV26 L1蛋白第259-289位的氨基酸残基。
突变蛋白H51N9-69T3-26S5与HPV51N9的区别在于：位于野生型HPV51 L1蛋白第170-181位的氨基酸残基被替换为野生型HPV69 L1蛋白第170-183位的氨基酸残基，并且位于野生型HPV51 L1蛋白第348-359位的氨基酸残基被替换为野生型HPV26 L1蛋白第348-360位的氨基酸残基。
突变蛋白H51N9-69T2-26S1与HPV51N9的区别在于：位于野生型HPV51 L1蛋白第125-147位的氨基酸残基被替换为野生型HPV69 L1蛋白第125-147位的氨基酸残基，并且位于野生型HPV51 L1蛋白第51-60位的氨基酸残基被替换为野生型HPV26 L1蛋白第51-60位的氨基酸残基。
突变蛋白H51N9-69T2-26S3与HPV51N9的区别在于：位于野生型HPV51 L1蛋白第125-147位的氨基酸残基被替换为野生型HPV69 L1蛋白第125-147位的氨基酸残基，并且位于野生型HPV51 L1蛋白第173-181位的氨基酸残基被替换为野生型HPV26 L1蛋白第173-181位的氨基酸残基。
突变蛋白H51N9-69T2-26S4与HPV51N9的区别在于：位于野生型HPV51 L1蛋白第125-147位的氨基酸残基被替换为野生型HPV69 L1蛋白第125-147位的氨基酸残基，并且位于野生型HPV51 L1蛋白第259-289位的氨基酸残基被替换为野生型HPV26 L1蛋白第259-289位的氨基酸残基。
突变蛋白H51N9-69T2-26S5与HPV51N9的区别在于：位于野生型HPV51 L1蛋白第125-147位的氨基酸残基被替换为野生型HPV69 L1蛋白第125-147位的氨基酸残基，并且位于野生型HPV51 L1蛋白第348-359位的氨基酸残基被替换为野生型HPV26 L1蛋白第348-360位的氨基酸残基。
突变蛋白H51N9-69T4-26S1与HPV51N9的区别在于：位于野生型HPV51 L1蛋白第259-289位的氨基酸残基被替换为野生型HPV69 L1蛋白第261-291位的氨基酸残基，并且位于野生型HPV51 L1蛋白第51-60位的氨基酸残基被替换为野生型HPV26 L1蛋白第51-60位的氨基酸残基。
突变蛋白H51N9-69T4-26S2与HPV51N9的区别在于：位于野生型HPV51 L1蛋白第259-289位的氨基酸残基被替换为野生型HPV69 L1蛋白第261-291位的氨基酸残基，并且位于野生型HPV51 L1蛋白第114-146位的氨基酸残基被替换为野生型HPV26 L1蛋白第114-146位的氨基酸残基。
突变蛋白H51N9-69T4-26S3与HPV51N9的区别在于：位于野生型HPV51 L1蛋白第259-289位的氨基酸残基被替换为野生型HPV69 L1蛋白第261-291位的氨基酸残基，并且位于野生型HPV51 L1蛋白第173-181位的氨基酸残基被替换为野生型HPV26 L1蛋白第173-181位的氨基酸残基。
突变蛋白H51N9-69T4-26S5与HPV51N9的区别在于：位于野生型HPV51 L1蛋白第259-289位的氨基酸残基被替换为野生型HPV69 L1蛋白第261-291位的氨基酸残基，并且位于野生型HPV51 L1蛋白第348-359位的氨基酸残基被替换为野生型HPV26 L1蛋白第348-360位的氨基酸残基。
表2用于构建表达载体的PCR反应的模板和引物
Figure BDA0002215675900000471
Figure BDA0002215675900000481
表3：所使用的引物的具体序列(SEQ ID NO:61-144)
Figure BDA0002215675900000482
Figure BDA0002215675900000491
Figure BDA0002215675900000501
Figure BDA0002215675900000511
突变蛋白的大量表达
从-70℃冰箱中取出携带重组质粒pTO-T7-H51N9-69T1、pTO-T7-H51N9-69T2、pTO-T7-H51N9-69T3、pTO-T7-H51N9-69T4、pTO-T7-H51N9-69T5、H51N9-69T1-26S2、H51N9-69T1-26S3、H51N9-69T1-26S4、H51N9-69T1-26S5、H51N9-69T2-26S1、H51N9-69T2-26S3、H51N9-69T2-26S4、H51N9-69T2-26S5、H51N9-69T3-26S1、H51N9-69T3-26S2、H51N9-69T3-26S4、H51N9-69T3-26S5、H51N9-69T4-26S1、H51N9-69T4-26S2、H51N9-69T4-26S3和H51N9-69T4-26S5的大肠杆菌菌液，分别接种入100ml含卡那霉素的LB液体培养基中，在200rpm，37℃下培养大约8小时；然后分别转接入500ml含卡那霉素的LB培养基中(接入1ml菌液)，并继续进行培养。当细菌浓度达到OD600为0.6左右时，将培养温度降至25℃，并向各培养瓶中加入500μL IPTG，继续培养8小时。培养结束后，离心收集菌体。获得表达了H51N9-69T1、H51N9-69T2、H51N9-69T3、H51N9-69T4、H51N9-69T5、H51N9-69T1-26S2、H51N9-69T1-26S3、H51N9-69T1-26S4、H51N9-69T1-26S5、H51N9-69T2-26S1、H51N9-69T2-26S3、H51N9-69T2-26S4、H51N9-69T2-26S5、H51N9-69T3-26S1、H51N9-69T3-26S2、H51N9-69T3-26S4、H51N9-69T3-26S5、H51N9-69T4-26S1、H51N9-69T4-26S2、H51N9-69T4-26S3和H51N9-69T4-26S5蛋白的菌体。
表达突变蛋白的菌体破碎
按1g菌体对应10mL裂解液(20mM Tris缓冲液，pH7.2，300mM NaCl)的比例重悬上述得到的菌体。用超声波仪破碎菌体30min。以13500rpm(30000g)离心含有经破碎的菌体的裂解液15min，留取上清(即，菌体破碎上清)。
突变蛋白的色谱纯化
仪器系统：GE Healthcare公司(原Amershan Pharmacia公司)生产的AKTAexplorer 100型制备型液相色谱系统。
层析介质：SP Sepharose 4Fast Flow(GE Healthcare公司)、CHT-Ⅱ(购自Bio－RAD)和Butyl Sepharose 4Fast Flow(GE Healthcare公司)。下面的洗脱程序中用到的含有不同浓度NaCl的缓冲液是由缓冲液A和B按比例混合配置而成。
缓冲液：缓冲液A(20mM磷酸盐缓冲液，pH8.0，20mM DTT)；以及，缓冲液B(20mM磷酸盐缓冲液，pH8.0，20mM DTT，2M NaCl)。
样品：如上获得的含有H51N9-69T1，H51N9-69T3的菌体破碎上清。
洗脱程序为：
(1)用SP Sepharose 4 Fast Flow对菌体破碎上清进行阳离子交换纯化：将样品上柱，然后用含有400mM NaCl的缓冲液(80％缓冲液A+20％缓冲液B)洗脱杂蛋白，然后用含有800mM NaCl的缓冲液(60％缓冲液A+40％缓冲液B)洗脱目的蛋白，并收集由含有800mMNaCl的缓冲液洗脱的级分；
(2)用CHTⅡ(羟基磷灰石色谱)对前一步获得的洗脱级分进行色谱纯化：对前一步骤获得的洗脱级分进行稀释，以使得NaCl的浓度降至0.5M；将样品上柱，然后用含有500mMNaCl的缓冲液(75％缓冲液A+25％缓冲液B)洗脱杂蛋白，然后用含有1000mM NaCl的缓冲液(50％缓冲液A+50％缓冲液B)洗脱目的蛋白，并收集由含有1000mM NaCl的缓冲液洗脱的级分；
(3)用HIC(疏水相互作用色谱)对前一步骤获得的洗脱级分进行色谱纯化：将样品上柱，然后用含有1000mM NaCl的缓冲液洗脱杂蛋白，然后用含有200mM NaCl的缓冲液(90％缓冲液A+10％缓冲液B)洗脱目的蛋白，并收集由含有200mM NaCl的缓冲液洗脱的级分。
取步骤(3)获得的洗脱级分150μL，加入30μL 6X Loading Buffer(1L中含有1M TB6.8 300ml、100％甘油600ml、SDS 120g、溴酚蓝6g、β-巯基乙醇50ml)中，混匀，并于80℃水浴中温育10min。然后取10μl样品于10％SDS-聚丙烯酰胺凝胶中以120V电压电泳120min；然后以考马斯亮兰染色显示电泳条带。电泳结果示于图1A、图1B、图1C和图1D中。结果显示，经过上述纯化步骤后，H51N9-69T1、H51N9-69T2、H51N9-69T3、H51N9-69T4、H51N9-69T5、H51N9-69T1-26S2、H51N9-69T1-26S3、H51N9-69T1-26S4、H51N9-69T1-26S5、H51N9-69T2-26S1、H51N9-69T2-26S3、H51N9-69T2-26S4、H51N9-69T2-26S5、H51N9-69T3-26S1、H51N9-69T3-26S2、H51N9-69T3-26S4、H51N9-69T3-26S5、H51N9-69T4-26S1、H51N9-69T4-26S2、H51N9-69T4-26S3和H51N9-69T4-26S5蛋白的纯度均在90％左右。
通过类似的方法，使用大肠杆菌和pTO-T7-HPV51N9C质粒制备和纯化了HPV51N9蛋白；使用大肠杆菌和pTO-T7-HPV69L1N0C质粒制备和纯化了HPV69N0蛋白；使用大肠杆菌和pTO-T7-HPV26L1N0C质粒制备和纯化了HPV26N0蛋白。
突变蛋白的免疫印迹实验
按上述方法对经纯化的H51N9-69T1、H51N9-69T2、H51N9-69T3、H51N9-69T4、H51N9-69T5、H51N9-69T1-26S2、H51N9-69T1-26S3、H51N9-69T1-26S4、H51N9-69T1-26S5、H51N9-69T2-26S1、H51N9-69T2-26S3、H51N9-69T2-26S4、H51N9-69T2-26S5、H51N9-69T3-26S1、H51N9-69T3-26S2、H51N9-69T3-26S4、H51N9-69T3-26S5、H51N9-69T4-26S1、H51N9-69T4-26S2、H51N9-69T4-26S3和H51N9-69T4-26S5蛋白进行电泳。电泳结束后，使用抗HPVL1蛋白的广谱抗体4B3进行Western Blot检测，结果示于图2A、图2B、图2C和图2D中。结果显示，突变蛋白H51N9-69T1、H51N9-69T2、H51N9-69T3、H51N9-69T4、H51N9-69T5、H51N9-69T1-26S2、H51N9-69T1-26S3、H51N9-69T1-26S4、H51N9-69T1-26S5、H51N9-69T2-26S1、H51N9-69T2-26S3、H51N9-69T2-26S4、H51N9-69T2-26S5、H51N9-69T3-26S1、H51N9-69T3-26S2、H51N9-69T3-26S4、H51N9-69T3-26S5、H51N9-69T4-26S1、H51N9-69T4-26S2、H51N9-69T4-26S3和H51N9-69T4-26S5都能够被广谱抗体4B3特异性识别。
实施例2：HPV病毒样颗粒的组装与颗粒形态学检测
HPV病毒样颗粒的组装
取一定体积(约2ml)的蛋白H51N9-69T1、H51N9-69T2、H51N9-69T3、H51N9-69T4、H51N9-69T5、H51N9-69T1-26S2、H51N9-69T1-26S3、H51N9-69T1-26S4、H51N9-69T1-26S5、H51N9-69T2-26S1、H51N9-69T2-26S3、H51N9-69T2-26S4、H51N9-69T2-26S5、H51N9-69T3-26S1、H51N9-69T3-26S2、H51N9-69T3-26S4、H51N9-69T3-26S5、H51N9-69T4-26S1、H51N9-69T4-26S2、H51N9-69T4-26S3和H51N9-69T4-26S5，分别依次透析至(1)2L储存缓冲液(20mM磷酸钠缓冲液pH 6.5，0.5M NaCl)；(2)2L复性缓冲液(50mM磷酸钠缓冲液pH 6.0，2mMCaCl2，2mM MgCl2，0.5M NaCl)；和(3)20mM磷酸钠缓冲液pH 7.0，0.5M NaCl中。在三种缓冲液中各自进行透析12h。
通过类似的方法，将HPV51N9、HPV69N0和HPV26N0蛋白分别组装为HPV51N9 VLP、HPV69N0 VLP和HPV26N0 VLP。
分子筛层析分析
用美国安捷伦公司的1120Compact LC高效液相色谱系统对经透析的样品进行分子筛层析分析，其中，所使用的分析柱为TSK Gel PW5000xl 7.8x300 mm。HPV26N0 VLP的分析结果如图9所示，其他样品的分析结果如图3和4所示，结果显示，包含H51N9-69T1、H51N9-69T2、H51N9-69T3、H51N9-69T4、H51N9-69T5、H51N9-69T1-26S2、H51N9-69T1-26S3、H51N9-69T1-26S4、H51N9-69T1-26S5、H51N9-69T2-26S1、H51N9-69T2-26S3、H51N9-69T2-26S4、H51N9-69T2-26S5、H51N9-69T3-26S1、H51N9-69T3-26S2、H51N9-69T3-26S4、H51N9-69T3-26S5、H51N9-69T4-26S1、H51N9-69T4-26S2、H51N9-69T4-26S3和H51N9-69T4-26S5的样品最先出现的蛋白峰均在13-14min左右，与HPV51N9 VLP相当，结果表明，除突变蛋白H51N9-69T1-26S4和H51N9-69T1-26S5，其余突变蛋白H51N9-69T1、H51N9-69T2、H51N9-69T3、H51N9-69T4和H51N9-69T5、H51N9-69T1-26S2、H51N9-69T1-26S3、H51N9-69T2-26S1、H51N9-69T2-26S3、H51N9-69T2-26S4、H51N9-69T2-26S5、H51N9-69T3-26S1、H51N9-69T3-26S2、H51N9-69T3-26S4、H51N9-69T3-26S5、H51N9-69T4-26S1、H51N9-69T4-26S2、H51N9-69T4-26S3和H51N9-69T4-26S5均可形成均一的VLP。突变蛋白H51N9-69T1-26S4和H51N9-69T1-26S5形成的颗粒不均一。
沉降速率分析
沉降速率分析所使用的仪器为Beckman XL-A分析型超速离心机，其配有光学检测系统及An-50Ti和An-60Ti转头。采用沉降速率法分析HPV51N9 VLP、HPV69N0 VLP、H51N9-69T1 VLP、H51N9-69T2 VLP、H51N9-69T3 VLP、H51N9-69T4 VLP、H51N9-69T1-26S2 VLP、H51N9-69T1-26S3 VLP、H51N9-69T1-26S4 VLP、H51N9-69T1-26S5VLP、H51N9-69T2-26S1VLP、H51N9-69T2-26S3 VLP、H51N9-69T2-26S4 VLP、H51N9-69T2-26S5 VLP、H51N9-69T3-26S1 VLP、H51N9-69T3-26S2 VLP、H51N9-69T3-26S4 VLP、H51N9-69T3-26S5 VLP、H51N9-69T4-26S1 VLP、H51N9-69T4-26S2 VLP、H51N9-69T4-26S3 VLP和H51N9-69T4-26S5 VLP的沉降系数。HPV26N0 VLP的分析结果如图9所示，其他样品的结果如图5和6所示。结果显示，H51N9-69T1 VLP、H51N9-69T2 VLP、H51N9-69T3 VLP、H51N9-69T4 VLP、H51N9-69T1-26S2VLP、H51N9-69T1-26S3 VLP、H51N9-69T1-26S4 VLP、H51N9-69T1-26S5VLP、H51N9-69T2-26S1 VLP、H51N9-69T2-26S3 VLP、H51N9-69T2-26S4 VLP、H51N9-69T2-26S5 VLP、H51N9-69T3-26S1 VLP、H51N9-69T3-26S2 VLP、H51N9-69T3-26S4 VLP、H51N9-69T3-26S5 VLP、H51N9-69T4-26S1 VLP、H51N9-69T4-26S2 VLP、H51N9-69T4-26S3 VLP和H51N9-69T4-26S5VLP的沉降系数分别为148S、135S、117S、131S、148S、130S、131S、130S、135S、140S、135S、144S、133S、131S、161S、140S、137S、132S、126S和48S，其中H51N9-69T1-26S3 VLP、H51N9-69T1-26S4 VLP、H51N9-69T1-26S5VLP、H51N9-69T2-26S3 VLP、H51N9-69T3-26S1 VLP、H51N9-69T3-26S5 VLP的均一性较差，存在两种不同大小的VLP。
病毒样颗粒的形态学检测
取100μL含有VLP的样品进行透射电镜观察。所使用的仪器为日本电子公司生产的100kV透射电镜，放大倍数为100,000倍。简言之，取13.5μL样品，用2％磷钨酸pH7.0进行负染，并固定于喷炭的铜网上，然后进行透射电镜观察。HPV26N0 VLP的观察结果如图9所示，其他样品的观察结果如图7和8所示。结果显示，除H51N9-69T1-26S4 VLP外，H51N9-69T1VLP、H51N9-69T2 VLP、H51N9-69T3 VLP、H51N9-69T4 VLP、H51N9-69T5 VLP、H51N9-69T1-26S2 VLP、H51N9-69T1-26S3 VLP、H51N9-69T1-26S5VLP、H51N9-69T2-26S1 VLP、H51N9-69T2-26S3 VLP、H51N9-69T2-26S4 VLP、H51N9-69T2-26S5 VLP、H51N9-69T3-26S1 VLP、H51N9-69T3-26S2 VLP、H51N9-69T3-26S4 VLP、H51N9-69T3-26S5 VLP、H51N9-69T4-26S1VLP、H51N9-69T4-26S2 VLP、H51N9-69T4-26S3 VLP和H51N9-69T4-26S5 VLP与HPV51N9 VLP类似，都能够组装成半径为25nm左右的VLP。
实施例3：用病毒样颗粒免疫后小鼠血清中的中和抗体滴度的评价1
本实验中，所用病毒样颗粒为：H51N9-69T1 VLP、H51N9-69T2 VLP、H51N9-69T3VLP、H51N9-69T4 VLP和H51N9-69T5 VLP。
在本实验中，免疫方案如表4所示。将所有小鼠(6周龄BalB/c雌性小鼠)分为2个组:铝佐剂组1(免疫剂量为5μg，使用铝佐剂)，铝佐剂组2(免疫剂量为1μg，使用铝佐剂)。各个组又细分为8个亚组，对照亚组1和2分别用单独的HPV51N9 VLP和单独的HPV69N0 VLP进行免疫，对照亚组3用混合的HPV51/HPV69 VLP(即，HPV51N9 VLP和HPV69N0 VLP的混合物，其中每种VLP均以指定的免疫剂量施用)进行免疫，实验亚组1、2、3、4、5分别用H51N9-69T1VLP，H51N9-69T2 VLP，H51N9-69T3 VLP，H51N9-69T4 VLP，H51N9-69T5 VLP进行免疫。
对于铝佐剂组1-2，采用腹腔注射方式免疫5只小鼠/亚组，免疫剂量分别为5μg和1μg，注射体积为1ml。所有小鼠均在第0周进行初次免疫，然后在第2和4周各自进行加强免疫一次。在第8周对小鼠进行眼眶采血，并分析血清中的抗HPV51和HPV69抗体的滴度。分析结果如图10A和图10B所示。结果显示，H51N9-69T1 VLP、H51N9-69T2 VLP、H51N9-69T3 VLP和H51N9-69T4 VLP能诱导小鼠产生高滴度的针对HPV51的中和抗体，其保护效果与同剂量的单独的HPV51N9 VLP、混合的HPV51/HPV69 VLP相当，且显著优于同剂量的单独的HPV69N0VLP；H51N9-69T1 VLP、H51N9-69T2 VLP、H51N9-69T3 VLP和H51N9-69T4 VLP也能诱导小鼠产生较高滴度的针对HPV69的中和抗体，其保护效果与同剂量的单独的HPV69N0 VLP、混合的HPV51/HPV69 VLP相当，但显著优于同剂量的单独的HPV51N9 VLP。
这表明，H51N9-69T1 VLP、H51N9-69T2 VLP、H51N9-69T3 VLP和H51N9-69T4 VLP对HPV51和HPV69具有良好的交叉免疫原性和交叉保护性。
表4免疫方案
Figure BDA0002215675900000581
实施例4：用病毒样颗粒免疫后小鼠血清中的中和抗体滴度的评价2
本实验中，所用病毒样颗粒为：H51N9-69T1-26S2 VLP、H51N9-69T1-26S3 VLP、H51N9-69T1-26S4 VLP、H51N9-69T1-26S5VLP、H51N9-69T3-26S1 VLP、H51N9-69T3-26S2VLP、H51N9-69T3-26S4 VLP、H51N9-69T3-26S5 VLP。
在本实验中，免疫方案如表5所示。将所有小鼠(6周龄BalB/c雌性小鼠)分为2个组:铝佐剂组1(免疫剂量为5μg，使用铝佐剂)，铝佐剂组2(免疫剂量为1μg，使用铝佐剂)。各个组又细分为12个亚组，对照亚组1、2和3分别用单独的HPV51N9 VLP、单独的HPV69N0 VLP和单独的HPV26N0 VLP进行免疫，对照亚组4用混合的HPV51/HPV69/HPV26 VLP(即，HPV51N9VLP、HPV69N0 VLP和HPV26N0 VLP的混合物，其中每种VLP均以指定的免疫剂量施用)进行免疫，实验亚组1、2、3、4、5、6、7、8分别用H51N9-69T1-26S2 VLP、H51N9-69T1-26S3 VLP、H51N9-69T1-26S4 VLP、H51N9-69T1-26S5VLP、H51N9-69T3-26S1 VLP、H51N9-69T3-26S2VLP、H51N9-69T3-26S4 VLP和H51N9-69T3-26S5 VLP进行免疫。
对于铝佐剂组1-2，采用腹腔注射方式免疫5只小鼠/亚组，免疫剂量分别为5μg和1μg，注射体积为1ml。所有小鼠均在第0周进行初次免疫，然后在第2和4周各自进行加强免疫一次。在第8周对小鼠进行眼眶采血，并分析血清中的抗HPV51、HPV69和HPV26抗体的滴度。分析结果如图11A和图11B所示。结果显示，H51N9-69T1-26S2 VLP、H51N9-69T3-26S1 VLP和H51N9-69T3-26S2 VLP能诱导小鼠产生高滴度的针对HPV51的中和抗体，其保护效果与同剂量的单独的HPV51N9 VLP、混合的HPV51/HPV69/HPV26 VLP相当，且显著优于同剂量的单独的HPV69N0 VLP和单独的HPV26N0 VLP；H51N9-69T1-26S2 VLP、H51N9-69T3-26S1 VLP和H51N9-69T3-26S2 VLP也能诱导小鼠产生较高滴度的针对HPV69的中和抗体，其保护效果与同剂量的单独的HPV69N0 VLP、混合的HPV51/HPV69/HPV26 VLP相当，但显著优于同剂量的单独的HPV51N9 VLP。H51N9-69T1-26S2 VLP、H51N9-69T3-26S1 VLP和H51N9-69T3-26S2VLP也能诱导小鼠产生较高滴度的针对HPV26的中和抗体，其保护效果与同剂量的单独的HPV26N0 VLP、混合的HPV51/HPV69/HPV26 VLP相当，但显著优于同剂量的单独的HPV51N9VLP。这表明，H51N9-69T1-26S2 VLP、H51N9-69T3-26S1 VLP和H51N9-69T3-26S2 VLP对HPV51、HPV69和HPV26具有良好的交叉免疫原性和交叉保护性。
表5免疫方案
Figure BDA0002215675900000601
Figure BDA0002215675900000611
实施例5：用病毒样颗粒免疫后小鼠血清中的中和抗体滴度的评价3
本实验中，所用病毒样颗粒为：H51N9-69T2-26S1 VLP、H51N9-69T2-26S3 VLP、H51N9-69T2-26S4 VLP、H51N9-69T2-26S5 VLP、H51N9-69T4-26S1 VLP、H51N9-69T4-26S2VLP、H51N9-69T4-26S3 VLP、H51N9-69T4-26S5 VLP。
在本实验中，免疫方案如表6所示。将所有小鼠(6周龄BalB/c雌性小鼠)分为2个组:铝佐剂组1(免疫剂量为5μg，使用铝佐剂)，铝佐剂组2(免疫剂量为1μg，使用铝佐剂)。各个组又细分为12个亚组，对照亚组1、2和3分别用单独的HPV51N9 VLP、单独的HPV69N0 VLP和单独的HPV26N0 VLP进行免疫，对照亚组4用混合的HPV51/HPV69/HPV26 VLP(即，HPV51N9VLP、HPV69N0 VLP和HPV26N0 VLP的混合物，其中每种VLP均以指定的免疫剂量施用)进行免疫，实验亚组1、2、3、4、5、6、7、8分别用H51N9-69T2-26S1 VLP、H51N9-69T2-26S3 VLP、H51N9-69T2-26S4 VLP、H51N9-69T2-26S5VLP、H51N9-69T4-26S1 VLP、H51N9-69T4-26S2VLP、H51N9-69T4-26S3 VLP和H51N9-69T4-26S5 VLP进行免疫。
对于铝佐剂组1-2，采用腹腔注射方式免疫5只小鼠/亚组，免疫剂量分别为5μg和1μg，注射体积为1ml。所有小鼠均在第0周进行初次免疫，然后在第2和4周各自进行加强免疫一次。在第8周对小鼠进行眼眶采血，并分析血清中的抗HPV51、HPV69和HPV26抗体的滴度。分析结果如图12A和图12B所示。结果显示，H51N9-69T2-26S3 VLP和H51N9-69T4-26S2 VLP能诱导小鼠产生高滴度的针对HPV51的中和抗体，其保护效果与同剂量的单独的HPV51N9VLP、混合的HPV51/HPV69/HPV26 VLP相当，且显著优于同剂量的单独的HPV69N0VLP和单独的HPV26N0 VLP。H51N9-69T2-26S3 VLP和H51N9-69T4-26S2 VLP也能诱导小鼠产生较高滴度的针对HPV69的中和抗体，其保护效果与同剂量的单独的HPV69N0 VLP、混合的HPV51/HPV69/HPV26 VLP相当，且显著优于同剂量的单独的HPV51N9 VLP。H51N9-69T2-26S3VLP和H51N9-69T4-26S2 VLP也能诱导小鼠产生较高滴度的针对HPV26的中和抗体，其保护效果与同剂量的单独的HPV26N0 VLP、混合的HPV51/HPV69/HPV26 VLP相当，且显著优于同剂量的单独的HPV51N9 VLP。这表明，H51N9-69T2-26S3 VLP和H51N9-69T4-26S2 VLP对HPV51、HPV69和HPV26具有良好的交叉免疫原性和交叉保护性。
表6免疫方案
Figure BDA0002215675900000621
Figure BDA0002215675900000631
实施例6：病毒样颗粒诱导血清转换的ED50的评价
本实验中，所用病毒样颗粒为H51N9-69T1-26S2 VLP、H51N9-69T2-26S3 VLP、H51N9-69T3-26S1 VLP和H51N9-69T4-26S2 VLP
采用铝佐剂、单次腹腔注射方式对6周龄的BalB/c雌鼠(8只)进行免疫，其中，实验组使用H51N9-69T1-26S2 VLP、H51N9-69T2-26S3 VLP、H51N9-69T3-26S1 VLP或H51N9-69T4-26S2VLP(免疫剂量为0.900μg、0.300μg、0.100μg、0.033μg或0.011μg)；对照组使用单独的HPV51N9 VLP、单独的HPV69N0 VLP或单独的HPV26N0 VLP(免疫剂量为0.900μg、0.300μg、0.100μg、0.033μg或0.011μg)，或者混合的HPV51/HPV69/HPV26 VLP(即，HPV51N9 VLP、HPV69N0 VLP和HPV26N10 VLP的混合物，每种VLP的免疫剂量各为0.900μg、0.300μg、0.100μg、0.033μg、0.011μg)；免疫体积为1mL。另外，还将用于稀释疫苗的稀释液用作空白对照。每组免疫8只小鼠，并且在免疫后第五周，抽取眼球静脉血，检测血清中的HPV抗体，并通过Reed-Muench法(Reed LJ MH.A simple method of estimating fifty percentendpoints.Am J Hyg.1938；27:493-7)来计算各个样品诱导血清转换(即，诱导小鼠产生抗体)的ED50。结果如表7所示。
表7H51N9-69T1-26S2 VLP、H51N9-69T2-26S3 VLP、H51N9-69T3-26S1 VLP和H51N9-69T4-26S2 VLP诱导小鼠产生抗HPV51、抗HPV69和抗HPV26抗体(血清转换)的ED50
Figure BDA0002215675900000641
结果显示，在免疫小鼠5周后，H51N9-69T2-26S3 VLP、H51N9-69T3-26S1 VLP和H51N9-69T4-26S2 VLP诱导小鼠产生抗HPV51的ED50与单独的HPV51N9 VLP以及混合的HPV51/HPV69/HPV26 VLP相当，且显著优于单独的HPV69N0 VLP和单独的HPV26N0 VLP；并且，其诱导小鼠产生抗HP69的ED50与单独的HPV69N0 VLP以及混合的HPV51/HPV69/HPV26VLP相当，且显著优于单独的HPV51N0 VLP；并且，其诱导小鼠产生抗HPV26的ED50与单独的HPV26N0 VLP以及混合的HPV69/HPV51/HPV26 VLP相当，且显著优于单独的HPV51N9 VLP。这表明，H51N9-69T2-26S3 VLP、H51N9-69T3-26S1 VLP和H51N9-69T4-26S2 VLP对HPV39、HPV68以及HPV70具有良好的交叉免疫原性和交叉保护性。
尽管本发明的具体实施方式已经得到详细的描述，本领域技术人员将会理解，根据已经公开的所有教导，可以对那些细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
SEQUENCE LISTING
<110> 厦门大学
厦门万泰沧海生物技术有限公司
<120> 一种人乳头瘤病毒51型L1蛋白的突变体
<130> IDC180158
<150> CN201811122822.1
<151> 2018-09-26
<160> 144
<170> PatentIn version 3.5
<210> 1
<211> 504
<212> PRT
<213> Human papillomavirus type 51
<400> 1
Met Ala Leu Trp Arg Thr Asn Asp Ser Lys Val Tyr Leu Pro Pro Ala
1 5 10 15
Pro Val Ser Arg Ile Val Asn Thr Glu Glu Tyr Ile Thr Arg Thr Gly
20 25 30
Ile Tyr Tyr Tyr Ala Gly Ser Ser Arg Leu Ile Thr Leu Gly His Pro
35 40 45
Tyr Phe Pro Leu Pro Lys Thr Ser Thr Arg Ala Ala Ile Pro Lys Val
50 55 60
Ser Ala Phe Gln Tyr Arg Val Phe Arg Val Gln Leu Pro Asp Pro Asn
65 70 75 80
Lys Phe Gly Leu Pro Asp Pro Asn Leu Tyr Asn Pro Asp Thr Asp Arg
85 90 95
Leu Val Trp Gly Cys Val Gly Val Glu Val Gly Arg Gly Gln Pro Leu
100 105 110
Gly Val Gly Leu Ser Gly His Pro Leu Phe Asn Lys Tyr Asp Asp Thr
115 120 125
Glu Asn Ser Arg Ile Ala Asn Gly Asn Ala Gln Gln Asp Val Arg Asp
130 135 140
Asn Thr Ser Val Asp Asn Lys Gln Thr Gln Leu Cys Ile Ile Gly Cys
145 150 155 160
Ala Pro Pro Ile Gly Glu His Trp Gly Ile Gly Thr Thr Cys Lys Asn
165 170 175
Thr Pro Val Pro Pro Gly Asp Cys Pro Pro Leu Glu Leu Val Ser Ser
180 185 190
Val Ile Gln Asp Gly Asp Met Ile Asp Thr Gly Phe Gly Ala Met Asp
195 200 205
Phe Ala Ala Leu Gln Ala Thr Lys Ser Asp Val Pro Leu Asp Ile Ser
210 215 220
Gln Ser Val Cys Lys Tyr Pro Asp Tyr Leu Lys Met Ser Ala Asp Thr
225 230 235 240
Tyr Gly Asn Ser Met Phe Phe His Leu Arg Arg Glu Gln Ile Phe Ala
245 250 255
Arg His Tyr Tyr Asn Lys Leu Gly Ser Val Gly Glu Asp Ile Pro Thr
260 265 270
Asp Tyr Tyr Ile Lys Gly Ser Gly Asn Gly Arg Asp Pro Ile Glu Ser
275 280 285
Tyr Ile Tyr Ser Ala Thr Pro Ser Gly Ser Met Ile Thr Ser Asp Ser
290 295 300
Gln Ile Phe Asn Lys Pro Tyr Trp Leu His Arg Ala Gln Gly His Asn
305 310 315 320
Asn Gly Ile Cys Trp Asn Asn Gln Leu Phe Ile Thr Cys Val Asp Thr
325 330 335
Thr Arg Ser Thr Asn Leu Thr Ile Ser Thr Ala Thr Ala Ala Val Ser
340 345 350
Pro Thr Phe Thr Pro Ser Asn Phe Lys Gln Tyr Ile Arg His Gly Glu
355 360 365
Glu Tyr Glu Leu Gln Phe Ile Phe Gln Leu Cys Lys Ile Thr Leu Thr
370 375 380
Thr Glu Val Met Ala Tyr Leu His Thr Met Asp Pro Thr Ile Leu Glu
385 390 395 400
Gln Trp Asn Phe Gly Leu Thr Leu Pro Pro Ser Ala Ser Leu Glu Asp
405 410 415
Ala Tyr Arg Phe Val Arg Asn Ala Ala Thr Ser Cys Gln Lys Asp Thr
420 425 430
Pro Pro Gln Ala Lys Pro Asp Pro Leu Ala Lys Tyr Lys Phe Trp Asp
435 440 445
Val Asp Leu Lys Glu Arg Phe Ser Leu Asp Leu Asp Gln Phe Ala Leu
450 455 460
Gly Arg Lys Phe Leu Leu Gln Val Gly Val Gln Arg Lys Pro Arg Pro
465 470 475 480
Gly Leu Lys Arg Pro Ala Ser Ser Ala Ser Ser Ser Ser Ser Ser Ser
485 490 495
Ala Lys Arg Lys Arg Val Lys Lys
500
<210> 2
<211> 508
<212> PRT
<213> Human papillomavirus type 69
<400> 2
Met Ala Leu Trp Arg Thr Ser Asp Ser Lys Val Tyr Leu Pro Pro Thr
1 5 10 15
Pro Val Ser Arg Val Val Ser Thr Asp Glu Tyr Val Thr Arg Thr Gly
20 25 30
Ile Tyr Tyr Tyr Ala Gly Ser Ser Arg Leu Leu Thr Leu Gly His Pro
35 40 45
Tyr Phe Pro Ile Pro Lys Ser Gly Ser Thr Ala Glu Ile Pro Lys Val
50 55 60
Ser Ala Tyr Gln Tyr Arg Val Phe Arg Val His Leu Pro Asp Pro Asn
65 70 75 80
Lys Phe Gly Leu Pro Asp Pro Gln Leu Tyr Asn Pro Glu Thr Glu Arg
85 90 95
Leu Val Trp Ala Cys Val Gly Val Glu Val Gly Arg Gly Gln Pro Leu
100 105 110
Gly Val Gly Leu Ser Gly His Pro Leu Phe Asn Lys Leu Asp Asp Thr
115 120 125
Glu Asn Ser His Leu Ala Thr Ala Asn Ala Asp Thr Asp Asn Arg Asp
130 135 140
Asn Val Cys Val Asp Asn Lys Gln Thr Gln Leu Cys Ile Ile Gly Cys
145 150 155 160
Thr Pro Pro Leu Gly Glu His Trp Gly Val Gly Thr Val Cys Lys Asn
165 170 175
Ala Gln Ser Gln Val Gln Arg Gly Asp Cys Pro Pro Leu Glu Leu Ile
180 185 190
Ser Ser Val Ile Glu Asp Gly Asp Met Ile Asp Thr Gly Phe Gly Ala
195 200 205
Met Asp Phe Thr Ala Leu Gln Ala Thr Lys Cys Asp Val Pro Leu Asp
210 215 220
Ile Asn Gln Ser Ile Cys Lys Tyr Pro Asp Tyr Leu Lys Met Ser Ala
225 230 235 240
Asp Thr Tyr Gly Asn Ser Met Phe Phe Phe Leu Arg Arg Glu Gln Leu
245 250 255
Phe Ala Arg His Phe Phe Asn Lys Ala Gly Thr Ile Gly Asp Pro Val
260 265 270
Pro Val Ser Met Tyr Ile Lys Gly Ala Gly Gln Gly Arg Glu Pro Pro
275 280 285
Thr Thr Ser Ile Tyr Ser Ala Thr Pro Ser Gly Ser Met Val Thr Ser
290 295 300
Asp Ala Gln Leu Phe Asn Lys Pro Tyr Trp Leu Gln Arg Ala Gln Gly
305 310 315 320
His Asn Asn Gly Ile Cys Trp Gly Asn Gln Leu Phe Val Thr Cys Val
325 330 335
Asp Thr Thr Arg Ser Thr Asn Leu Thr Ile Ser Thr Val Ser Ala Gln
340 345 350
Ser Ala Ser Ala Thr Phe Lys Pro Ser Asp Tyr Lys Gln Phe Ile Arg
355 360 365
His Gly Glu Glu Tyr Glu Leu Gln Phe Ile Phe Gln Leu Cys Lys Ile
370 375 380
Thr Leu Thr Thr Asp Val Met Ala Tyr Ile His Thr Met Asn Ser Thr
385 390 395 400
Ile Leu Glu Asn Trp Asn Phe Gly Leu Thr Leu Pro Pro Thr Ala Ser
405 410 415
Leu Glu Asp Ala Tyr Arg Phe Ile Lys Asn Ser Ala Thr Thr Cys Gln
420 425 430
Arg Asp Ala Pro Ala Gln Pro Lys Glu Asp Pro Phe Ser Lys Leu Lys
435 440 445
Phe Trp Asp Val Asp Leu Lys Glu Lys Phe Ser Ile Asp Leu Asp Gln
450 455 460
Phe Pro Leu Gly Arg Lys Phe Met Leu Gln Ala Gly Ile Gln Arg Arg
465 470 475 480
Pro Lys Leu Gly Thr Lys Arg Pro Ala Ser Ser Leu Ser Ala Ser Ser
485 490 495
Ser Ser Thr Thr Arg Lys Lys Arg Lys Leu Thr Lys
500 505
<210> 3
<211> 496
<212> PRT
<213> Human papillomavirus type 51
<400> 3
Met Lys Val Tyr Leu Pro Pro Ala Pro Val Ser Arg Ile Val Asn Thr
1 5 10 15
Glu Glu Tyr Ile Thr Arg Thr Gly Ile Tyr Tyr Tyr Ala Gly Ser Ser
20 25 30
Arg Leu Ile Thr Leu Gly His Pro Tyr Phe Pro Leu Pro Lys Thr Ser
35 40 45
Thr Arg Ala Ala Ile Pro Lys Val Ser Ala Phe Gln Tyr Arg Val Phe
50 55 60
Arg Val Gln Leu Pro Asp Pro Asn Lys Phe Gly Leu Pro Asp Pro Asn
65 70 75 80
Leu Tyr Asn Pro Asp Thr Asp Arg Leu Val Trp Gly Cys Val Gly Val
85 90 95
Glu Val Gly Arg Gly Gln Pro Leu Gly Val Gly Leu Ser Gly His Pro
100 105 110
Leu Phe Asn Lys Tyr Asp Asp Thr Glu Asn Ser Arg Ile Ala Asn Gly
115 120 125
Asn Ala Gln Gln Asp Val Arg Asp Asn Thr Ser Val Asp Asn Lys Gln
130 135 140
Thr Gln Leu Cys Ile Ile Gly Cys Ala Pro Pro Ile Gly Glu His Trp
145 150 155 160
Gly Ile Gly Thr Thr Cys Lys Asn Thr Pro Val Pro Pro Gly Asp Cys
165 170 175
Pro Pro Leu Glu Leu Val Ser Ser Val Ile Gln Asp Gly Asp Met Ile
180 185 190
Asp Thr Gly Phe Gly Ala Met Asp Phe Ala Ala Leu Gln Ala Thr Lys
195 200 205
Ser Asp Val Pro Leu Asp Ile Ser Gln Ser Val Cys Lys Tyr Pro Asp
210 215 220
Tyr Leu Lys Met Ser Ala Asp Thr Tyr Gly Asn Ser Met Phe Phe His
225 230 235 240
Leu Arg Arg Glu Gln Ile Phe Ala Arg His Tyr Tyr Asn Lys Leu Gly
245 250 255
Ser Val Gly Glu Asp Ile Pro Thr Asp Tyr Tyr Ile Lys Gly Ser Gly
260 265 270
Asn Gly Arg Asp Pro Ile Glu Ser Tyr Ile Tyr Ser Ala Thr Pro Ser
275 280 285
Gly Ser Met Ile Thr Ser Asp Ser Gln Ile Phe Asn Lys Pro Tyr Trp
290 295 300
Leu His Arg Ala Gln Gly His Asn Asn Gly Ile Cys Trp Asn Asn Gln
305 310 315 320
Leu Phe Ile Thr Cys Val Asp Thr Thr Arg Ser Thr Asn Leu Thr Ile
325 330 335
Ser Thr Ala Thr Ala Ala Val Ser Pro Thr Phe Thr Pro Ser Asn Phe
340 345 350
Lys Gln Tyr Ile Arg His Gly Glu Glu Tyr Glu Leu Gln Phe Ile Phe
355 360 365
Gln Leu Cys Lys Ile Thr Leu Thr Thr Glu Val Met Ala Tyr Leu His
370 375 380
Thr Met Asp Pro Thr Ile Leu Glu Gln Trp Asn Phe Gly Leu Thr Leu
385 390 395 400
Pro Pro Ser Ala Ser Leu Glu Asp Ala Tyr Arg Phe Val Arg Asn Ala
405 410 415
Ala Thr Ser Cys Gln Lys Asp Thr Pro Pro Gln Ala Lys Pro Asp Pro
420 425 430
Leu Ala Lys Tyr Lys Phe Trp Asp Val Asp Leu Lys Glu Arg Phe Ser
435 440 445
Leu Asp Leu Asp Gln Phe Ala Leu Gly Arg Lys Phe Leu Leu Gln Val
450 455 460
Gly Val Gln Arg Lys Pro Arg Pro Gly Leu Lys Arg Pro Ala Ser Ser
465 470 475 480
Ala Ser Ser Ser Ser Ser Ser Ser Ala Lys Arg Lys Arg Val Lys Lys
485 490 495
<210> 4
<211> 496
<212> PRT
<213> Artificial Sequence
<220>
<223> H51N9-69T1
<400> 4
Met Lys Val Tyr Leu Pro Pro Ala Pro Val Ser Arg Ile Val Asn Thr
1 5 10 15
Glu Glu Tyr Ile Thr Arg Thr Gly Ile Tyr Tyr Tyr Ala Gly Ser Ser
20 25 30
Arg Leu Ile Thr Leu Gly His Pro Tyr Phe Pro Ile Pro Lys Ser Gly
35 40 45
Ser Thr Ala Glu Ile Pro Lys Val Ser Ala Phe Gln Tyr Arg Val Phe
50 55 60
Arg Val Gln Leu Pro Asp Pro Asn Lys Phe Gly Leu Pro Asp Pro Asn
65 70 75 80
Leu Tyr Asn Pro Asp Thr Asp Arg Leu Val Trp Gly Cys Val Gly Val
85 90 95
Glu Val Gly Arg Gly Gln Pro Leu Gly Val Gly Leu Ser Gly His Pro
100 105 110
Leu Phe Asn Lys Tyr Asp Asp Thr Glu Asn Ser Arg Ile Ala Asn Gly
115 120 125
Asn Ala Gln Gln Asp Val Arg Asp Asn Thr Ser Val Asp Asn Lys Gln
130 135 140
Thr Gln Leu Cys Ile Ile Gly Cys Ala Pro Pro Ile Gly Glu His Trp
145 150 155 160
Gly Ile Gly Thr Thr Cys Lys Asn Thr Pro Val Pro Pro Gly Asp Cys
165 170 175
Pro Pro Leu Glu Leu Val Ser Ser Val Ile Gln Asp Gly Asp Met Ile
180 185 190
Asp Thr Gly Phe Gly Ala Met Asp Phe Ala Ala Leu Gln Ala Thr Lys
195 200 205
Ser Asp Val Pro Leu Asp Ile Ser Gln Ser Val Cys Lys Tyr Pro Asp
210 215 220
Tyr Leu Lys Met Ser Ala Asp Thr Tyr Gly Asn Ser Met Phe Phe His
225 230 235 240
Leu Arg Arg Glu Gln Ile Phe Ala Arg His Tyr Tyr Asn Lys Leu Gly
245 250 255
Ser Val Gly Glu Asp Ile Pro Thr Asp Tyr Tyr Ile Lys Gly Ser Gly
260 265 270
Asn Gly Arg Asp Pro Ile Glu Ser Tyr Ile Tyr Ser Ala Thr Pro Ser
275 280 285
Gly Ser Met Ile Thr Ser Asp Ser Gln Ile Phe Asn Lys Pro Tyr Trp
290 295 300
Leu His Arg Ala Gln Gly His Asn Asn Gly Ile Cys Trp Asn Asn Gln
305 310 315 320
Leu Phe Ile Thr Cys Val Asp Thr Thr Arg Ser Thr Asn Leu Thr Ile
325 330 335
Ser Thr Ala Thr Ala Ala Val Ser Pro Thr Phe Thr Pro Ser Asn Phe
340 345 350
Lys Gln Tyr Ile Arg His Gly Glu Glu Tyr Glu Leu Gln Phe Ile Phe
355 360 365
Gln Leu Cys Lys Ile Thr Leu Thr Thr Glu Val Met Ala Tyr Leu His
370 375 380
Thr Met Asp Pro Thr Ile Leu Glu Gln Trp Asn Phe Gly Leu Thr Leu
385 390 395 400
Pro Pro Ser Ala Ser Leu Glu Asp Ala Tyr Arg Phe Val Arg Asn Ala
405 410 415
Ala Thr Ser Cys Gln Lys Asp Thr Pro Pro Gln Ala Lys Pro Asp Pro
420 425 430
Leu Ala Lys Tyr Lys Phe Trp Asp Val Asp Leu Lys Glu Arg Phe Ser
435 440 445
Leu Asp Leu Asp Gln Phe Ala Leu Gly Arg Lys Phe Leu Leu Gln Val
450 455 460
Gly Val Gln Arg Lys Pro Arg Pro Gly Leu Lys Arg Pro Ala Ser Ser
465 470 475 480
Ala Ser Ser Ser Ser Ser Ser Ser Ala Lys Arg Lys Arg Val Lys Lys
485 490 495
<210> 5
<211> 496
<212> PRT
<213> Artificial Sequence
<220>
<223> H51N9-69T2
<400> 5
Met Lys Val Tyr Leu Pro Pro Ala Pro Val Ser Arg Ile Val Asn Thr
1 5 10 15
Glu Glu Tyr Ile Thr Arg Thr Gly Ile Tyr Tyr Tyr Ala Gly Ser Ser
20 25 30
Arg Leu Ile Thr Leu Gly His Pro Tyr Phe Pro Leu Pro Lys Thr Ser
35 40 45
Thr Arg Ala Ala Ile Pro Lys Val Ser Ala Phe Gln Tyr Arg Val Phe
50 55 60
Arg Val Gln Leu Pro Asp Pro Asn Lys Phe Gly Leu Pro Asp Pro Asn
65 70 75 80
Leu Tyr Asn Pro Asp Thr Asp Arg Leu Val Trp Gly Cys Val Gly Val
85 90 95
Glu Val Gly Arg Gly Gln Pro Leu Gly Val Gly Leu Ser Gly His Pro
100 105 110
Leu Phe Asn Lys Leu Asp Asp Thr Glu Asn Ser His Leu Ala Thr Ala
115 120 125
Asn Ala Asp Thr Asp Asn Arg Asp Asn Val Cys Val Asp Asn Lys Gln
130 135 140
Thr Gln Leu Cys Ile Ile Gly Cys Ala Pro Pro Ile Gly Glu His Trp
145 150 155 160
Gly Ile Gly Thr Thr Cys Lys Asn Thr Pro Val Pro Pro Gly Asp Cys
165 170 175
Pro Pro Leu Glu Leu Val Ser Ser Val Ile Gln Asp Gly Asp Met Ile
180 185 190
Asp Thr Gly Phe Gly Ala Met Asp Phe Ala Ala Leu Gln Ala Thr Lys
195 200 205
Ser Asp Val Pro Leu Asp Ile Ser Gln Ser Val Cys Lys Tyr Pro Asp
210 215 220
Tyr Leu Lys Met Ser Ala Asp Thr Tyr Gly Asn Ser Met Phe Phe His
225 230 235 240
Leu Arg Arg Glu Gln Ile Phe Ala Arg His Tyr Tyr Asn Lys Leu Gly
245 250 255
Ser Val Gly Glu Asp Ile Pro Thr Asp Tyr Tyr Ile Lys Gly Ser Gly
260 265 270
Asn Gly Arg Asp Pro Ile Glu Ser Tyr Ile Tyr Ser Ala Thr Pro Ser
275 280 285
Gly Ser Met Ile Thr Ser Asp Ser Gln Ile Phe Asn Lys Pro Tyr Trp
290 295 300
Leu His Arg Ala Gln Gly His Asn Asn Gly Ile Cys Trp Asn Asn Gln
305 310 315 320
Leu Phe Ile Thr Cys Val Asp Thr Thr Arg Ser Thr Asn Leu Thr Ile
325 330 335
Ser Thr Ala Thr Ala Ala Val Ser Pro Thr Phe Thr Pro Ser Asn Phe
340 345 350
Lys Gln Tyr Ile Arg His Gly Glu Glu Tyr Glu Leu Gln Phe Ile Phe
355 360 365
Gln Leu Cys Lys Ile Thr Leu Thr Thr Glu Val Met Ala Tyr Leu His
370 375 380
Thr Met Asp Pro Thr Ile Leu Glu Gln Trp Asn Phe Gly Leu Thr Leu
385 390 395 400
Pro Pro Ser Ala Ser Leu Glu Asp Ala Tyr Arg Phe Val Arg Asn Ala
405 410 415
Ala Thr Ser Cys Gln Lys Asp Thr Pro Pro Gln Ala Lys Pro Asp Pro
420 425 430
Leu Ala Lys Tyr Lys Phe Trp Asp Val Asp Leu Lys Glu Arg Phe Ser
435 440 445
Leu Asp Leu Asp Gln Phe Ala Leu Gly Arg Lys Phe Leu Leu Gln Val
450 455 460
Gly Val Gln Arg Lys Pro Arg Pro Gly Leu Lys Arg Pro Ala Ser Ser
465 470 475 480
Ala Ser Ser Ser Ser Ser Ser Ser Ala Lys Arg Lys Arg Val Lys Lys
485 490 495
<210> 6
<211> 498
<212> PRT
<213> Artificial Sequence
<220>
<223> H51N9-69T3
<400> 6
Met Lys Val Tyr Leu Pro Pro Ala Pro Val Ser Arg Ile Val Asn Thr
1 5 10 15
Glu Glu Tyr Ile Thr Arg Thr Gly Ile Tyr Tyr Tyr Ala Gly Ser Ser
20 25 30
Arg Leu Ile Thr Leu Gly His Pro Tyr Phe Pro Leu Pro Lys Thr Ser
35 40 45
Thr Arg Ala Ala Ile Pro Lys Val Ser Ala Phe Gln Tyr Arg Val Phe
50 55 60
Arg Val Gln Leu Pro Asp Pro Asn Lys Phe Gly Leu Pro Asp Pro Asn
65 70 75 80
Leu Tyr Asn Pro Asp Thr Asp Arg Leu Val Trp Gly Cys Val Gly Val
85 90 95
Glu Val Gly Arg Gly Gln Pro Leu Gly Val Gly Leu Ser Gly His Pro
100 105 110
Leu Phe Asn Lys Tyr Asp Asp Thr Glu Asn Ser Arg Ile Ala Asn Gly
115 120 125
Asn Ala Gln Gln Asp Val Arg Asp Asn Thr Ser Val Asp Asn Lys Gln
130 135 140
Thr Gln Leu Cys Ile Ile Gly Cys Ala Pro Pro Ile Gly Glu His Trp
145 150 155 160
Gly Val Gly Thr Val Cys Lys Asn Ala Gln Ser Gln Val Gln Arg Gly
165 170 175
Asp Cys Pro Pro Leu Glu Leu Val Ser Ser Val Ile Gln Asp Gly Asp
180 185 190
Met Ile Asp Thr Gly Phe Gly Ala Met Asp Phe Ala Ala Leu Gln Ala
195 200 205
Thr Lys Ser Asp Val Pro Leu Asp Ile Ser Gln Ser Val Cys Lys Tyr
210 215 220
Pro Asp Tyr Leu Lys Met Ser Ala Asp Thr Tyr Gly Asn Ser Met Phe
225 230 235 240
Phe His Leu Arg Arg Glu Gln Ile Phe Ala Arg His Tyr Tyr Asn Lys
245 250 255
Leu Gly Ser Val Gly Glu Asp Ile Pro Thr Asp Tyr Tyr Ile Lys Gly
260 265 270
Ser Gly Asn Gly Arg Asp Pro Ile Glu Ser Tyr Ile Tyr Ser Ala Thr
275 280 285
Pro Ser Gly Ser Met Ile Thr Ser Asp Ser Gln Ile Phe Asn Lys Pro
290 295 300
Tyr Trp Leu His Arg Ala Gln Gly His Asn Asn Gly Ile Cys Trp Asn
305 310 315 320
Asn Gln Leu Phe Ile Thr Cys Val Asp Thr Thr Arg Ser Thr Asn Leu
325 330 335
Thr Ile Ser Thr Ala Thr Ala Ala Val Ser Pro Thr Phe Thr Pro Ser
340 345 350
Asn Phe Lys Gln Tyr Ile Arg His Gly Glu Glu Tyr Glu Leu Gln Phe
355 360 365
Ile Phe Gln Leu Cys Lys Ile Thr Leu Thr Thr Glu Val Met Ala Tyr
370 375 380
Leu His Thr Met Asp Pro Thr Ile Leu Glu Gln Trp Asn Phe Gly Leu
385 390 395 400
Thr Leu Pro Pro Ser Ala Ser Leu Glu Asp Ala Tyr Arg Phe Val Arg
405 410 415
Asn Ala Ala Thr Ser Cys Gln Lys Asp Thr Pro Pro Gln Ala Lys Pro
420 425 430
Asp Pro Leu Ala Lys Tyr Lys Phe Trp Asp Val Asp Leu Lys Glu Arg
435 440 445
Phe Ser Leu Asp Leu Asp Gln Phe Ala Leu Gly Arg Lys Phe Leu Leu
450 455 460
Gln Val Gly Val Gln Arg Lys Pro Arg Pro Gly Leu Lys Arg Pro Ala
465 470 475 480
Ser Ser Ala Ser Ser Ser Ser Ser Ser Ser Ala Lys Arg Lys Arg Val
485 490 495
Lys Lys
<210> 7
<211> 496
<212> PRT
<213> Artificial Sequence
<220>
<223> H51N9-69T4
<400> 7
Met Lys Val Tyr Leu Pro Pro Ala Pro Val Ser Arg Ile Val Asn Thr
1 5 10 15
Glu Glu Tyr Ile Thr Arg Thr Gly Ile Tyr Tyr Tyr Ala Gly Ser Ser
20 25 30
Arg Leu Ile Thr Leu Gly His Pro Tyr Phe Pro Leu Pro Lys Thr Ser
35 40 45
Thr Arg Ala Ala Ile Pro Lys Val Ser Ala Phe Gln Tyr Arg Val Phe
50 55 60
Arg Val Gln Leu Pro Asp Pro Asn Lys Phe Gly Leu Pro Asp Pro Asn
65 70 75 80
Leu Tyr Asn Pro Asp Thr Asp Arg Leu Val Trp Gly Cys Val Gly Val
85 90 95
Glu Val Gly Arg Gly Gln Pro Leu Gly Val Gly Leu Ser Gly His Pro
100 105 110
Leu Phe Asn Lys Tyr Asp Asp Thr Glu Asn Ser Arg Ile Ala Asn Gly
115 120 125
Asn Ala Gln Gln Asp Val Arg Asp Asn Thr Ser Val Asp Asn Lys Gln
130 135 140
Thr Gln Leu Cys Ile Ile Gly Cys Ala Pro Pro Ile Gly Glu His Trp
145 150 155 160
Gly Ile Gly Thr Thr Cys Lys Asn Thr Pro Val Pro Pro Gly Asp Cys
165 170 175
Pro Pro Leu Glu Leu Val Ser Ser Val Ile Gln Asp Gly Asp Met Ile
180 185 190
Asp Thr Gly Phe Gly Ala Met Asp Phe Ala Ala Leu Gln Ala Thr Lys
195 200 205
Ser Asp Val Pro Leu Asp Ile Ser Gln Ser Val Cys Lys Tyr Pro Asp
210 215 220
Tyr Leu Lys Met Ser Ala Asp Thr Tyr Gly Asn Ser Met Phe Phe His
225 230 235 240
Leu Arg Arg Glu Gln Ile Phe Ala Arg His Phe Phe Asn Lys Ala Gly
245 250 255
Thr Ile Gly Asp Pro Val Pro Val Ser Met Tyr Ile Lys Gly Ala Gly
260 265 270
Gln Gly Arg Glu Pro Pro Thr Thr Ser Ile Tyr Ser Ala Thr Pro Ser
275 280 285
Gly Ser Met Ile Thr Ser Asp Ser Gln Ile Phe Asn Lys Pro Tyr Trp
290 295 300
Leu His Arg Ala Gln Gly His Asn Asn Gly Ile Cys Trp Asn Asn Gln
305 310 315 320
Leu Phe Ile Thr Cys Val Asp Thr Thr Arg Ser Thr Asn Leu Thr Ile
325 330 335
Ser Thr Ala Thr Ala Ala Val Ser Pro Thr Phe Thr Pro Ser Asn Phe
340 345 350
Lys Gln Tyr Ile Arg His Gly Glu Glu Tyr Glu Leu Gln Phe Ile Phe
355 360 365
Gln Leu Cys Lys Ile Thr Leu Thr Thr Glu Val Met Ala Tyr Leu His
370 375 380
Thr Met Asp Pro Thr Ile Leu Glu Gln Trp Asn Phe Gly Leu Thr Leu
385 390 395 400
Pro Pro Ser Ala Ser Leu Glu Asp Ala Tyr Arg Phe Val Arg Asn Ala
405 410 415
Ala Thr Ser Cys Gln Lys Asp Thr Pro Pro Gln Ala Lys Pro Asp Pro
420 425 430
Leu Ala Lys Tyr Lys Phe Trp Asp Val Asp Leu Lys Glu Arg Phe Ser
435 440 445
Leu Asp Leu Asp Gln Phe Ala Leu Gly Arg Lys Phe Leu Leu Gln Val
450 455 460
Gly Val Gln Arg Lys Pro Arg Pro Gly Leu Lys Arg Pro Ala Ser Ser
465 470 475 480
Ala Ser Ser Ser Ser Ser Ser Ser Ala Lys Arg Lys Arg Val Lys Lys
485 490 495
<210> 8
<211> 497
<212> PRT
<213> Artificial Sequence
<220>
<223> H51N9-69T5
<400> 8
Met Lys Val Tyr Leu Pro Pro Ala Pro Val Ser Arg Ile Val Asn Thr
1 5 10 15
Glu Glu Tyr Ile Thr Arg Thr Gly Ile Tyr Tyr Tyr Ala Gly Ser Ser
20 25 30
Arg Leu Ile Thr Leu Gly His Pro Tyr Phe Pro Leu Pro Lys Thr Ser
35 40 45
Thr Arg Ala Ala Ile Pro Lys Val Ser Ala Phe Gln Tyr Arg Val Phe
50 55 60
Arg Val Gln Leu Pro Asp Pro Asn Lys Phe Gly Leu Pro Asp Pro Asn
65 70 75 80
Leu Tyr Asn Pro Asp Thr Asp Arg Leu Val Trp Gly Cys Val Gly Val
85 90 95
Glu Val Gly Arg Gly Gln Pro Leu Gly Val Gly Leu Ser Gly His Pro
100 105 110
Leu Phe Asn Lys Tyr Asp Asp Thr Glu Asn Ser Arg Ile Ala Asn Gly
115 120 125
Asn Ala Gln Gln Asp Val Arg Asp Asn Thr Ser Val Asp Asn Lys Gln
130 135 140
Thr Gln Leu Cys Ile Ile Gly Cys Ala Pro Pro Ile Gly Glu His Trp
145 150 155 160
Gly Ile Gly Thr Thr Cys Lys Asn Thr Pro Val Pro Pro Gly Asp Cys
165 170 175
Pro Pro Leu Glu Leu Val Ser Ser Val Ile Gln Asp Gly Asp Met Ile
180 185 190
Asp Thr Gly Phe Gly Ala Met Asp Phe Ala Ala Leu Gln Ala Thr Lys
195 200 205
Ser Asp Val Pro Leu Asp Ile Ser Gln Ser Val Cys Lys Tyr Pro Asp
210 215 220
Tyr Leu Lys Met Ser Ala Asp Thr Tyr Gly Asn Ser Met Phe Phe His
225 230 235 240
Leu Arg Arg Glu Gln Ile Phe Ala Arg His Tyr Tyr Asn Lys Leu Gly
245 250 255
Ser Val Gly Glu Asp Ile Pro Thr Asp Tyr Tyr Ile Lys Gly Ser Gly
260 265 270
Asn Gly Arg Asp Pro Ile Glu Ser Tyr Ile Tyr Ser Ala Thr Pro Ser
275 280 285
Gly Ser Met Ile Thr Ser Asp Ser Gln Ile Phe Asn Lys Pro Tyr Trp
290 295 300
Leu His Arg Ala Gln Gly His Asn Asn Gly Ile Cys Trp Asn Asn Gln
305 310 315 320
Leu Phe Ile Thr Cys Val Asp Thr Thr Arg Ser Thr Asn Leu Thr Ile
325 330 335
Ser Thr Ala Ser Ala Gln Ser Ala Ser Ala Thr Phe Lys Pro Ser Asp
340 345 350
Phe Lys Gln Tyr Ile Arg His Gly Glu Glu Tyr Glu Leu Gln Phe Ile
355 360 365
Phe Gln Leu Cys Lys Ile Thr Leu Thr Thr Glu Val Met Ala Tyr Leu
370 375 380
His Thr Met Asp Pro Thr Ile Leu Glu Gln Trp Asn Phe Gly Leu Thr
385 390 395 400
Leu Pro Pro Ser Ala Ser Leu Glu Asp Ala Tyr Arg Phe Val Arg Asn
405 410 415
Ala Ala Thr Ser Cys Gln Lys Asp Thr Pro Pro Gln Ala Lys Pro Asp
420 425 430
Pro Leu Ala Lys Tyr Lys Phe Trp Asp Val Asp Leu Lys Glu Arg Phe
435 440 445
Ser Leu Asp Leu Asp Gln Phe Ala Leu Gly Arg Lys Phe Leu Leu Gln
450 455 460
Val Gly Val Gln Arg Lys Pro Arg Pro Gly Leu Lys Arg Pro Ala Ser
465 470 475 480
Ser Ala Ser Ser Ser Ser Ser Ser Ser Ala Lys Arg Lys Arg Val Lys
485 490 495
Lys
<210> 9
<211> 1515
<212> DNA
<213> Human papillomavirus type 51
<400> 9
atggccctgt ggaggaccaa cgacagcaag gtgtacctgc cccccgcccc cgtgagcagg 60
atcgtgaaca ccgaggagta catcaccagg accggcatct actactacgc cggcagcagc 120
aggctgatca ccctgggcca cccctacttc cccctgccca agaccagcac cagggccgcc 180
atccccaagg tgagcgcctt ccagtacagg gtgttcaggg tgcagctccc cgaccccaac 240
aagttcggcc tgcccgaccc caacctgtac aaccccgaca ccgacaggct ggtgtggggc 300
tgcgtgggcg tggaggtggg caggggccag cccctgggcg tgggcctgag cggccacccc 360
ctgttcaaca agtacgacga caccgagaac agcaggatcg ccaacggcaa cgcccagcag 420
gacgtgaggg acaacaccag cgtggacaac aagcagaccc agctgtgcat catcggctgc 480
gcccccccca tcggcgagca ctggggcatc ggcaccacct gcaagaacac ccccgtgccc 540
cccggcgact gcccccccct ggagctggtg agcagcgtga tccaggacgg cgacatgatc 600
gacaccggct tcggcgccat ggacttcgcc gccctgcagg ccaccaagag cgacgtgccc 660
ctggacatca gccagagcgt gtgcaagtac cccgactacc tgaagatgag cgccgacacc 720
tacggcaaca gcatgttctt ccacctgagg agggagcaga tcttcgccag gcactactac 780
aacaagctgg gcagcgtggg cgaggacatc cccaccgact actacatcaa gggcagcggc 840
aacggcaggg accccatcga gagctacatc tacagcgcca cccccagcgg cagcatgatc 900
accagcgaca gccagatctt caacaagccc tactggctgc acagggccca gggccacaac 960
aacggcatct gctggaacaa ccagctgttc atcacctgcg tggacaccac caggagcacc 1020
aacctgacca tcagcaccgc caccgccgcc gtgagcccca ccttcacccc cagcaacttc 1080
aagcagtaca tcaggcacgg cgaggagtac gagctgcagt tcatcttcca gctgtgcaag 1140
atcaccctga ccaccgaggt gatggcctac ctgcacacca tggaccccac catcctggag 1200
cagtggaact tcggcctgac cctgcccccc agcgccagcc tggaggacgc ctacaggttc 1260
gtgaggaacg ccgccaccag ctgccagaag gacacccccc cccaggccaa gcccgacccc 1320
ctggccaagt acaagttctg ggacgtggac ctgaaggaga ggttcagcct ggacctggac 1380
cagttcgccc tgggcaggaa gttcctgctg caggtgggcg tgcagaggaa gcccaggccc 1440
ggcctgaaga ggcccgctag cagcgccagc tccagcagct ccagcagcgc caagaggaag 1500
agggtgaaga agtaa 1515
<210> 10
<211> 1527
<212> DNA
<213> Human papillomavirus type 69
<400> 10
atggctctgt ggcgtacctc tgactctaaa gtttacctgc cgccgacccc ggtttctcgt 60
gttgtttcta ccgacgaata cgttacccgt accggtatct actactacgc tggttcttct 120
cgtctgctga ccctgggtca cccgtacttc ccgatcccga aatctggttc taccgctgaa 180
atcccgaagg tctctgctta ccagtaccgg gtattccgtg tccacctgcc ggacccgaac 240
aaattcggtc tgccggaccc gcagctgtac aatccagaaa ccgaacgtct ggtttgggct 300
tgcgttggtg tcgaggtcgg tcgtggtcag ccgctgggtg tcggtctgtc tggtcacccg 360
ctgttcaaca aactggacga caccgaaaac tctcacctgg ctaccgctaa cgctgacacc 420
gacaaccgtg acaacgtttg cgttgacaac aaacagaccc agctgtgcat catcggttgc 480
accccgccgc tgggtgaaca ctggggtgtc ggtaccgttt gcaaaaacgc tcagtctcag 540
gttcagcgtg gtgactgccc gccgctggaa ctgatctctt ctgttatcga agacggtgac 600
atgatcgaca ccggtttcgg tgctatggac ttcaccgctc tgcaggctac caaatgcgac 660
gttccgctgg acatcaacca gtctatctgc aaataccccg actacctgaa aatgtctgct 720
gacacctacg gtaactctat gttcttcttc ctgcgtcgtg aacagctgtt cgctcgtcac 780
ttcttcaaca aagctggtac catcggtgac cctgttccgg tttctatgta catcaaaggt 840
gctggtcagg gtcgtgaacc gccgaccaca tccatctact ctgctacccc gtctggttct 900
atggttacat ccgacgctca gctgttcaac aaaccgtact ggctgcagcg tgctcagggt 960
cacaacaacg gtatctgctg gggtaaccag ctgttcgtta cctgcgttga caccacccgt 1020
tctaccaacc tgaccatctc taccgtttct gctcagtctg cttctgctac cttcaaaccg 1080
tctgactaca aacaatttat ccgtcacggt gaagaatacg aactgcagtt catcttccag 1140
ctgtgcaaaa tcaccctgac caccgacgtt atggcttaca tccacaccat gaactctacc 1200
atcctggaaa actggaactt cggtctgacc ctgccgccga ccgcttctct ggaagacgct 1260
taccgtttca tcaaaaactc tgctaccacc tgccagcgtg acgctccggc tcagccgaaa 1320
gaagacccgt tctctaaact gaaattctgg gacgttgacc tgaaagaaaa attctctatc 1380
gacctggacc agttcccgct gggtcgtaaa ttcatgctgc aggctggtat ccagcgtcgt 1440
ccgaaactgg gtaccaaacg tccggcttct tctctgtctg cttcttcttc ttctaccacc 1500
cgtaaaaaac gtaaactgac caaataa 1527
<210> 11
<211> 1491
<212> DNA
<213> Human papillomavirus type 51
<400> 11
atgaaggtgt acctgccccc cgcccccgtg agcaggatcg tgaacaccga ggagtacatc 60
accaggaccg gcatctacta ctacgccggc agcagcaggc tgatcaccct gggccacccc 120
tacttccccc tgcccaagac cagcaccagg gccgccatcc ccaaggtgag cgccttccag 180
tacagggtgt tcagggtgca gctccccgac cccaacaagt tcggcctgcc cgaccccaac 240
ctgtacaacc ccgacaccga caggctggtg tggggctgcg tgggcgtgga ggtgggcagg 300
ggccagcccc tgggcgtggg cctgagcggc caccccctgt tcaacaagta cgacgacacc 360
gagaacagca ggatcgccaa cggcaacgcc cagcaggacg tgagggacaa caccagcgtg 420
gacaacaagc agacccagct gtgcatcatc ggctgcgccc cccccatcgg cgagcactgg 480
ggcatcggca ccacctgcaa gaacaccccc gtgccccccg gcgactgccc ccccctggag 540
ctggtgagca gcgtgatcca ggacggcgac atgatcgaca ccggcttcgg cgccatggac 600
ttcgccgccc tgcaggccac caagagcgac gtgcccctgg acatcagcca gagcgtgtgc 660
aagtaccccg actacctgaa gatgagcgcc gacacctacg gcaacagcat gttcttccac 720
ctgaggaggg agcagatctt cgccaggcac tactacaaca agctgggcag cgtgggcgag 780
gacatcccca ccgactacta catcaagggc agcggcaacg gcagggaccc catcgagagc 840
tacatctaca gcgccacccc cagcggcagc atgatcacca gcgacagcca gatcttcaac 900
aagccctact ggctgcacag ggcccagggc cacaacaacg gcatctgctg gaacaaccag 960
ctgttcatca cctgcgtgga caccaccagg agcaccaacc tgaccatcag caccgccacc 1020
gccgccgtga gccccacctt cacccccagc aacttcaagc agtacatcag gcacggcgag 1080
gagtacgagc tgcagttcat cttccagctg tgcaagatca ccctgaccac cgaggtgatg 1140
gcctacctgc acaccatgga ccccaccatc ctggagcagt ggaacttcgg cctgaccctg 1200
ccccccagcg ccagcctgga ggacgcctac aggttcgtga ggaacgccgc caccagctgc 1260
cagaaggaca ccccccccca ggccaagccc gaccccctgg ccaagtacaa gttctgggac 1320
gtggacctga aggagaggtt cagcctggac ctggaccagt tcgccctggg caggaagttc 1380
ctgctgcagg tgggcgtgca gaggaagccc aggcccggcc tgaagaggcc cgctagcagc 1440
gccagctcca gcagctccag cagcgccaag aggaagaggg tgaagaagta a 1491
<210> 12
<211> 1491
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码H51N9-69T1的DNA序列
<400> 12
atgaaggtgt acctgccccc cgcccccgtg agcaggatcg tgaacaccga ggagtacatc 60
accaggaccg gcatctacta ctacgccggc agcagcaggc tgatcaccct gggccacccc 120
tacttcccga tcccgaaatc tggttctacc gctgaaatcc cgaaggtctc tgccttccag 180
tacagggtgt tcagggtgca gctccccgac cccaacaagt tcggcctgcc cgaccccaac 240
ctgtacaacc ccgacaccga caggctggtg tggggctgcg tgggcgtgga ggtgggcagg 300
ggccagcccc tgggcgtggg cctgagcggc caccccctgt tcaacaagta cgacgacacc 360
gagaacagca ggatcgccaa cggcaacgcc cagcaggacg tgagggacaa caccagcgtg 420
gacaacaagc agacccagct gtgcatcatc ggctgcgccc cccccatcgg cgagcactgg 480
ggcatcggca ccacctgcaa gaacaccccc gtgccccccg gcgactgccc ccccctggag 540
ctggtgagca gcgtgatcca ggacggcgac atgatcgaca ccggcttcgg cgccatggac 600
ttcgccgccc tgcaggccac caagagcgac gtgcccctgg acatcagcca gagcgtgtgc 660
aagtaccccg actacctgaa gatgagcgcc gacacctacg gcaacagcat gttcttccac 720
ctgaggaggg agcagatctt cgccaggcac tactacaaca agctgggcag cgtgggcgag 780
gacatcccca ccgactacta catcaagggc agcggcaacg gcagggaccc catcgagagc 840
tacatctaca gcgccacccc cagcggcagc atgatcacca gcgacagcca gatcttcaac 900
aagccctact ggctgcacag ggcccagggc cacaacaacg gcatctgctg gaacaaccag 960
ctgttcatca cctgcgtgga caccaccagg agcaccaacc tgaccatcag caccgccacc 1020
gccgccgtga gccccacctt cacccccagc aacttcaagc agtacatcag gcacggcgag 1080
gagtacgagc tgcagttcat cttccagctg tgcaagatca ccctgaccac cgaggtgatg 1140
gcctacctgc acaccatgga ccccaccatc ctggagcagt ggaacttcgg cctgaccctg 1200
ccccccagcg ccagcctgga ggacgcctac aggttcgtga ggaacgccgc caccagctgc 1260
cagaaggaca ccccccccca ggccaagccc gaccccctgg ccaagtacaa gttctgggac 1320
gtggacctga aggagaggtt cagcctggac ctggaccagt tcgccctggg caggaagttc 1380
ctgctgcagg tgggcgtgca gaggaagccc aggcccggcc tgaagaggcc cgctagcagc 1440
gccagctcca gcagctccag cagcgccaag aggaagaggg tgaagaagta a 1491
<210> 13
<211> 1491
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码H51N9-69T2的DNA序列
<400> 13
atgaaggtgt acctgccccc cgcccccgtg agcaggatcg tgaacaccga ggagtacatc 60
accaggaccg gcatctacta ctacgccggc agcagcaggc tgatcaccct gggccacccc 120
tacttccccc tgcccaagac cagcaccagg gccgccatcc ccaaggtgag cgccttccag 180
tacagggtgt tcagggtgca gctccccgac cccaacaagt tcggcctgcc cgaccccaac 240
ctgtacaacc ccgacaccga caggctggtg tggggctgcg tgggcgtgga ggtgggtcgt 300
ggtcagccgc tgggtgtcgg tctgtctggt cacccgctgt tcaacaaact ggacgacacc 360
gaaaactctc acctggctac cgctaacgct gacaccgaca accgtgacaa cgtttgcgtt 420
gacaacaagc agacccagct gtgcatcatc ggctgcgccc cccccatcgg cgagcactgg 480
ggcatcggca ccacctgcaa gaacaccccc gtgccccccg gcgactgccc ccccctggag 540
ctggtgagca gcgtgatcca ggacggcgac atgatcgaca ccggcttcgg cgccatggac 600
ttcgccgccc tgcaggccac caagagcgac gtgcccctgg acatcagcca gagcgtgtgc 660
aagtaccccg actacctgaa gatgagcgcc gacacctacg gcaacagcat gttcttccac 720
ctgaggaggg agcagatctt cgccaggcac tactacaaca agctgggcag cgtgggcgag 780
gacatcccca ccgactacta catcaagggc agcggcaacg gcagggaccc catcgagagc 840
tacatctaca gcgccacccc cagcggcagc atgatcacca gcgacagcca gatcttcaac 900
aagccctact ggctgcacag ggcccagggc cacaacaacg gcatctgctg gaacaaccag 960
ctgttcatca cctgcgtgga caccaccagg agcaccaacc tgaccatcag caccgccacc 1020
gccgccgtga gccccacctt cacccccagc aacttcaagc agtacatcag gcacggcgag 1080
gagtacgagc tgcagttcat cttccagctg tgcaagatca ccctgaccac cgaggtgatg 1140
gcctacctgc acaccatgga ccccaccatc ctggagcagt ggaacttcgg cctgaccctg 1200
ccccccagcg ccagcctgga ggacgcctac aggttcgtga ggaacgccgc caccagctgc 1260
cagaaggaca ccccccccca ggccaagccc gaccccctgg ccaagtacaa gttctgggac 1320
gtggacctga aggagaggtt cagcctggac ctggaccagt tcgccctggg caggaagttc 1380
ctgctgcagg tgggcgtgca gaggaagccc aggcccggcc tgaagaggcc cgctagcagc 1440
gccagctcca gcagctccag cagcgccaag aggaagaggg tgaagaagta a 1491
<210> 14
<211> 1497
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码H51N9-69T3的DNA序列
<400> 14
atgaaggtgt acctgccccc cgcccccgtg agcaggatcg tgaacaccga ggagtacatc 60
accaggaccg gcatctacta ctacgccggc agcagcaggc tgatcaccct gggccacccc 120
tacttccccc tgcccaagac cagcaccagg gccgccatcc ccaaggtgag cgccttccag 180
tacagggtgt tcagggtgca gctccccgac cccaacaagt tcggcctgcc cgaccccaac 240
ctgtacaacc ccgacaccga caggctggtg tggggctgcg tgggcgtgga ggtgggcagg 300
ggccagcccc tgggcgtggg cctgagcggc caccccctgt tcaacaagta cgacgacacc 360
gagaacagca ggatcgccaa cggcaacgcc cagcaggacg tgagggacaa caccagcgtg 420
gacaacaagc agacccagct gtgcatcatc ggctgcgccc cccccatcgg cgagcactgg 480
ggtgtcggta ccgtttgcaa aaacgctcag tctcaggttc agcgtggtga ctgcccgccg 540
ctggagctgg tgagcagcgt gatccaggac ggcgacatga tcgacaccgg cttcggcgcc 600
atggacttcg ccgccctgca ggccaccaag agcgacgtgc ccctggacat cagccagagc 660
gtgtgcaagt accccgacta cctgaagatg agcgccgaca cctacggcaa cagcatgttc 720
ttccacctga ggagggagca gatcttcgcc aggcactact acaacaagct gggcagcgtg 780
ggcgaggaca tccccaccga ctactacatc aagggcagcg gcaacggcag ggaccccatc 840
gagagctaca tctacagcgc cacccccagc ggcagcatga tcaccagcga cagccagatc 900
ttcaacaagc cctactggct gcacagggcc cagggccaca acaacggcat ctgctggaac 960
aaccagctgt tcatcacctg cgtggacacc accaggagca ccaacctgac catcagcacc 1020
gccaccgccg ccgtgagccc caccttcacc cccagcaact tcaagcagta catcaggcac 1080
ggcgaggagt acgagctgca gttcatcttc cagctgtgca agatcaccct gaccaccgag 1140
gtgatggcct acctgcacac catggacccc accatcctgg agcagtggaa cttcggcctg 1200
accctgcccc ccagcgccag cctggaggac gcctacaggt tcgtgaggaa cgccgccacc 1260
agctgccaga aggacacccc cccccaggcc aagcccgacc ccctggccaa gtacaagttc 1320
tgggacgtgg acctgaagga gaggttcagc ctggacctgg accagttcgc cctgggcagg 1380
aagttcctgc tgcaggtggg cgtgcagagg aagcccaggc ccggcctgaa gaggcccgct 1440
agcagcgcca gctccagcag ctccagcagc gccaagagga agagggtgaa gaagtaa 1497
<210> 15
<211> 1491
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码H51N9-69T4的DNA序列
<400> 15
atgaaggtgt acctgccccc cgcccccgtg agcaggatcg tgaacaccga ggagtacatc 60
accaggaccg gcatctacta ctacgccggc agcagcaggc tgatcaccct gggccacccc 120
tacttccccc tgcccaagac cagcaccagg gccgccatcc ccaaggtgag cgccttccag 180
tacagggtgt tcagggtgca gctccccgac cccaacaagt tcggcctgcc cgaccccaac 240
ctgtacaacc ccgacaccga caggctggtg tggggctgcg tgggcgtgga ggtgggcagg 300
ggccagcccc tgggcgtggg cctgagcggc caccccctgt tcaacaagta cgacgacacc 360
gagaacagca ggatcgccaa cggcaacgcc cagcaggacg tgagggacaa caccagcgtg 420
gacaacaagc agacccagct gtgcatcatc ggctgcgccc cccccatcgg cgagcactgg 480
ggcatcggca ccacctgcaa gaacaccccc gtgccccccg gcgactgccc ccccctggag 540
ctggtgagca gcgtgatcca ggacggcgac atgatcgaca ccggcttcgg cgccatggac 600
ttcgccgccc tgcaggccac caagagcgac gtgcccctgg acatcagcca gagcgtgtgc 660
aagtaccccg actacctgaa gatgagcgcc gacacctacg gcaacagcat gttcttccac 720
ctgaggaggg agcagatctt cgccaggcac ttcttcaaca aagctggtac catcggtgac 780
cctgttccgg tttctatgta catcaaaggt gctggtcagg gtcgtgaacc gccgaccaca 840
tccatctact ctgccacccc cagcggcagc atgatcacca gcgacagcca gatcttcaac 900
aagccctact ggctgcacag ggcccagggc cacaacaacg gcatctgctg gaacaaccag 960
ctgttcatca cctgcgtgga caccaccagg agcaccaacc tgaccatcag caccgccacc 1020
gccgccgtga gccccacctt cacccccagc aacttcaagc agtacatcag gcacggcgag 1080
gagtacgagc tgcagttcat cttccagctg tgcaagatca ccctgaccac cgaggtgatg 1140
gcctacctgc acaccatgga ccccaccatc ctggagcagt ggaacttcgg cctgaccctg 1200
ccccccagcg ccagcctgga ggacgcctac aggttcgtga ggaacgccgc caccagctgc 1260
cagaaggaca ccccccccca ggccaagccc gaccccctgg ccaagtacaa gttctgggac 1320
gtggacctga aggagaggtt cagcctggac ctggaccagt tcgccctggg caggaagttc 1380
ctgctgcagg tgggcgtgca gaggaagccc aggcccggcc tgaagaggcc cgctagcagc 1440
gccagctcca gcagctccag cagcgccaag aggaagaggg tgaagaagta a 1491
<210> 16
<211> 1494
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码H51N9-69T5的DNA序列
<400> 16
atgaaggtgt acctgccccc cgcccccgtg agcaggatcg tgaacaccga ggagtacatc 60
accaggaccg gcatctacta ctacgccggc agcagcaggc tgatcaccct gggccacccc 120
tacttccccc tgcccaagac cagcaccagg gccgccatcc ccaaggtgag cgccttccag 180
tacagggtgt tcagggtgca gctccccgac cccaacaagt tcggcctgcc cgaccccaac 240
ctgtacaacc ccgacaccga caggctggtg tggggctgcg tgggcgtgga ggtgggcagg 300
ggccagcccc tgggcgtggg cctgagcggc caccccctgt tcaacaagta cgacgacacc 360
gagaacagca ggatcgccaa cggcaacgcc cagcaggacg tgagggacaa caccagcgtg 420
gacaacaagc agacccagct gtgcatcatc ggctgcgccc cccccatcgg cgagcactgg 480
ggcatcggca ccacctgcaa gaacaccccc gtgccccccg gcgactgccc ccccctggag 540
ctggtgagca gcgtgatcca ggacggcgac atgatcgaca ccggcttcgg cgccatggac 600
ttcgccgccc tgcaggccac caagagcgac gtgcccctgg acatcagcca gagcgtgtgc 660
aagtaccccg actacctgaa gatgagcgcc gacacctacg gcaacagcat gttcttccac 720
ctgaggaggg agcagatctt cgccaggcac tactacaaca agctgggcag cgtgggcgag 780
gacatcccca ccgactacta catcaagggc agcggcaacg gcagggaccc catcgagagc 840
tacatctaca gcgccacccc cagcggcagc atgatcacca gcgacagcca gatcttcaac 900
aagccctact ggctgcacag ggcccagggc cacaacaacg gcatctgctg gaacaaccag 960
ctgttcatca cctgcgtgga caccaccagg agcaccaacc tgaccatcag caccgcctct 1020
gctcagtctg cttctgctac cttcaaaccg tctgacttca agcagtacat caggcacggc 1080
gaggagtacg agctgcagtt catcttccag ctgtgcaaga tcaccctgac caccgaggtg 1140
atggcctacc tgcacaccat ggaccccacc atcctggagc agtggaactt cggcctgacc 1200
ctgcccccca gcgccagcct ggaggacgcc tacaggttcg tgaggaacgc cgccaccagc 1260
tgccagaagg acaccccccc ccaggccaag cccgaccccc tggccaagta caagttctgg 1320
gacgtggacc tgaaggagag gttcagcctg gacctggacc agttcgccct gggcaggaag 1380
ttcctgctgc aggtgggcgt gcagaggaag cccaggcccg gcctgaagag gcccgctagc 1440
agcgccagct ccagcagctc cagcagcgcc aagaggaaga gggtgaagaa gtaa 1494
<210> 17
<211> 9
<212> PRT
<213> Human papillomavirus type 69
<400> 17
Ile Pro Lys Ser Gly Ser Thr Ala Glu
1 5
<210> 18
<211> 23
<212> PRT
<213> Human papillomavirus type 69
<400> 18
Leu Asp Asp Thr Glu Asn Ser His Leu Ala Thr Ala Asn Ala Asp Thr
1 5 10 15
Asp Asn Arg Asp Asn Val Cys
20
<210> 19
<211> 14
<212> PRT
<213> Human papillomavirus type 69
<400> 19
Val Gly Thr Val Cys Lys Asn Ala Gln Ser Gln Val Gln Arg
1 5 10
<210> 20
<211> 31
<212> PRT
<213> Human papillomavirus type 69
<400> 20
Phe Phe Asn Lys Ala Gly Thr Ile Gly Asp Pro Val Pro Val Ser Met
1 5 10 15
Tyr Ile Lys Gly Ala Gly Gln Gly Arg Glu Pro Pro Thr Thr Ser
20 25 30
<210> 21
<211> 13
<212> PRT
<213> Human papillomavirus type 69
<400> 21
Ser Ala Gln Ser Ala Ser Ala Thr Phe Lys Pro Ser Asp
1 5 10
<210> 22
<211> 503
<212> PRT
<213> Human papillomavirus type 26
<400> 22
Met Ala Leu Trp Arg Thr Ser Asp Ser Lys Val Tyr Leu Pro Pro Thr
1 5 10 15
Pro Val Ser Arg Val Val Asn Thr Asp Glu Tyr Val Thr Arg Thr Gly
20 25 30
Ile Tyr Tyr Tyr Ala Gly Ser Ser Arg Leu Leu Thr Leu Gly His Pro
35 40 45
Tyr Phe Ser Ile Pro Lys Thr Gly Gln Lys Ala Glu Ile Pro Lys Val
50 55 60
Ser Ala Tyr Gln Tyr Arg Val Phe Arg Val His Leu Pro Asp Pro Asn
65 70 75 80
Lys Phe Gly Leu Pro Asp Pro Gln Leu Tyr Asn Pro Asp Thr Glu Arg
85 90 95
Leu Val Trp Ala Cys Val Gly Val Glu Val Gly Arg Gly Gln Pro Leu
100 105 110
Gly Ile Gly Leu Ser Gly His Pro Leu Phe Asn Lys Leu Asp Asp Thr
115 120 125
Glu Asn Ser His Leu Ala Thr Val Asn Ala Asp Thr Asp Asn Arg Asp
130 135 140
Asn Val Ser Val Asp Asn Lys Gln Thr Gln Leu Cys Ile Ile Gly Cys
145 150 155 160
Thr Pro Pro Leu Gly Glu His Trp Gly Ile Gly Thr Ile Cys Lys Asn
165 170 175
Thr Gln Thr Gln Arg Gly Asp Cys Pro Pro Leu Glu Leu Ile Ser Ser
180 185 190
Ile Ile Glu Asp Gly Asp Met Ile Asp Thr Gly Phe Gly Ala Met Asp
195 200 205
Phe Thr Ala Leu Gln Ala Thr Lys Ser Asp Val Pro Ile Asp Ile Ser
210 215 220
Gln Ser Thr Cys Lys Tyr Pro Asp Tyr Leu Lys Met Ser Ala Asp Thr
225 230 235 240
Tyr Gly Asn Ser Met Phe Phe Phe Leu Arg Arg Glu Gln Leu Phe Ala
245 250 255
Arg His Phe Tyr Asn Lys Ala Gly Ala Val Gly Asp Ala Ile Pro Thr
260 265 270
Thr Leu Tyr Ile Lys Gly Ala Glu Ser Gly Arg Glu Pro Pro Thr Ser
275 280 285
Ser Ile Tyr Ser Ala Thr Pro Ser Gly Ser Met Val Thr Ser Asp Ala
290 295 300
Gln Leu Phe Asn Lys Pro Tyr Trp Leu Gln Arg Ala Gln Gly His Asn
305 310 315 320
Asn Gly Ile Cys Trp Gly Asn Gln Leu Phe Val Thr Cys Val Asp Thr
325 330 335
Thr Arg Ser Thr Asn Leu Thr Ile Ser Thr Leu Ser Ala Ala Ser Ala
340 345 350
Ser Thr Pro Phe Lys Pro Ser Asp Tyr Lys Gln Phe Ile Arg His Gly
355 360 365
Glu Glu Tyr Glu Leu Gln Phe Ile Phe Gln Leu Cys Lys Ile Thr Leu
370 375 380
Thr Thr Asp Val Met Ala Tyr Ile His Leu Met Asn Ala Ser Ile Leu
385 390 395 400
Glu Asp Trp Asn Phe Gly Leu Thr Leu Pro Pro Thr Ala Ser Leu Glu
405 410 415
Asp Ala Tyr Arg Phe Ile Lys Asn Ser Ala Thr Thr Cys Gln Arg Asn
420 425 430
Ala Pro Pro Val Pro Lys Glu Asp Pro Phe Gln Lys Phe Lys Phe Trp
435 440 445
Asp Val Asp Leu Lys Glu Lys Phe Ser Ile Asp Leu Asp Gln Phe Pro
450 455 460
Leu Gly Arg Lys Phe Met Leu Gln Ala Gly Ile Gln Arg Arg Pro Lys
465 470 475 480
Leu Gly Thr Lys Arg Pro Leu Ser Ser Thr Ser Ser Ser Thr Lys Arg
485 490 495
Lys Lys Arg Lys Leu Thr Lys
500
<210> 23
<211> 496
<212> PRT
<213> Artificial Sequence
<220>
<223> H51N9-69T1-26S2
<400> 23
Met Lys Val Tyr Leu Pro Pro Ala Pro Val Ser Arg Ile Val Asn Thr
1 5 10 15
Glu Glu Tyr Ile Thr Arg Thr Gly Ile Tyr Tyr Tyr Ala Gly Ser Ser
20 25 30
Arg Leu Ile Thr Leu Gly His Pro Tyr Phe Pro Ile Pro Lys Ser Gly
35 40 45
Ser Thr Ala Glu Ile Pro Lys Val Ser Ala Phe Gln Tyr Arg Val Phe
50 55 60
Arg Val Gln Leu Pro Asp Pro Asn Lys Phe Gly Leu Pro Asp Pro Asn
65 70 75 80
Leu Tyr Asn Pro Asp Thr Asp Arg Leu Val Trp Gly Cys Val Gly Val
85 90 95
Glu Val Gly Arg Gly Gln Pro Leu Gly Ile Gly Leu Ser Gly His Pro
100 105 110
Leu Phe Asn Lys Leu Asp Asp Thr Glu Asn Ser His Leu Ala Thr Val
115 120 125
Asn Ala Asp Thr Asp Asn Arg Asp Asn Val Ser Val Asp Asn Lys Gln
130 135 140
Thr Gln Leu Cys Ile Ile Gly Cys Ala Pro Pro Ile Gly Glu His Trp
145 150 155 160
Gly Ile Gly Thr Thr Cys Lys Asn Thr Pro Val Pro Pro Gly Asp Cys
165 170 175
Pro Pro Leu Glu Leu Val Ser Ser Val Ile Gln Asp Gly Asp Met Ile
180 185 190
Asp Thr Gly Phe Gly Ala Met Asp Phe Ala Ala Leu Gln Ala Thr Lys
195 200 205
Ser Asp Val Pro Leu Asp Ile Ser Gln Ser Val Cys Lys Tyr Pro Asp
210 215 220
Tyr Leu Lys Met Ser Ala Asp Thr Tyr Gly Asn Ser Met Phe Phe His
225 230 235 240
Leu Arg Arg Glu Gln Ile Phe Ala Arg His Tyr Tyr Asn Lys Leu Gly
245 250 255
Ser Val Gly Glu Asp Ile Pro Thr Asp Tyr Tyr Ile Lys Gly Ser Gly
260 265 270
Asn Gly Arg Asp Pro Ile Glu Ser Tyr Ile Tyr Ser Ala Thr Pro Ser
275 280 285
Gly Ser Met Ile Thr Ser Asp Ser Gln Ile Phe Asn Lys Pro Tyr Trp
290 295 300
Leu His Arg Ala Gln Gly His Asn Asn Gly Ile Cys Trp Asn Asn Gln
305 310 315 320
Leu Phe Ile Thr Cys Val Asp Thr Thr Arg Ser Thr Asn Leu Thr Ile
325 330 335
Ser Thr Ala Thr Ala Ala Val Ser Pro Thr Phe Thr Pro Ser Asn Phe
340 345 350
Lys Gln Tyr Ile Arg His Gly Glu Glu Tyr Glu Leu Gln Phe Ile Phe
355 360 365
Gln Leu Cys Lys Ile Thr Leu Thr Thr Glu Val Met Ala Tyr Leu His
370 375 380
Thr Met Asp Pro Thr Ile Leu Glu Gln Trp Asn Phe Gly Leu Thr Leu
385 390 395 400
Pro Pro Ser Ala Ser Leu Glu Asp Ala Tyr Arg Phe Val Arg Asn Ala
405 410 415
Ala Thr Ser Cys Gln Lys Asp Thr Pro Pro Gln Ala Lys Pro Asp Pro
420 425 430
Leu Ala Lys Tyr Lys Phe Trp Asp Val Asp Leu Lys Glu Arg Phe Ser
435 440 445
Leu Asp Leu Asp Gln Phe Ala Leu Gly Arg Lys Phe Leu Leu Gln Val
450 455 460
Gly Val Gln Arg Lys Pro Arg Pro Gly Leu Lys Arg Pro Ala Ser Ser
465 470 475 480
Ala Ser Ser Ser Ser Ser Ser Ser Ala Lys Arg Lys Arg Val Lys Lys
485 490 495
<210> 24
<211> 496
<212> PRT
<213> Artificial Sequence
<220>
<223> H51N9-69T1-26S3
<400> 24
Met Lys Val Tyr Leu Pro Pro Ala Pro Val Ser Arg Ile Val Asn Thr
1 5 10 15
Glu Glu Tyr Ile Thr Arg Thr Gly Ile Tyr Tyr Tyr Ala Gly Ser Ser
20 25 30
Arg Leu Ile Thr Leu Gly His Pro Tyr Phe Pro Ile Pro Lys Ser Gly
35 40 45
Ser Thr Ala Glu Ile Pro Lys Val Ser Ala Phe Gln Tyr Arg Val Phe
50 55 60
Arg Val Gln Leu Pro Asp Pro Asn Lys Phe Gly Leu Pro Asp Pro Asn
65 70 75 80
Leu Tyr Asn Pro Asp Thr Asp Arg Leu Val Trp Gly Cys Val Gly Val
85 90 95
Glu Val Gly Arg Gly Gln Pro Leu Gly Val Gly Leu Ser Gly His Pro
100 105 110
Leu Phe Asn Lys Tyr Asp Asp Thr Glu Asn Ser Arg Ile Ala Asn Gly
115 120 125
Asn Ala Gln Gln Asp Val Arg Asp Asn Thr Ser Val Asp Asn Lys Gln
130 135 140
Thr Gln Leu Cys Ile Ile Gly Cys Ala Pro Pro Ile Gly Glu His Trp
145 150 155 160
Gly Ile Gly Thr Ile Cys Lys Asn Thr Gln Thr Gln Arg Gly Asp Cys
165 170 175
Pro Pro Leu Glu Leu Val Ser Ser Val Ile Gln Asp Gly Asp Met Ile
180 185 190
Asp Thr Gly Phe Gly Ala Met Asp Phe Ala Ala Leu Gln Ala Thr Lys
195 200 205
Ser Asp Val Pro Leu Asp Ile Ser Gln Ser Val Cys Lys Tyr Pro Asp
210 215 220
Tyr Leu Lys Met Ser Ala Asp Thr Tyr Gly Asn Ser Met Phe Phe His
225 230 235 240
Leu Arg Arg Glu Gln Ile Phe Ala Arg His Tyr Tyr Asn Lys Leu Gly
245 250 255
Ser Val Gly Glu Asp Ile Pro Thr Asp Tyr Tyr Ile Lys Gly Ser Gly
260 265 270
Asn Gly Arg Asp Pro Ile Glu Ser Tyr Ile Tyr Ser Ala Thr Pro Ser
275 280 285
Gly Ser Met Ile Thr Ser Asp Ser Gln Ile Phe Asn Lys Pro Tyr Trp
290 295 300
Leu His Arg Ala Gln Gly His Asn Asn Gly Ile Cys Trp Asn Asn Gln
305 310 315 320
Leu Phe Ile Thr Cys Val Asp Thr Thr Arg Ser Thr Asn Leu Thr Ile
325 330 335
Ser Thr Ala Thr Ala Ala Val Ser Pro Thr Phe Thr Pro Ser Asn Phe
340 345 350
Lys Gln Tyr Ile Arg His Gly Glu Glu Tyr Glu Leu Gln Phe Ile Phe
355 360 365
Gln Leu Cys Lys Ile Thr Leu Thr Thr Glu Val Met Ala Tyr Leu His
370 375 380
Thr Met Asp Pro Thr Ile Leu Glu Gln Trp Asn Phe Gly Leu Thr Leu
385 390 395 400
Pro Pro Ser Ala Ser Leu Glu Asp Ala Tyr Arg Phe Val Arg Asn Ala
405 410 415
Ala Thr Ser Cys Gln Lys Asp Thr Pro Pro Gln Ala Lys Pro Asp Pro
420 425 430
Leu Ala Lys Tyr Lys Phe Trp Asp Val Asp Leu Lys Glu Arg Phe Ser
435 440 445
Leu Asp Leu Asp Gln Phe Ala Leu Gly Arg Lys Phe Leu Leu Gln Val
450 455 460
Gly Val Gln Arg Lys Pro Arg Pro Gly Leu Lys Arg Pro Ala Ser Ser
465 470 475 480
Ala Ser Ser Ser Ser Ser Ser Ser Ala Lys Arg Lys Arg Val Lys Lys
485 490 495
<210> 25
<211> 496
<212> PRT
<213> Artificial Sequence
<220>
<223> H51N9-69T1-26S4
<400> 25
Met Lys Val Tyr Leu Pro Pro Ala Pro Val Ser Arg Ile Val Asn Thr
1 5 10 15
Glu Glu Tyr Ile Thr Arg Thr Gly Ile Tyr Tyr Tyr Ala Gly Ser Ser
20 25 30
Arg Leu Ile Thr Leu Gly His Pro Tyr Phe Pro Ile Pro Lys Ser Gly
35 40 45
Ser Thr Ala Glu Ile Pro Lys Val Ser Ala Phe Gln Tyr Arg Val Phe
50 55 60
Arg Val Gln Leu Pro Asp Pro Asn Lys Phe Gly Leu Pro Asp Pro Asn
65 70 75 80
Leu Tyr Asn Pro Asp Thr Asp Arg Leu Val Trp Gly Cys Val Gly Val
85 90 95
Glu Val Gly Arg Gly Gln Pro Leu Gly Val Gly Leu Ser Gly His Pro
100 105 110
Leu Phe Asn Lys Tyr Asp Asp Thr Glu Asn Ser Arg Ile Ala Asn Gly
115 120 125
Asn Ala Gln Gln Asp Val Arg Asp Asn Thr Ser Val Asp Asn Lys Gln
130 135 140
Thr Gln Leu Cys Ile Ile Gly Cys Ala Pro Pro Ile Gly Glu His Trp
145 150 155 160
Gly Ile Gly Thr Thr Cys Lys Asn Thr Pro Val Pro Pro Gly Asp Cys
165 170 175
Pro Pro Leu Glu Leu Val Ser Ser Val Ile Gln Asp Gly Asp Met Ile
180 185 190
Asp Thr Gly Phe Gly Ala Met Asp Phe Ala Ala Leu Gln Ala Thr Lys
195 200 205
Ser Asp Val Pro Leu Asp Ile Ser Gln Ser Val Cys Lys Tyr Pro Asp
210 215 220
Tyr Leu Lys Met Ser Ala Asp Thr Tyr Gly Asn Ser Met Phe Phe His
225 230 235 240
Leu Arg Arg Glu Gln Ile Phe Ala Arg His Phe Tyr Asn Lys Ala Gly
245 250 255
Ala Val Gly Asp Ala Ile Pro Thr Thr Leu Tyr Ile Lys Gly Ala Glu
260 265 270
Ser Gly Arg Glu Pro Pro Thr Ser Ser Ile Tyr Ser Ala Thr Pro Ser
275 280 285
Gly Ser Met Ile Thr Ser Asp Ser Gln Ile Phe Asn Lys Pro Tyr Trp
290 295 300
Leu His Arg Ala Gln Gly His Asn Asn Gly Ile Cys Trp Asn Asn Gln
305 310 315 320
Leu Phe Ile Thr Cys Val Asp Thr Thr Arg Ser Thr Asn Leu Thr Ile
325 330 335
Ser Thr Ala Thr Ala Ala Val Ser Pro Thr Phe Thr Pro Ser Asn Phe
340 345 350
Lys Gln Tyr Ile Arg His Gly Glu Glu Tyr Glu Leu Gln Phe Ile Phe
355 360 365
Gln Leu Cys Lys Ile Thr Leu Thr Thr Glu Val Met Ala Tyr Leu His
370 375 380
Thr Met Asp Pro Thr Ile Leu Glu Gln Trp Asn Phe Gly Leu Thr Leu
385 390 395 400
Pro Pro Ser Ala Ser Leu Glu Asp Ala Tyr Arg Phe Val Arg Asn Ala
405 410 415
Ala Thr Ser Cys Gln Lys Asp Thr Pro Pro Gln Ala Lys Pro Asp Pro
420 425 430
Leu Ala Lys Tyr Lys Phe Trp Asp Val Asp Leu Lys Glu Arg Phe Ser
435 440 445
Leu Asp Leu Asp Gln Phe Ala Leu Gly Arg Lys Phe Leu Leu Gln Val
450 455 460
Gly Val Gln Arg Lys Pro Arg Pro Gly Leu Lys Arg Pro Ala Ser Ser
465 470 475 480
Ala Ser Ser Ser Ser Ser Ser Ser Ala Lys Arg Lys Arg Val Lys Lys
485 490 495
<210> 26
<211> 497
<212> PRT
<213> Artificial Sequence
<220>
<223> H51N9-69T1-26S5
<400> 26
Met Lys Val Tyr Leu Pro Pro Ala Pro Val Ser Arg Ile Val Asn Thr
1 5 10 15
Glu Glu Tyr Ile Thr Arg Thr Gly Ile Tyr Tyr Tyr Ala Gly Ser Ser
20 25 30
Arg Leu Ile Thr Leu Gly His Pro Tyr Phe Pro Ile Pro Lys Ser Gly
35 40 45
Ser Thr Ala Glu Ile Pro Lys Val Ser Ala Phe Gln Tyr Arg Val Phe
50 55 60
Arg Val Gln Leu Pro Asp Pro Asn Lys Phe Gly Leu Pro Asp Pro Asn
65 70 75 80
Leu Tyr Asn Pro Asp Thr Asp Arg Leu Val Trp Gly Cys Val Gly Val
85 90 95
Glu Val Gly Arg Gly Gln Pro Leu Gly Val Gly Leu Ser Gly His Pro
100 105 110
Leu Phe Asn Lys Tyr Asp Asp Thr Glu Asn Ser Arg Ile Ala Asn Gly
115 120 125
Asn Ala Gln Gln Asp Val Arg Asp Asn Thr Ser Val Asp Asn Lys Gln
130 135 140
Thr Gln Leu Cys Ile Ile Gly Cys Ala Pro Pro Ile Gly Glu His Trp
145 150 155 160
Gly Ile Gly Thr Thr Cys Lys Asn Thr Pro Val Pro Pro Gly Asp Cys
165 170 175
Pro Pro Leu Glu Leu Val Ser Ser Val Ile Gln Asp Gly Asp Met Ile
180 185 190
Asp Thr Gly Phe Gly Ala Met Asp Phe Ala Ala Leu Gln Ala Thr Lys
195 200 205
Ser Asp Val Pro Leu Asp Ile Ser Gln Ser Val Cys Lys Tyr Pro Asp
210 215 220
Tyr Leu Lys Met Ser Ala Asp Thr Tyr Gly Asn Ser Met Phe Phe His
225 230 235 240
Leu Arg Arg Glu Gln Ile Phe Ala Arg His Tyr Tyr Asn Lys Leu Gly
245 250 255
Ser Val Gly Glu Asp Ile Pro Thr Asp Tyr Tyr Ile Lys Gly Ser Gly
260 265 270
Asn Gly Arg Asp Pro Ile Glu Ser Tyr Ile Tyr Ser Ala Thr Pro Ser
275 280 285
Gly Ser Met Ile Thr Ser Asp Ser Gln Ile Phe Asn Lys Pro Tyr Trp
290 295 300
Leu His Arg Ala Gln Gly His Asn Asn Gly Ile Cys Trp Asn Asn Gln
305 310 315 320
Leu Phe Ile Thr Cys Val Asp Thr Thr Arg Ser Thr Asn Leu Thr Ile
325 330 335
Ser Thr Ala Ser Ala Ala Ser Ala Ser Thr Pro Phe Lys Pro Ser Asp
340 345 350
Phe Lys Gln Tyr Ile Arg His Gly Glu Glu Tyr Glu Leu Gln Phe Ile
355 360 365
Phe Gln Leu Cys Lys Ile Thr Leu Thr Thr Glu Val Met Ala Tyr Leu
370 375 380
His Thr Met Asp Pro Thr Ile Leu Glu Gln Trp Asn Phe Gly Leu Thr
385 390 395 400
Leu Pro Pro Ser Ala Ser Leu Glu Asp Ala Tyr Arg Phe Val Arg Asn
405 410 415
Ala Ala Thr Ser Cys Gln Lys Asp Thr Pro Pro Gln Ala Lys Pro Asp
420 425 430
Pro Leu Ala Lys Tyr Lys Phe Trp Asp Val Asp Leu Lys Glu Arg Phe
435 440 445
Ser Leu Asp Leu Asp Gln Phe Ala Leu Gly Arg Lys Phe Leu Leu Gln
450 455 460
Val Gly Val Gln Arg Lys Pro Arg Pro Gly Leu Lys Arg Pro Ala Ser
465 470 475 480
Ser Ala Ser Ser Ser Ser Ser Ser Ser Ala Lys Arg Lys Arg Val Lys
485 490 495
Lys
<210> 27
<211> 498
<212> PRT
<213> Artificial Sequence
<220>
<223> H51N9-69T3-26S1
<400> 27
Met Lys Val Tyr Leu Pro Pro Ala Pro Val Ser Arg Ile Val Asn Thr
1 5 10 15
Glu Glu Tyr Ile Thr Arg Thr Gly Ile Tyr Tyr Tyr Ala Gly Ser Ser
20 25 30
Arg Leu Ile Thr Leu Gly His Pro Tyr Phe Ser Ile Pro Lys Thr Gly
35 40 45
Gln Lys Ala Glu Ile Pro Lys Val Ser Ala Phe Gln Tyr Arg Val Phe
50 55 60
Arg Val Gln Leu Pro Asp Pro Asn Lys Phe Gly Leu Pro Asp Pro Asn
65 70 75 80
Leu Tyr Asn Pro Asp Thr Asp Arg Leu Val Trp Gly Cys Val Gly Val
85 90 95
Glu Val Gly Arg Gly Gln Pro Leu Gly Val Gly Leu Ser Gly His Pro
100 105 110
Leu Phe Asn Lys Tyr Asp Asp Thr Glu Asn Ser Arg Ile Ala Asn Gly
115 120 125
Asn Ala Gln Gln Asp Val Arg Asp Asn Thr Ser Val Asp Asn Lys Gln
130 135 140
Thr Gln Leu Cys Ile Ile Gly Cys Ala Pro Pro Ile Gly Glu His Trp
145 150 155 160
Gly Val Gly Thr Val Cys Lys Asn Ala Gln Ser Gln Val Gln Arg Gly
165 170 175
Asp Cys Pro Pro Leu Glu Leu Val Ser Ser Val Ile Gln Asp Gly Asp
180 185 190
Met Ile Asp Thr Gly Phe Gly Ala Met Asp Phe Ala Ala Leu Gln Ala
195 200 205
Thr Lys Ser Asp Val Pro Leu Asp Ile Ser Gln Ser Val Cys Lys Tyr
210 215 220
Pro Asp Tyr Leu Lys Met Ser Ala Asp Thr Tyr Gly Asn Ser Met Phe
225 230 235 240
Phe His Leu Arg Arg Glu Gln Ile Phe Ala Arg His Tyr Tyr Asn Lys
245 250 255
Leu Gly Ser Val Gly Glu Asp Ile Pro Thr Asp Tyr Tyr Ile Lys Gly
260 265 270
Ser Gly Asn Gly Arg Asp Pro Ile Glu Ser Tyr Ile Tyr Ser Ala Thr
275 280 285
Pro Ser Gly Ser Met Ile Thr Ser Asp Ser Gln Ile Phe Asn Lys Pro
290 295 300
Tyr Trp Leu His Arg Ala Gln Gly His Asn Asn Gly Ile Cys Trp Asn
305 310 315 320
Asn Gln Leu Phe Ile Thr Cys Val Asp Thr Thr Arg Ser Thr Asn Leu
325 330 335
Thr Ile Ser Thr Ala Thr Ala Ala Val Ser Pro Thr Phe Thr Pro Ser
340 345 350
Asn Phe Lys Gln Tyr Ile Arg His Gly Glu Glu Tyr Glu Leu Gln Phe
355 360 365
Ile Phe Gln Leu Cys Lys Ile Thr Leu Thr Thr Glu Val Met Ala Tyr
370 375 380
Leu His Thr Met Asp Pro Thr Ile Leu Glu Gln Trp Asn Phe Gly Leu
385 390 395 400
Thr Leu Pro Pro Ser Ala Ser Leu Glu Asp Ala Tyr Arg Phe Val Arg
405 410 415
Asn Ala Ala Thr Ser Cys Gln Lys Asp Thr Pro Pro Gln Ala Lys Pro
420 425 430
Asp Pro Leu Ala Lys Tyr Lys Phe Trp Asp Val Asp Leu Lys Glu Arg
435 440 445
Phe Ser Leu Asp Leu Asp Gln Phe Ala Leu Gly Arg Lys Phe Leu Leu
450 455 460
Gln Val Gly Val Gln Arg Lys Pro Arg Pro Gly Leu Lys Arg Pro Ala
465 470 475 480
Ser Ser Ala Ser Ser Ser Ser Ser Ser Ser Ala Lys Arg Lys Arg Val
485 490 495
Lys Lys
<210> 28
<211> 498
<212> PRT
<213> Artificial Sequence
<220>
<223> H51N9-69T3-26S2
<400> 28
Met Lys Val Tyr Leu Pro Pro Ala Pro Val Ser Arg Ile Val Asn Thr
1 5 10 15
Glu Glu Tyr Ile Thr Arg Thr Gly Ile Tyr Tyr Tyr Ala Gly Ser Ser
20 25 30
Arg Leu Ile Thr Leu Gly His Pro Tyr Phe Pro Leu Pro Lys Thr Ser
35 40 45
Thr Arg Ala Ala Ile Pro Lys Val Ser Ala Phe Gln Tyr Arg Val Phe
50 55 60
Arg Val Gln Leu Pro Asp Pro Asn Lys Phe Gly Leu Pro Asp Pro Asn
65 70 75 80
Leu Tyr Asn Pro Asp Thr Asp Arg Leu Val Trp Gly Cys Val Gly Val
85 90 95
Glu Val Gly Arg Gly Gln Pro Leu Gly Ile Gly Leu Ser Gly His Pro
100 105 110
Leu Phe Asn Lys Leu Asp Asp Thr Glu Asn Ser His Leu Ala Thr Val
115 120 125
Asn Ala Asp Thr Asp Asn Arg Asp Asn Val Ser Val Asp Asn Lys Gln
130 135 140
Thr Gln Leu Cys Ile Ile Gly Cys Ala Pro Pro Ile Gly Glu His Trp
145 150 155 160
Gly Val Gly Thr Val Cys Lys Asn Ala Gln Ser Gln Val Gln Arg Gly
165 170 175
Asp Cys Pro Pro Leu Glu Leu Val Ser Ser Val Ile Gln Asp Gly Asp
180 185 190
Met Ile Asp Thr Gly Phe Gly Ala Met Asp Phe Ala Ala Leu Gln Ala
195 200 205
Thr Lys Ser Asp Val Pro Leu Asp Ile Ser Gln Ser Val Cys Lys Tyr
210 215 220
Pro Asp Tyr Leu Lys Met Ser Ala Asp Thr Tyr Gly Asn Ser Met Phe
225 230 235 240
Phe His Leu Arg Arg Glu Gln Ile Phe Ala Arg His Tyr Tyr Asn Lys
245 250 255
Leu Gly Ser Val Gly Glu Asp Ile Pro Thr Asp Tyr Tyr Ile Lys Gly
260 265 270
Ser Gly Asn Gly Arg Asp Pro Ile Glu Ser Tyr Ile Tyr Ser Ala Thr
275 280 285
Pro Ser Gly Ser Met Ile Thr Ser Asp Ser Gln Ile Phe Asn Lys Pro
290 295 300
Tyr Trp Leu His Arg Ala Gln Gly His Asn Asn Gly Ile Cys Trp Asn
305 310 315 320
Asn Gln Leu Phe Ile Thr Cys Val Asp Thr Thr Arg Ser Thr Asn Leu
325 330 335
Thr Ile Ser Thr Ala Thr Ala Ala Val Ser Pro Thr Phe Thr Pro Ser
340 345 350
Asn Phe Lys Gln Tyr Ile Arg His Gly Glu Glu Tyr Glu Leu Gln Phe
355 360 365
Ile Phe Gln Leu Cys Lys Ile Thr Leu Thr Thr Glu Val Met Ala Tyr
370 375 380
Leu His Thr Met Asp Pro Thr Ile Leu Glu Gln Trp Asn Phe Gly Leu
385 390 395 400
Thr Leu Pro Pro Ser Ala Ser Leu Glu Asp Ala Tyr Arg Phe Val Arg
405 410 415
Asn Ala Ala Thr Ser Cys Gln Lys Asp Thr Pro Pro Gln Ala Lys Pro
420 425 430
Asp Pro Leu Ala Lys Tyr Lys Phe Trp Asp Val Asp Leu Lys Glu Arg
435 440 445
Phe Ser Leu Asp Leu Asp Gln Phe Ala Leu Gly Arg Lys Phe Leu Leu
450 455 460
Gln Val Gly Val Gln Arg Lys Pro Arg Pro Gly Leu Lys Arg Pro Ala
465 470 475 480
Ser Ser Ala Ser Ser Ser Ser Ser Ser Ser Ala Lys Arg Lys Arg Val
485 490 495
Lys Lys
<210> 29
<211> 498
<212> PRT
<213> Artificial Sequence
<220>
<223> H51N9-69T3-26S4
<400> 29
Met Lys Val Tyr Leu Pro Pro Ala Pro Val Ser Arg Ile Val Asn Thr
1 5 10 15
Glu Glu Tyr Ile Thr Arg Thr Gly Ile Tyr Tyr Tyr Ala Gly Ser Ser
20 25 30
Arg Leu Ile Thr Leu Gly His Pro Tyr Phe Pro Leu Pro Lys Thr Ser
35 40 45
Thr Arg Ala Ala Ile Pro Lys Val Ser Ala Phe Gln Tyr Arg Val Phe
50 55 60
Arg Val Gln Leu Pro Asp Pro Asn Lys Phe Gly Leu Pro Asp Pro Asn
65 70 75 80
Leu Tyr Asn Pro Asp Thr Asp Arg Leu Val Trp Gly Cys Val Gly Val
85 90 95
Glu Val Gly Arg Gly Gln Pro Leu Gly Val Gly Leu Ser Gly His Pro
100 105 110
Leu Phe Asn Lys Tyr Asp Asp Thr Glu Asn Ser Arg Ile Ala Asn Gly
115 120 125
Asn Ala Gln Gln Asp Val Arg Asp Asn Thr Ser Val Asp Asn Lys Gln
130 135 140
Thr Gln Leu Cys Ile Ile Gly Cys Ala Pro Pro Ile Gly Glu His Trp
145 150 155 160
Gly Val Gly Thr Val Cys Lys Asn Ala Gln Ser Gln Val Gln Arg Gly
165 170 175
Asp Cys Pro Pro Leu Glu Leu Val Ser Ser Val Ile Gln Asp Gly Asp
180 185 190
Met Ile Asp Thr Gly Phe Gly Ala Met Asp Phe Ala Ala Leu Gln Ala
195 200 205
Thr Lys Ser Asp Val Pro Leu Asp Ile Ser Gln Ser Val Cys Lys Tyr
210 215 220
Pro Asp Tyr Leu Lys Met Ser Ala Asp Thr Tyr Gly Asn Ser Met Phe
225 230 235 240
Phe His Leu Arg Arg Glu Gln Ile Phe Ala Arg His Phe Tyr Asn Lys
245 250 255
Ala Gly Ala Val Gly Asp Ala Ile Pro Thr Thr Leu Tyr Ile Lys Gly
260 265 270
Ala Glu Ser Gly Arg Glu Pro Pro Thr Ser Ser Ile Tyr Ser Ala Thr
275 280 285
Pro Ser Gly Ser Met Ile Thr Ser Asp Ser Gln Ile Phe Asn Lys Pro
290 295 300
Tyr Trp Leu His Arg Ala Gln Gly His Asn Asn Gly Ile Cys Trp Asn
305 310 315 320
Asn Gln Leu Phe Ile Thr Cys Val Asp Thr Thr Arg Ser Thr Asn Leu
325 330 335
Thr Ile Ser Thr Ala Thr Ala Ala Val Ser Pro Thr Phe Thr Pro Ser
340 345 350
Asn Phe Lys Gln Tyr Ile Arg His Gly Glu Glu Tyr Glu Leu Gln Phe
355 360 365
Ile Phe Gln Leu Cys Lys Ile Thr Leu Thr Thr Glu Val Met Ala Tyr
370 375 380
Leu His Thr Met Asp Pro Thr Ile Leu Glu Gln Trp Asn Phe Gly Leu
385 390 395 400
Thr Leu Pro Pro Ser Ala Ser Leu Glu Asp Ala Tyr Arg Phe Val Arg
405 410 415
Asn Ala Ala Thr Ser Cys Gln Lys Asp Thr Pro Pro Gln Ala Lys Pro
420 425 430
Asp Pro Leu Ala Lys Tyr Lys Phe Trp Asp Val Asp Leu Lys Glu Arg
435 440 445
Phe Ser Leu Asp Leu Asp Gln Phe Ala Leu Gly Arg Lys Phe Leu Leu
450 455 460
Gln Val Gly Val Gln Arg Lys Pro Arg Pro Gly Leu Lys Arg Pro Ala
465 470 475 480
Ser Ser Ala Ser Ser Ser Ser Ser Ser Ser Ala Lys Arg Lys Arg Val
485 490 495
Lys Lys
<210> 30
<211> 499
<212> PRT
<213> Artificial Sequence
<220>
<223> H51N9-69T3-26S5
<400> 30
Met Lys Val Tyr Leu Pro Pro Ala Pro Val Ser Arg Ile Val Asn Thr
1 5 10 15
Glu Glu Tyr Ile Thr Arg Thr Gly Ile Tyr Tyr Tyr Ala Gly Ser Ser
20 25 30
Arg Leu Ile Thr Leu Gly His Pro Tyr Phe Pro Leu Pro Lys Thr Ser
35 40 45
Thr Arg Ala Ala Ile Pro Lys Val Ser Ala Phe Gln Tyr Arg Val Phe
50 55 60
Arg Val Gln Leu Pro Asp Pro Asn Lys Phe Gly Leu Pro Asp Pro Asn
65 70 75 80
Leu Tyr Asn Pro Asp Thr Asp Arg Leu Val Trp Gly Cys Val Gly Val
85 90 95
Glu Val Gly Arg Gly Gln Pro Leu Gly Val Gly Leu Ser Gly His Pro
100 105 110
Leu Phe Asn Lys Tyr Asp Asp Thr Glu Asn Ser Arg Ile Ala Asn Gly
115 120 125
Asn Ala Gln Gln Asp Val Arg Asp Asn Thr Ser Val Asp Asn Lys Gln
130 135 140
Thr Gln Leu Cys Ile Ile Gly Cys Ala Pro Pro Ile Gly Glu His Trp
145 150 155 160
Gly Val Gly Thr Val Cys Lys Asn Ala Gln Ser Gln Val Gln Arg Gly
165 170 175
Asp Cys Pro Pro Leu Glu Leu Val Ser Ser Val Ile Gln Asp Gly Asp
180 185 190
Met Ile Asp Thr Gly Phe Gly Ala Met Asp Phe Ala Ala Leu Gln Ala
195 200 205
Thr Lys Ser Asp Val Pro Leu Asp Ile Ser Gln Ser Val Cys Lys Tyr
210 215 220
Pro Asp Tyr Leu Lys Met Ser Ala Asp Thr Tyr Gly Asn Ser Met Phe
225 230 235 240
Phe His Leu Arg Arg Glu Gln Ile Phe Ala Arg His Tyr Tyr Asn Lys
245 250 255
Leu Gly Ser Val Gly Glu Asp Ile Pro Thr Asp Tyr Tyr Ile Lys Gly
260 265 270
Ser Gly Asn Gly Arg Asp Pro Ile Glu Ser Tyr Ile Tyr Ser Ala Thr
275 280 285
Pro Ser Gly Ser Met Ile Thr Ser Asp Ser Gln Ile Phe Asn Lys Pro
290 295 300
Tyr Trp Leu His Arg Ala Gln Gly His Asn Asn Gly Ile Cys Trp Asn
305 310 315 320
Asn Gln Leu Phe Ile Thr Cys Val Asp Thr Thr Arg Ser Thr Asn Leu
325 330 335
Thr Ile Ser Thr Ala Ser Ala Ala Ser Ala Ser Thr Pro Phe Lys Pro
340 345 350
Ser Asp Phe Lys Gln Tyr Ile Arg His Gly Glu Glu Tyr Glu Leu Gln
355 360 365
Phe Ile Phe Gln Leu Cys Lys Ile Thr Leu Thr Thr Glu Val Met Ala
370 375 380
Tyr Leu His Thr Met Asp Pro Thr Ile Leu Glu Gln Trp Asn Phe Gly
385 390 395 400
Leu Thr Leu Pro Pro Ser Ala Ser Leu Glu Asp Ala Tyr Arg Phe Val
405 410 415
Arg Asn Ala Ala Thr Ser Cys Gln Lys Asp Thr Pro Pro Gln Ala Lys
420 425 430
Pro Asp Pro Leu Ala Lys Tyr Lys Phe Trp Asp Val Asp Leu Lys Glu
435 440 445
Arg Phe Ser Leu Asp Leu Asp Gln Phe Ala Leu Gly Arg Lys Phe Leu
450 455 460
Leu Gln Val Gly Val Gln Arg Lys Pro Arg Pro Gly Leu Lys Arg Pro
465 470 475 480
Ala Ser Ser Ala Ser Ser Ser Ser Ser Ser Ser Ala Lys Arg Lys Arg
485 490 495
Val Lys Lys
<210> 31
<211> 1512
<212> DNA
<213> Human papillomavirus type 26
<400> 31
atggctctgt ggcgtacctc tgactctaaa gtttacctgc cgccgacccc ggtttctcgt 60
gttgttaaca ccgacgaata cgttacccgt accggtatct actactacgc tggttcttct 120
cgtctgctga ccctgggtca cccgtacttc tctatcccga aaaccggtca gaaagctgaa 180
atcccgaaag tttctgctta ccagtaccgt gttttccgtg ttcacctgcc ggacccgaac 240
aaattcggtc tgccggaccc gcagctgtac aacccggaca ccgaacgtct ggtttgggct 300
tgcgttggtg ttgaagttgg tcgtggtcag ccgctgggta tcggtctgtc tggtcacccg 360
ctgttcaaca aactggacga caccgaaaac tctcacctgg ctaccgttaa cgctgacacc 420
gacaaccgtg acaacgtttc tgttgacaac aaacagaccc agctgtgcat catcggttgc 480
accccgccgc tgggtgaaca ctggggtatc ggtaccatct gcaaaaacac ccagacccag 540
cgtggtgact gcccgccgct ggaactgatc tcttctatca tcgaagacgg tgacatgatc 600
gacaccggtt tcggtgctat ggacttcacc gctctgcagg ctaccaaatc tgacgttccg 660
atcgacatct ctcagtctac ctgcaaatac ccggactacc tgaaaatgtc tgctgacacc 720
tacggtaact ctatgttctt cttcctgcgt cgtgaacagc tgttcgctcg tcacttctac 780
aacaaagctg gtgctgttgg tgacgctatc ccgaccaccc tgtacatcaa aggtgctgaa 840
tctggtcgtg aaccgccgac ctcttctatc tactctgcta ccccgtctgg ttctatggtt 900
acctctgacg ctcagctgtt caacaaaccg tactggctgc agcgtgctca gggtcacaac 960
aacggtatct gctggggtaa ccagctgttc gttacctgcg ttgacaccac ccgttctacc 1020
aacctgacca tctctaccct gtctgctgct tctgcttcta ccccgttcaa accgtctgac 1080
tacaaacagt tcatccgtca cggtgaagaa tacgaactgc agttcatctt ccagctgtgc 1140
aaaatcaccc tgaccaccga cgttatggct tacatccacc tgatgaacgc ttctatcctg 1200
gaagactgga acttcggtct gaccctgccg ccgaccgctt ctctggaaga cgcttaccgt 1260
ttcatcaaaa actctgctac cacctgccag cgtaacgctc cgccggttcc gaaagaagac 1320
ccgttccaga aattcaaatt ctgggacgtt gacctgaaag aaaaattctc tatcgacctg 1380
gaccagttcc cgctgggtcg taaattcatg ctgcaggctg gtatccagcg tcgtccgaaa 1440
ctgggtacca aacgtccgct gtcttctacc tcttcttcta ccaaacgtaa aaaacgtaaa 1500
ctgaccaaat aa 1512
<210> 32
<211> 1491
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码H51N9-69T1-26S2的DNA序列
<400> 32
atgaaggtgt acctgccccc cgcccccgtg agcaggatcg tgaacaccga ggagtacatc 60
accaggaccg gcatctacta ctacgccggc agcagcaggc tgatcaccct gggccacccc 120
tacttcccga tcccgaaatc tggttctacc gctgaaatcc cgaaggtctc tgccttccag 180
tacagggtgt tcagggtgca gctccccgac cccaacaagt tcggcctgcc cgaccccaac 240
ctgtacaacc ccgacaccga caggctggtg tggggctgcg tgggcgtgga ggtgggtcgt 300
ggtcagccgc tgggtatcgg tctgtctggt cacccgctgt tcaacaaact ggacgacacc 360
gaaaactctc acctggctac cgttaacgct gacaccgaca accgtgacaa cgtttctgtt 420
gacaacaagc agacccagct gtgcatcatc ggctgcgccc cccccatcgg cgagcactgg 480
ggcatcggca ccacctgcaa gaacaccccc gtgccccccg gcgactgccc ccccctggag 540
ctggtgagca gcgtgatcca ggacggcgac atgatcgaca ccggcttcgg cgccatggac 600
ttcgccgccc tgcaggccac caagagcgac gtgcccctgg acatcagcca gagcgtgtgc 660
aagtaccccg actacctgaa gatgagcgcc gacacctacg gcaacagcat gttcttccac 720
ctgaggaggg agcagatctt cgccaggcac tactacaaca agctgggcag cgtgggcgag 780
gacatcccca ccgactacta catcaagggc agcggcaacg gcagggaccc catcgagagc 840
tacatctaca gcgccacccc cagcggcagc atgatcacca gcgacagcca gatcttcaac 900
aagccctact ggctgcacag ggcccagggc cacaacaacg gcatctgctg gaacaaccag 960
ctgttcatca cctgcgtgga caccaccagg agcaccaacc tgaccatcag caccgccacc 1020
gccgccgtga gccccacctt cacccccagc aacttcaagc agtacatcag gcacggcgag 1080
gagtacgagc tgcagttcat cttccagctg tgcaagatca ccctgaccac cgaggtgatg 1140
gcctacctgc acaccatgga ccccaccatc ctggagcagt ggaacttcgg cctgaccctg 1200
ccccccagcg ccagcctgga ggacgcctac aggttcgtga ggaacgccgc caccagctgc 1260
cagaaggaca ccccccccca ggccaagccc gaccccctgg ccaagtacaa gttctgggac 1320
gtggacctga aggagaggtt cagcctggac ctggaccagt tcgccctggg caggaagttc 1380
ctgctgcagg tgggcgtgca gaggaagccc aggcccggcc tgaagaggcc cgctagcagc 1440
gccagctcca gcagctccag cagcgccaag aggaagaggg tgaagaagta a 1491
<210> 33
<211> 1491
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码H51N9-69T1-26S3的DNA序列
<400> 33
atgaaggtgt acctgccccc cgcccccgtg agcaggatcg tgaacaccga ggagtacatc 60
accaggaccg gcatctacta ctacgccggc agcagcaggc tgatcaccct gggccacccc 120
tacttcccga tcccgaaatc tggttctacc gctgaaatcc cgaaggtctc tgccttccag 180
tacagggtgt tcagggtgca gctccccgac cccaacaagt tcggcctgcc cgaccccaac 240
ctgtacaacc ccgacaccga caggctggtg tggggctgcg tgggcgtgga ggtgggcagg 300
ggccagcccc tgggcgtggg cctgagcggc caccccctgt tcaacaagta cgacgacacc 360
gagaacagca ggatcgccaa cggcaacgcc cagcaggacg tgagggacaa caccagcgtg 420
gacaacaagc agacccagct gtgcatcatc ggctgcgccc cccccatcgg cgagcactgg 480
ggtatcggta ccatctgcaa aaacacccag acccagcgtg gtgactgccc gccgctggag 540
ctggtgagca gcgtgatcca ggacggcgac atgatcgaca ccggcttcgg cgccatggac 600
ttcgccgccc tgcaggccac caagagcgac gtgcccctgg acatcagcca gagcgtgtgc 660
aagtaccccg actacctgaa gatgagcgcc gacacctacg gcaacagcat gttcttccac 720
ctgaggaggg agcagatctt cgccaggcac tactacaaca agctgggcag cgtgggcgag 780
gacatcccca ccgactacta catcaagggc agcggcaacg gcagggaccc catcgagagc 840
tacatctaca gcgccacccc cagcggcagc atgatcacca gcgacagcca gatcttcaac 900
aagccctact ggctgcacag ggcccagggc cacaacaacg gcatctgctg gaacaaccag 960
ctgttcatca cctgcgtgga caccaccagg agcaccaacc tgaccatcag caccgccacc 1020
gccgccgtga gccccacctt cacccccagc aacttcaagc agtacatcag gcacggcgag 1080
gagtacgagc tgcagttcat cttccagctg tgcaagatca ccctgaccac cgaggtgatg 1140
gcctacctgc acaccatgga ccccaccatc ctggagcagt ggaacttcgg cctgaccctg 1200
ccccccagcg ccagcctgga ggacgcctac aggttcgtga ggaacgccgc caccagctgc 1260
cagaaggaca ccccccccca ggccaagccc gaccccctgg ccaagtacaa gttctgggac 1320
gtggacctga aggagaggtt cagcctggac ctggaccagt tcgccctggg caggaagttc 1380
ctgctgcagg tgggcgtgca gaggaagccc aggcccggcc tgaagaggcc cgctagcagc 1440
gccagctcca gcagctccag cagcgccaag aggaagaggg tgaagaagta a 1491
<210> 34
<211> 1491
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码H51N9-69T1-26S4的DNA序列
<400> 34
atgaaggtgt acctgccccc cgcccccgtg agcaggatcg tgaacaccga ggagtacatc 60
accaggaccg gcatctacta ctacgccggc agcagcaggc tgatcaccct gggccacccc 120
tacttcccga tcccgaaatc tggttctacc gctgaaatcc cgaaggtctc tgccttccag 180
tacagggtgt tcagggtgca gctccccgac cccaacaagt tcggcctgcc cgaccccaac 240
ctgtacaacc ccgacaccga caggctggtg tggggctgcg tgggcgtgga ggtgggcagg 300
ggccagcccc tgggcgtggg cctgagcggc caccccctgt tcaacaagta cgacgacacc 360
gagaacagca ggatcgccaa cggcaacgcc cagcaggacg tgagggacaa caccagcgtg 420
gacaacaagc agacccagct gtgcatcatc ggctgcgccc cccccatcgg cgagcactgg 480
ggcatcggca ccacctgcaa gaacaccccc gtgccccccg gcgactgccc ccccctggag 540
ctggtgagca gcgtgatcca ggacggcgac atgatcgaca ccggcttcgg cgccatggac 600
ttcgccgccc tgcaggccac caagagcgac gtgcccctgg acatcagcca gagcgtgtgc 660
aagtaccccg actacctgaa gatgagcgcc gacacctacg gcaacagcat gttcttccac 720
ctgaggaggg agcagatctt cgccaggcac ttctacaaca aagctggtgc tgttggtgac 780
gctatcccga ccaccctgta catcaaaggt gctgaatctg gtcgtgaacc gccgacctct 840
tctatctact ctgccacccc cagcggcagc atgatcacca gcgacagcca gatcttcaac 900
aagccctact ggctgcacag ggcccagggc cacaacaacg gcatctgctg gaacaaccag 960
ctgttcatca cctgcgtgga caccaccagg agcaccaacc tgaccatcag caccgccacc 1020
gccgccgtga gccccacctt cacccccagc aacttcaagc agtacatcag gcacggcgag 1080
gagtacgagc tgcagttcat cttccagctg tgcaagatca ccctgaccac cgaggtgatg 1140
gcctacctgc acaccatgga ccccaccatc ctggagcagt ggaacttcgg cctgaccctg 1200
ccccccagcg ccagcctgga ggacgcctac aggttcgtga ggaacgccgc caccagctgc 1260
cagaaggaca ccccccccca ggccaagccc gaccccctgg ccaagtacaa gttctgggac 1320
gtggacctga aggagaggtt cagcctggac ctggaccagt tcgccctggg caggaagttc 1380
ctgctgcagg tgggcgtgca gaggaagccc aggcccggcc tgaagaggcc cgctagcagc 1440
gccagctcca gcagctccag cagcgccaag aggaagaggg tgaagaagta a 1491
<210> 35
<211> 1494
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码H51N9-69T1-26S5的DNA序列
<400> 35
atgaaggtgt acctgccccc cgcccccgtg agcaggatcg tgaacaccga ggagtacatc 60
accaggaccg gcatctacta ctacgccggc agcagcaggc tgatcaccct gggccacccc 120
tacttcccga tcccgaaatc tggttctacc gctgaaatcc cgaaggtctc tgccttccag 180
tacagggtgt tcagggtgca gctccccgac cccaacaagt tcggcctgcc cgaccccaac 240
ctgtacaacc ccgacaccga caggctggtg tggggctgcg tgggcgtgga ggtgggcagg 300
ggccagcccc tgggcgtggg cctgagcggc caccccctgt tcaacaagta cgacgacacc 360
gagaacagca ggatcgccaa cggcaacgcc cagcaggacg tgagggacaa caccagcgtg 420
gacaacaagc agacccagct gtgcatcatc ggctgcgccc cccccatcgg cgagcactgg 480
ggcatcggca ccacctgcaa gaacaccccc gtgccccccg gcgactgccc ccccctggag 540
ctggtgagca gcgtgatcca ggacggcgac atgatcgaca ccggcttcgg cgccatggac 600
ttcgccgccc tgcaggccac caagagcgac gtgcccctgg acatcagcca gagcgtgtgc 660
aagtaccccg actacctgaa gatgagcgcc gacacctacg gcaacagcat gttcttccac 720
ctgaggaggg agcagatctt cgccaggcac tactacaaca agctgggcag cgtgggcgag 780
gacatcccca ccgactacta catcaagggc agcggcaacg gcagggaccc catcgagagc 840
tacatctaca gcgccacccc cagcggcagc atgatcacca gcgacagcca gatcttcaac 900
aagccctact ggctgcacag ggcccagggc cacaacaacg gcatctgctg gaacaaccag 960
ctgttcatca cctgcgtgga caccaccagg agcaccaacc tgaccatcag caccgcctct 1020
gctgcttctg cttctacccc gttcaaaccg tctgacttca agcagtacat caggcacggc 1080
gaggagtacg agctgcagtt catcttccag ctgtgcaaga tcaccctgac caccgaggtg 1140
atggcctacc tgcacaccat ggaccccacc atcctggagc agtggaactt cggcctgacc 1200
ctgcccccca gcgccagcct ggaggacgcc tacaggttcg tgaggaacgc cgccaccagc 1260
tgccagaagg acaccccccc ccaggccaag cccgaccccc tggccaagta caagttctgg 1320
gacgtggacc tgaaggagag gttcagcctg gacctggacc agttcgccct gggcaggaag 1380
ttcctgctgc aggtgggcgt gcagaggaag cccaggcccg gcctgaagag gcccgctagc 1440
agcgccagct ccagcagctc cagcagcgcc aagaggaaga gggtgaagaa gtaa 1494
<210> 36
<211> 1497
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码H51N9-69T3-26S1的DNA序列
<400> 36
atgaaggtgt acctgccccc cgcccccgtg agcaggatcg tgaacaccga ggagtacatc 60
accaggaccg gcatctacta ctacgccggc agcagcaggc tgatcaccct gggccacccc 120
tacttctcta tcccgaaaac cggtcagaaa gctgaaatcc cgaaagtttc tgccttccag 180
tacagggtgt tcagggtgca gctccccgac cccaacaagt tcggcctgcc cgaccccaac 240
ctgtacaacc ccgacaccga caggctggtg tggggctgcg tgggcgtgga ggtgggcagg 300
ggccagcccc tgggcgtggg cctgagcggc caccccctgt tcaacaagta cgacgacacc 360
gagaacagca ggatcgccaa cggcaacgcc cagcaggacg tgagggacaa caccagcgtg 420
gacaacaagc agacccagct gtgcatcatc ggctgcgccc cccccatcgg cgagcactgg 480
ggtgtcggta ccgtttgcaa aaacgctcag tctcaggttc agcgtggtga ctgcccgccg 540
ctggagctgg tgagcagcgt gatccaggac ggcgacatga tcgacaccgg cttcggcgcc 600
atggacttcg ccgccctgca ggccaccaag agcgacgtgc ccctggacat cagccagagc 660
gtgtgcaagt accccgacta cctgaagatg agcgccgaca cctacggcaa cagcatgttc 720
ttccacctga ggagggagca gatcttcgcc aggcactact acaacaagct gggcagcgtg 780
ggcgaggaca tccccaccga ctactacatc aagggcagcg gcaacggcag ggaccccatc 840
gagagctaca tctacagcgc cacccccagc ggcagcatga tcaccagcga cagccagatc 900
ttcaacaagc cctactggct gcacagggcc cagggccaca acaacggcat ctgctggaac 960
aaccagctgt tcatcacctg cgtggacacc accaggagca ccaacctgac catcagcacc 1020
gccaccgccg ccgtgagccc caccttcacc cccagcaact tcaagcagta catcaggcac 1080
ggcgaggagt acgagctgca gttcatcttc cagctgtgca agatcaccct gaccaccgag 1140
gtgatggcct acctgcacac catggacccc accatcctgg agcagtggaa cttcggcctg 1200
accctgcccc ccagcgccag cctggaggac gcctacaggt tcgtgaggaa cgccgccacc 1260
agctgccaga aggacacccc cccccaggcc aagcccgacc ccctggccaa gtacaagttc 1320
tgggacgtgg acctgaagga gaggttcagc ctggacctgg accagttcgc cctgggcagg 1380
aagttcctgc tgcaggtggg cgtgcagagg aagcccaggc ccggcctgaa gaggcccgct 1440
agcagcgcca gctccagcag ctccagcagc gccaagagga agagggtgaa gaagtaa 1497
<210> 37
<211> 1497
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码H51N9-69T3-26S2的DNA序列
<400> 37
atgaaggtgt acctgccccc cgcccccgtg agcaggatcg tgaacaccga ggagtacatc 60
accaggaccg gcatctacta ctacgccggc agcagcaggc tgatcaccct gggccacccc 120
tacttccccc tgcccaagac cagcaccagg gccgccatcc ccaaggtgag cgccttccag 180
tacagggtgt tcagggtgca gctccccgac cccaacaagt tcggcctgcc cgaccccaac 240
ctgtacaacc ccgacaccga caggctggtg tggggctgcg tgggcgtgga ggtgggtcgt 300
ggtcagccgc tgggtatcgg tctgtctggt cacccgctgt tcaacaaact ggacgacacc 360
gaaaactctc acctggctac cgttaacgct gacaccgaca accgtgacaa cgtttctgtt 420
gacaacaagc agacccagct gtgcatcatc ggctgcgccc cccccatcgg cgagcactgg 480
ggtgtcggta ccgtttgcaa aaacgctcag tctcaggttc agcgtggtga ctgcccgccg 540
ctggagctgg tgagcagcgt gatccaggac ggcgacatga tcgacaccgg cttcggcgcc 600
atggacttcg ccgccctgca ggccaccaag agcgacgtgc ccctggacat cagccagagc 660
gtgtgcaagt accccgacta cctgaagatg agcgccgaca cctacggcaa cagcatgttc 720
ttccacctga ggagggagca gatcttcgcc aggcactact acaacaagct gggcagcgtg 780
ggcgaggaca tccccaccga ctactacatc aagggcagcg gcaacggcag ggaccccatc 840
gagagctaca tctacagcgc cacccccagc ggcagcatga tcaccagcga cagccagatc 900
ttcaacaagc cctactggct gcacagggcc cagggccaca acaacggcat ctgctggaac 960
aaccagctgt tcatcacctg cgtggacacc accaggagca ccaacctgac catcagcacc 1020
gccaccgccg ccgtgagccc caccttcacc cccagcaact tcaagcagta catcaggcac 1080
ggcgaggagt acgagctgca gttcatcttc cagctgtgca agatcaccct gaccaccgag 1140
gtgatggcct acctgcacac catggacccc accatcctgg agcagtggaa cttcggcctg 1200
accctgcccc ccagcgccag cctggaggac gcctacaggt tcgtgaggaa cgccgccacc 1260
agctgccaga aggacacccc cccccaggcc aagcccgacc ccctggccaa gtacaagttc 1320
tgggacgtgg acctgaagga gaggttcagc ctggacctgg accagttcgc cctgggcagg 1380
aagttcctgc tgcaggtggg cgtgcagagg aagcccaggc ccggcctgaa gaggcccgct 1440
agcagcgcca gctccagcag ctccagcagc gccaagagga agagggtgaa gaagtaa 1497
<210> 38
<211> 1497
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码H51N9-69T3-26S4的DNA序列
<400> 38
atgaaggtgt acctgccccc cgcccccgtg agcaggatcg tgaacaccga ggagtacatc 60
accaggaccg gcatctacta ctacgccggc agcagcaggc tgatcaccct gggccacccc 120
tacttccccc tgcccaagac cagcaccagg gccgccatcc ccaaggtgag cgccttccag 180
tacagggtgt tcagggtgca gctccccgac cccaacaagt tcggcctgcc cgaccccaac 240
ctgtacaacc ccgacaccga caggctggtg tggggctgcg tgggcgtgga ggtgggcagg 300
ggccagcccc tgggcgtggg cctgagcggc caccccctgt tcaacaagta cgacgacacc 360
gagaacagca ggatcgccaa cggcaacgcc cagcaggacg tgagggacaa caccagcgtg 420
gacaacaagc agacccagct gtgcatcatc ggctgcgccc cccccatcgg cgagcactgg 480
ggtgtcggta ccgtttgcaa aaacgctcag tctcaggttc agcgtggtga ctgcccgccg 540
ctggagctgg tgagcagcgt gatccaggac ggcgacatga tcgacaccgg cttcggcgcc 600
atggacttcg ccgccctgca ggccaccaag agcgacgtgc ccctggacat cagccagagc 660
gtgtgcaagt accccgacta cctgaagatg agcgccgaca cctacggcaa cagcatgttc 720
ttccacctga ggagggagca gatcttcgcc aggcacttct acaacaaagc tggtgctgtt 780
ggtgacgcta tcccgaccac cctgtacatc aaaggtgctg aatctggtcg tgaaccgccg 840
acctcttcta tctactctgc cacccccagc ggcagcatga tcaccagcga cagccagatc 900
ttcaacaagc cctactggct gcacagggcc cagggccaca acaacggcat ctgctggaac 960
aaccagctgt tcatcacctg cgtggacacc accaggagca ccaacctgac catcagcacc 1020
gccaccgccg ccgtgagccc caccttcacc cccagcaact tcaagcagta catcaggcac 1080
ggcgaggagt acgagctgca gttcatcttc cagctgtgca agatcaccct gaccaccgag 1140
gtgatggcct acctgcacac catggacccc accatcctgg agcagtggaa cttcggcctg 1200
accctgcccc ccagcgccag cctggaggac gcctacaggt tcgtgaggaa cgccgccacc 1260
agctgccaga aggacacccc cccccaggcc aagcccgacc ccctggccaa gtacaagttc 1320
tgggacgtgg acctgaagga gaggttcagc ctggacctgg accagttcgc cctgggcagg 1380
aagttcctgc tgcaggtggg cgtgcagagg aagcccaggc ccggcctgaa gaggcccgct 1440
agcagcgcca gctccagcag ctccagcagc gccaagagga agagggtgaa gaagtaa 1497
<210> 39
<211> 1500
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码H51N9-69T3-26S5的DNA序列
<400> 39
atgaaggtgt acctgccccc cgcccccgtg agcaggatcg tgaacaccga ggagtacatc 60
accaggaccg gcatctacta ctacgccggc agcagcaggc tgatcaccct gggccacccc 120
tacttccccc tgcccaagac cagcaccagg gccgccatcc ccaaggtgag cgccttccag 180
tacagggtgt tcagggtgca gctccccgac cccaacaagt tcggcctgcc cgaccccaac 240
ctgtacaacc ccgacaccga caggctggtg tggggctgcg tgggcgtgga ggtgggcagg 300
ggccagcccc tgggcgtggg cctgagcggc caccccctgt tcaacaagta cgacgacacc 360
gagaacagca ggatcgccaa cggcaacgcc cagcaggacg tgagggacaa caccagcgtg 420
gacaacaagc agacccagct gtgcatcatc ggctgcgccc cccccatcgg cgagcactgg 480
ggtgtcggta ccgtttgcaa aaacgctcag tctcaggttc agcgtggtga ctgcccgccg 540
ctggagctgg tgagcagcgt gatccaggac ggcgacatga tcgacaccgg cttcggcgcc 600
atggacttcg ccgccctgca ggccaccaag agcgacgtgc ccctggacat cagccagagc 660
gtgtgcaagt accccgacta cctgaagatg agcgccgaca cctacggcaa cagcatgttc 720
ttccacctga ggagggagca gatcttcgcc aggcactact acaacaagct gggcagcgtg 780
ggcgaggaca tccccaccga ctactacatc aagggcagcg gcaacggcag ggaccccatc 840
gagagctaca tctacagcgc cacccccagc ggcagcatga tcaccagcga cagccagatc 900
ttcaacaagc cctactggct gcacagggcc cagggccaca acaacggcat ctgctggaac 960
aaccagctgt tcatcacctg cgtggacacc accaggagca ccaacctgac catcagcacc 1020
gcctctgctg cttctgcttc taccccgttc aaaccgtctg acttcaagca gtacatcagg 1080
cacggcgagg agtacgagct gcagttcatc ttccagctgt gcaagatcac cctgaccacc 1140
gaggtgatgg cctacctgca caccatggac cccaccatcc tggagcagtg gaacttcggc 1200
ctgaccctgc cccccagcgc cagcctggag gacgcctaca ggttcgtgag gaacgccgcc 1260
accagctgcc agaaggacac ccccccccag gccaagcccg accccctggc caagtacaag 1320
ttctgggacg tggacctgaa ggagaggttc agcctggacc tggaccagtt cgccctgggc 1380
aggaagttcc tgctgcaggt gggcgtgcag aggaagccca ggcccggcct gaagaggccc 1440
gctagcagcg ccagctccag cagctccagc agcgccaaga ggaagagggt gaagaagtaa 1500
<210> 40
<211> 496
<212> PRT
<213> Artificial Sequence
<220>
<223> H51N9-69T2-26S1
<400> 40
Met Lys Val Tyr Leu Pro Pro Ala Pro Val Ser Arg Ile Val Asn Thr
1 5 10 15
Glu Glu Tyr Ile Thr Arg Thr Gly Ile Tyr Tyr Tyr Ala Gly Ser Ser
20 25 30
Arg Leu Ile Thr Leu Gly His Pro Tyr Phe Ser Ile Pro Lys Thr Gly
35 40 45
Gln Lys Ala Glu Ile Pro Lys Val Ser Ala Phe Gln Tyr Arg Val Phe
50 55 60
Arg Val Gln Leu Pro Asp Pro Asn Lys Phe Gly Leu Pro Asp Pro Asn
65 70 75 80
Leu Tyr Asn Pro Asp Thr Asp Arg Leu Val Trp Gly Cys Val Gly Val
85 90 95
Glu Val Gly Arg Gly Gln Pro Leu Gly Val Gly Leu Ser Gly His Pro
100 105 110
Leu Phe Asn Lys Leu Asp Asp Thr Glu Asn Ser His Leu Ala Thr Ala
115 120 125
Asn Ala Asp Thr Asp Asn Arg Asp Asn Val Cys Val Asp Asn Lys Gln
130 135 140
Thr Gln Leu Cys Ile Ile Gly Cys Ala Pro Pro Ile Gly Glu His Trp
145 150 155 160
Gly Ile Gly Thr Thr Cys Lys Asn Thr Pro Val Pro Pro Gly Asp Cys
165 170 175
Pro Pro Leu Glu Leu Val Ser Ser Val Ile Gln Asp Gly Asp Met Ile
180 185 190
Asp Thr Gly Phe Gly Ala Met Asp Phe Ala Ala Leu Gln Ala Thr Lys
195 200 205
Ser Asp Val Pro Leu Asp Ile Ser Gln Ser Val Cys Lys Tyr Pro Asp
210 215 220
Tyr Leu Lys Met Ser Ala Asp Thr Tyr Gly Asn Ser Met Phe Phe His
225 230 235 240
Leu Arg Arg Glu Gln Ile Phe Ala Arg His Tyr Tyr Asn Lys Leu Gly
245 250 255
Ser Val Gly Glu Asp Ile Pro Thr Asp Tyr Tyr Ile Lys Gly Ser Gly
260 265 270
Asn Gly Arg Asp Pro Ile Glu Ser Tyr Ile Tyr Ser Ala Thr Pro Ser
275 280 285
Gly Ser Met Ile Thr Ser Asp Ser Gln Ile Phe Asn Lys Pro Tyr Trp
290 295 300
Leu His Arg Ala Gln Gly His Asn Asn Gly Ile Cys Trp Asn Asn Gln
305 310 315 320
Leu Phe Ile Thr Cys Val Asp Thr Thr Arg Ser Thr Asn Leu Thr Ile
325 330 335
Ser Thr Ala Thr Ala Ala Val Ser Pro Thr Phe Thr Pro Ser Asn Phe
340 345 350
Lys Gln Tyr Ile Arg His Gly Glu Glu Tyr Glu Leu Gln Phe Ile Phe
355 360 365
Gln Leu Cys Lys Ile Thr Leu Thr Thr Glu Val Met Ala Tyr Leu His
370 375 380
Thr Met Asp Pro Thr Ile Leu Glu Gln Trp Asn Phe Gly Leu Thr Leu
385 390 395 400
Pro Pro Ser Ala Ser Leu Glu Asp Ala Tyr Arg Phe Val Arg Asn Ala
405 410 415
Ala Thr Ser Cys Gln Lys Asp Thr Pro Pro Gln Ala Lys Pro Asp Pro
420 425 430
Leu Ala Lys Tyr Lys Phe Trp Asp Val Asp Leu Lys Glu Arg Phe Ser
435 440 445
Leu Asp Leu Asp Gln Phe Ala Leu Gly Arg Lys Phe Leu Leu Gln Val
450 455 460
Gly Val Gln Arg Lys Pro Arg Pro Gly Leu Lys Arg Pro Ala Ser Ser
465 470 475 480
Ala Ser Ser Ser Ser Ser Ser Ser Ala Lys Arg Lys Arg Val Lys Lys
485 490 495
<210> 41
<211> 496
<212> PRT
<213> Artificial Sequence
<220>
<223> H51N9-69T2-26S3
<400> 41
Met Lys Val Tyr Leu Pro Pro Ala Pro Val Ser Arg Ile Val Asn Thr
1 5 10 15
Glu Glu Tyr Ile Thr Arg Thr Gly Ile Tyr Tyr Tyr Ala Gly Ser Ser
20 25 30
Arg Leu Ile Thr Leu Gly His Pro Tyr Phe Pro Leu Pro Lys Thr Ser
35 40 45
Thr Arg Ala Ala Ile Pro Lys Val Ser Ala Phe Gln Tyr Arg Val Phe
50 55 60
Arg Val Gln Leu Pro Asp Pro Asn Lys Phe Gly Leu Pro Asp Pro Asn
65 70 75 80
Leu Tyr Asn Pro Asp Thr Asp Arg Leu Val Trp Gly Cys Val Gly Val
85 90 95
Glu Val Gly Arg Gly Gln Pro Leu Gly Val Gly Leu Ser Gly His Pro
100 105 110
Leu Phe Asn Lys Leu Asp Asp Thr Glu Asn Ser His Leu Ala Thr Ala
115 120 125
Asn Ala Asp Thr Asp Asn Arg Asp Asn Val Cys Val Asp Asn Lys Gln
130 135 140
Thr Gln Leu Cys Ile Ile Gly Cys Ala Pro Pro Ile Gly Glu His Trp
145 150 155 160
Gly Ile Gly Thr Ile Cys Lys Asn Thr Gln Thr Gln Arg Gly Asp Cys
165 170 175
Pro Pro Leu Glu Leu Val Ser Ser Val Ile Gln Asp Gly Asp Met Ile
180 185 190
Asp Thr Gly Phe Gly Ala Met Asp Phe Ala Ala Leu Gln Ala Thr Lys
195 200 205
Ser Asp Val Pro Leu Asp Ile Ser Gln Ser Val Cys Lys Tyr Pro Asp
210 215 220
Tyr Leu Lys Met Ser Ala Asp Thr Tyr Gly Asn Ser Met Phe Phe His
225 230 235 240
Leu Arg Arg Glu Gln Ile Phe Ala Arg His Tyr Tyr Asn Lys Leu Gly
245 250 255
Ser Val Gly Glu Asp Ile Pro Thr Asp Tyr Tyr Ile Lys Gly Ser Gly
260 265 270
Asn Gly Arg Asp Pro Ile Glu Ser Tyr Ile Tyr Ser Ala Thr Pro Ser
275 280 285
Gly Ser Met Ile Thr Ser Asp Ser Gln Ile Phe Asn Lys Pro Tyr Trp
290 295 300
Leu His Arg Ala Gln Gly His Asn Asn Gly Ile Cys Trp Asn Asn Gln
305 310 315 320
Leu Phe Ile Thr Cys Val Asp Thr Thr Arg Ser Thr Asn Leu Thr Ile
325 330 335
Ser Thr Ala Thr Ala Ala Val Ser Pro Thr Phe Thr Pro Ser Asn Phe
340 345 350
Lys Gln Tyr Ile Arg His Gly Glu Glu Tyr Glu Leu Gln Phe Ile Phe
355 360 365
Gln Leu Cys Lys Ile Thr Leu Thr Thr Glu Val Met Ala Tyr Leu His
370 375 380
Thr Met Asp Pro Thr Ile Leu Glu Gln Trp Asn Phe Gly Leu Thr Leu
385 390 395 400
Pro Pro Ser Ala Ser Leu Glu Asp Ala Tyr Arg Phe Val Arg Asn Ala
405 410 415
Ala Thr Ser Cys Gln Lys Asp Thr Pro Pro Gln Ala Lys Pro Asp Pro
420 425 430
Leu Ala Lys Tyr Lys Phe Trp Asp Val Asp Leu Lys Glu Arg Phe Ser
435 440 445
Leu Asp Leu Asp Gln Phe Ala Leu Gly Arg Lys Phe Leu Leu Gln Val
450 455 460
Gly Val Gln Arg Lys Pro Arg Pro Gly Leu Lys Arg Pro Ala Ser Ser
465 470 475 480
Ala Ser Ser Ser Ser Ser Ser Ser Ala Lys Arg Lys Arg Val Lys Lys
485 490 495
<210> 42
<211> 496
<212> PRT
<213> Artificial Sequence
<220>
<223> H51N9-69T2-26S4
<400> 42
Met Lys Val Tyr Leu Pro Pro Ala Pro Val Ser Arg Ile Val Asn Thr
1 5 10 15
Glu Glu Tyr Ile Thr Arg Thr Gly Ile Tyr Tyr Tyr Ala Gly Ser Ser
20 25 30
Arg Leu Ile Thr Leu Gly His Pro Tyr Phe Pro Leu Pro Lys Thr Ser
35 40 45
Thr Arg Ala Ala Ile Pro Lys Val Ser Ala Phe Gln Tyr Arg Val Phe
50 55 60
Arg Val Gln Leu Pro Asp Pro Asn Lys Phe Gly Leu Pro Asp Pro Asn
65 70 75 80
Leu Tyr Asn Pro Asp Thr Asp Arg Leu Val Trp Gly Cys Val Gly Val
85 90 95
Glu Val Gly Arg Gly Gln Pro Leu Gly Val Gly Leu Ser Gly His Pro
100 105 110
Leu Phe Asn Lys Leu Asp Asp Thr Glu Asn Ser His Leu Ala Thr Ala
115 120 125
Asn Ala Asp Thr Asp Asn Arg Asp Asn Val Cys Val Asp Asn Lys Gln
130 135 140
Thr Gln Leu Cys Ile Ile Gly Cys Ala Pro Pro Ile Gly Glu His Trp
145 150 155 160
Gly Ile Gly Thr Thr Cys Lys Asn Thr Pro Val Pro Pro Gly Asp Cys
165 170 175
Pro Pro Leu Glu Leu Val Ser Ser Val Ile Gln Asp Gly Asp Met Ile
180 185 190
Asp Thr Gly Phe Gly Ala Met Asp Phe Ala Ala Leu Gln Ala Thr Lys
195 200 205
Ser Asp Val Pro Leu Asp Ile Ser Gln Ser Val Cys Lys Tyr Pro Asp
210 215 220
Tyr Leu Lys Met Ser Ala Asp Thr Tyr Gly Asn Ser Met Phe Phe His
225 230 235 240
Leu Arg Arg Glu Gln Ile Phe Ala Arg His Phe Tyr Asn Lys Ala Gly
245 250 255
Ala Val Gly Asp Ala Ile Pro Thr Thr Leu Tyr Ile Lys Gly Ala Glu
260 265 270
Ser Gly Arg Glu Pro Pro Thr Ser Ser Ile Tyr Ser Ala Thr Pro Ser
275 280 285
Gly Ser Met Ile Thr Ser Asp Ser Gln Ile Phe Asn Lys Pro Tyr Trp
290 295 300
Leu His Arg Ala Gln Gly His Asn Asn Gly Ile Cys Trp Asn Asn Gln
305 310 315 320
Leu Phe Ile Thr Cys Val Asp Thr Thr Arg Ser Thr Asn Leu Thr Ile
325 330 335
Ser Thr Ala Thr Ala Ala Val Ser Pro Thr Phe Thr Pro Ser Asn Phe
340 345 350
Lys Gln Tyr Ile Arg His Gly Glu Glu Tyr Glu Leu Gln Phe Ile Phe
355 360 365
Gln Leu Cys Lys Ile Thr Leu Thr Thr Glu Val Met Ala Tyr Leu His
370 375 380
Thr Met Asp Pro Thr Ile Leu Glu Gln Trp Asn Phe Gly Leu Thr Leu
385 390 395 400
Pro Pro Ser Ala Ser Leu Glu Asp Ala Tyr Arg Phe Val Arg Asn Ala
405 410 415
Ala Thr Ser Cys Gln Lys Asp Thr Pro Pro Gln Ala Lys Pro Asp Pro
420 425 430
Leu Ala Lys Tyr Lys Phe Trp Asp Val Asp Leu Lys Glu Arg Phe Ser
435 440 445
Leu Asp Leu Asp Gln Phe Ala Leu Gly Arg Lys Phe Leu Leu Gln Val
450 455 460
Gly Val Gln Arg Lys Pro Arg Pro Gly Leu Lys Arg Pro Ala Ser Ser
465 470 475 480
Ala Ser Ser Ser Ser Ser Ser Ser Ala Lys Arg Lys Arg Val Lys Lys
485 490 495
<210> 43
<211> 497
<212> PRT
<213> Artificial Sequence
<220>
<223> H51N9-69T2-26S5
<400> 43
Met Lys Val Tyr Leu Pro Pro Ala Pro Val Ser Arg Ile Val Asn Thr
1 5 10 15
Glu Glu Tyr Ile Thr Arg Thr Gly Ile Tyr Tyr Tyr Ala Gly Ser Ser
20 25 30
Arg Leu Ile Thr Leu Gly His Pro Tyr Phe Pro Leu Pro Lys Thr Ser
35 40 45
Thr Arg Ala Ala Ile Pro Lys Val Ser Ala Phe Gln Tyr Arg Val Phe
50 55 60
Arg Val Gln Leu Pro Asp Pro Asn Lys Phe Gly Leu Pro Asp Pro Asn
65 70 75 80
Leu Tyr Asn Pro Asp Thr Asp Arg Leu Val Trp Gly Cys Val Gly Val
85 90 95
Glu Val Gly Arg Gly Gln Pro Leu Gly Val Gly Leu Ser Gly His Pro
100 105 110
Leu Phe Asn Lys Leu Asp Asp Thr Glu Asn Ser His Leu Ala Thr Ala
115 120 125
Asn Ala Asp Thr Asp Asn Arg Asp Asn Val Cys Val Asp Asn Lys Gln
130 135 140
Thr Gln Leu Cys Ile Ile Gly Cys Ala Pro Pro Ile Gly Glu His Trp
145 150 155 160
Gly Ile Gly Thr Thr Cys Lys Asn Thr Pro Val Pro Pro Gly Asp Cys
165 170 175
Pro Pro Leu Glu Leu Val Ser Ser Val Ile Gln Asp Gly Asp Met Ile
180 185 190
Asp Thr Gly Phe Gly Ala Met Asp Phe Ala Ala Leu Gln Ala Thr Lys
195 200 205
Ser Asp Val Pro Leu Asp Ile Ser Gln Ser Val Cys Lys Tyr Pro Asp
210 215 220
Tyr Leu Lys Met Ser Ala Asp Thr Tyr Gly Asn Ser Met Phe Phe His
225 230 235 240
Leu Arg Arg Glu Gln Ile Phe Ala Arg His Tyr Tyr Asn Lys Leu Gly
245 250 255
Ser Val Gly Glu Asp Ile Pro Thr Asp Tyr Tyr Ile Lys Gly Ser Gly
260 265 270
Asn Gly Arg Asp Pro Ile Glu Ser Tyr Ile Tyr Ser Ala Thr Pro Ser
275 280 285
Gly Ser Met Ile Thr Ser Asp Ser Gln Ile Phe Asn Lys Pro Tyr Trp
290 295 300
Leu His Arg Ala Gln Gly His Asn Asn Gly Ile Cys Trp Asn Asn Gln
305 310 315 320
Leu Phe Ile Thr Cys Val Asp Thr Thr Arg Ser Thr Asn Leu Thr Ile
325 330 335
Ser Thr Ala Ser Ala Ala Ser Ala Ser Thr Pro Phe Lys Pro Ser Asp
340 345 350
Phe Lys Gln Tyr Ile Arg His Gly Glu Glu Tyr Glu Leu Gln Phe Ile
355 360 365
Phe Gln Leu Cys Lys Ile Thr Leu Thr Thr Glu Val Met Ala Tyr Leu
370 375 380
His Thr Met Asp Pro Thr Ile Leu Glu Gln Trp Asn Phe Gly Leu Thr
385 390 395 400
Leu Pro Pro Ser Ala Ser Leu Glu Asp Ala Tyr Arg Phe Val Arg Asn
405 410 415
Ala Ala Thr Ser Cys Gln Lys Asp Thr Pro Pro Gln Ala Lys Pro Asp
420 425 430
Pro Leu Ala Lys Tyr Lys Phe Trp Asp Val Asp Leu Lys Glu Arg Phe
435 440 445
Ser Leu Asp Leu Asp Gln Phe Ala Leu Gly Arg Lys Phe Leu Leu Gln
450 455 460
Val Gly Val Gln Arg Lys Pro Arg Pro Gly Leu Lys Arg Pro Ala Ser
465 470 475 480
Ser Ala Ser Ser Ser Ser Ser Ser Ser Ala Lys Arg Lys Arg Val Lys
485 490 495
Lys
<210> 44
<211> 496
<212> PRT
<213> Artificial Sequence
<220>
<223> H51N9-69T4-26S1
<400> 44
Met Lys Val Tyr Leu Pro Pro Ala Pro Val Ser Arg Ile Val Asn Thr
1 5 10 15
Glu Glu Tyr Ile Thr Arg Thr Gly Ile Tyr Tyr Tyr Ala Gly Ser Ser
20 25 30
Arg Leu Ile Thr Leu Gly His Pro Tyr Phe Ser Ile Pro Lys Thr Gly
35 40 45
Gln Lys Ala Glu Ile Pro Lys Val Ser Ala Phe Gln Tyr Arg Val Phe
50 55 60
Arg Val Gln Leu Pro Asp Pro Asn Lys Phe Gly Leu Pro Asp Pro Asn
65 70 75 80
Leu Tyr Asn Pro Asp Thr Asp Arg Leu Val Trp Gly Cys Val Gly Val
85 90 95
Glu Val Gly Arg Gly Gln Pro Leu Gly Val Gly Leu Ser Gly His Pro
100 105 110
Leu Phe Asn Lys Tyr Asp Asp Thr Glu Asn Ser Arg Ile Ala Asn Gly
115 120 125
Asn Ala Gln Gln Asp Val Arg Asp Asn Thr Ser Val Asp Asn Lys Gln
130 135 140
Thr Gln Leu Cys Ile Ile Gly Cys Ala Pro Pro Ile Gly Glu His Trp
145 150 155 160
Gly Ile Gly Thr Thr Cys Lys Asn Thr Pro Val Pro Pro Gly Asp Cys
165 170 175
Pro Pro Leu Glu Leu Val Ser Ser Val Ile Gln Asp Gly Asp Met Ile
180 185 190
Asp Thr Gly Phe Gly Ala Met Asp Phe Ala Ala Leu Gln Ala Thr Lys
195 200 205
Ser Asp Val Pro Leu Asp Ile Ser Gln Ser Val Cys Lys Tyr Pro Asp
210 215 220
Tyr Leu Lys Met Ser Ala Asp Thr Tyr Gly Asn Ser Met Phe Phe His
225 230 235 240
Leu Arg Arg Glu Gln Ile Phe Ala Arg His Phe Phe Asn Lys Ala Gly
245 250 255
Thr Ile Gly Asp Pro Val Pro Val Ser Met Tyr Ile Lys Gly Ala Gly
260 265 270
Gln Gly Arg Glu Pro Pro Thr Thr Ser Ile Tyr Ser Ala Thr Pro Ser
275 280 285
Gly Ser Met Ile Thr Ser Asp Ser Gln Ile Phe Asn Lys Pro Tyr Trp
290 295 300
Leu His Arg Ala Gln Gly His Asn Asn Gly Ile Cys Trp Asn Asn Gln
305 310 315 320
Leu Phe Ile Thr Cys Val Asp Thr Thr Arg Ser Thr Asn Leu Thr Ile
325 330 335
Ser Thr Ala Thr Ala Ala Val Ser Pro Thr Phe Thr Pro Ser Asn Phe
340 345 350
Lys Gln Tyr Ile Arg His Gly Glu Glu Tyr Glu Leu Gln Phe Ile Phe
355 360 365
Gln Leu Cys Lys Ile Thr Leu Thr Thr Glu Val Met Ala Tyr Leu His
370 375 380
Thr Met Asp Pro Thr Ile Leu Glu Gln Trp Asn Phe Gly Leu Thr Leu
385 390 395 400
Pro Pro Ser Ala Ser Leu Glu Asp Ala Tyr Arg Phe Val Arg Asn Ala
405 410 415
Ala Thr Ser Cys Gln Lys Asp Thr Pro Pro Gln Ala Lys Pro Asp Pro
420 425 430
Leu Ala Lys Tyr Lys Phe Trp Asp Val Asp Leu Lys Glu Arg Phe Ser
435 440 445
Leu Asp Leu Asp Gln Phe Ala Leu Gly Arg Lys Phe Leu Leu Gln Val
450 455 460
Gly Val Gln Arg Lys Pro Arg Pro Gly Leu Lys Arg Pro Ala Ser Ser
465 470 475 480
Ala Ser Ser Ser Ser Ser Ser Ser Ala Lys Arg Lys Arg Val Lys Lys
485 490 495
<210> 45
<211> 496
<212> PRT
<213> Artificial Sequence
<220>
<223> H51N9-69T4-26S2
<400> 45
Met Lys Val Tyr Leu Pro Pro Ala Pro Val Ser Arg Ile Val Asn Thr
1 5 10 15
Glu Glu Tyr Ile Thr Arg Thr Gly Ile Tyr Tyr Tyr Ala Gly Ser Ser
20 25 30
Arg Leu Ile Thr Leu Gly His Pro Tyr Phe Pro Leu Pro Lys Thr Ser
35 40 45
Thr Arg Ala Ala Ile Pro Lys Val Ser Ala Phe Gln Tyr Arg Val Phe
50 55 60
Arg Val Gln Leu Pro Asp Pro Asn Lys Phe Gly Leu Pro Asp Pro Asn
65 70 75 80
Leu Tyr Asn Pro Asp Thr Asp Arg Leu Val Trp Gly Cys Val Gly Val
85 90 95
Glu Val Gly Arg Gly Gln Pro Leu Gly Ile Gly Leu Ser Gly His Pro
100 105 110
Leu Phe Asn Lys Leu Asp Asp Thr Glu Asn Ser His Leu Ala Thr Val
115 120 125
Asn Ala Asp Thr Asp Asn Arg Asp Asn Val Ser Val Asp Asn Lys Gln
130 135 140
Thr Gln Leu Cys Ile Ile Gly Cys Ala Pro Pro Ile Gly Glu His Trp
145 150 155 160
Gly Ile Gly Thr Thr Cys Lys Asn Thr Pro Val Pro Pro Gly Asp Cys
165 170 175
Pro Pro Leu Glu Leu Val Ser Ser Val Ile Gln Asp Gly Asp Met Ile
180 185 190
Asp Thr Gly Phe Gly Ala Met Asp Phe Ala Ala Leu Gln Ala Thr Lys
195 200 205
Ser Asp Val Pro Leu Asp Ile Ser Gln Ser Val Cys Lys Tyr Pro Asp
210 215 220
Tyr Leu Lys Met Ser Ala Asp Thr Tyr Gly Asn Ser Met Phe Phe His
225 230 235 240
Leu Arg Arg Glu Gln Ile Phe Ala Arg His Phe Phe Asn Lys Ala Gly
245 250 255
Thr Ile Gly Asp Pro Val Pro Val Ser Met Tyr Ile Lys Gly Ala Gly
260 265 270
Gln Gly Arg Glu Pro Pro Thr Thr Ser Ile Tyr Ser Ala Thr Pro Ser
275 280 285
Gly Ser Met Ile Thr Ser Asp Ser Gln Ile Phe Asn Lys Pro Tyr Trp
290 295 300
Leu His Arg Ala Gln Gly His Asn Asn Gly Ile Cys Trp Asn Asn Gln
305 310 315 320
Leu Phe Ile Thr Cys Val Asp Thr Thr Arg Ser Thr Asn Leu Thr Ile
325 330 335
Ser Thr Ala Thr Ala Ala Val Ser Pro Thr Phe Thr Pro Ser Asn Phe
340 345 350
Lys Gln Tyr Ile Arg His Gly Glu Glu Tyr Glu Leu Gln Phe Ile Phe
355 360 365
Gln Leu Cys Lys Ile Thr Leu Thr Thr Glu Val Met Ala Tyr Leu His
370 375 380
Thr Met Asp Pro Thr Ile Leu Glu Gln Trp Asn Phe Gly Leu Thr Leu
385 390 395 400
Pro Pro Ser Ala Ser Leu Glu Asp Ala Tyr Arg Phe Val Arg Asn Ala
405 410 415
Ala Thr Ser Cys Gln Lys Asp Thr Pro Pro Gln Ala Lys Pro Asp Pro
420 425 430
Leu Ala Lys Tyr Lys Phe Trp Asp Val Asp Leu Lys Glu Arg Phe Ser
435 440 445
Leu Asp Leu Asp Gln Phe Ala Leu Gly Arg Lys Phe Leu Leu Gln Val
450 455 460
Gly Val Gln Arg Lys Pro Arg Pro Gly Leu Lys Arg Pro Ala Ser Ser
465 470 475 480
Ala Ser Ser Ser Ser Ser Ser Ser Ala Lys Arg Lys Arg Val Lys Lys
485 490 495
<210> 46
<211> 496
<212> PRT
<213> Artificial Sequence
<220>
<223> H51N9-69T4-26S3
<400> 46
Met Lys Val Tyr Leu Pro Pro Ala Pro Val Ser Arg Ile Val Asn Thr
1 5 10 15
Glu Glu Tyr Ile Thr Arg Thr Gly Ile Tyr Tyr Tyr Ala Gly Ser Ser
20 25 30
Arg Leu Ile Thr Leu Gly His Pro Tyr Phe Pro Leu Pro Lys Thr Ser
35 40 45
Thr Arg Ala Ala Ile Pro Lys Val Ser Ala Phe Gln Tyr Arg Val Phe
50 55 60
Arg Val Gln Leu Pro Asp Pro Asn Lys Phe Gly Leu Pro Asp Pro Asn
65 70 75 80
Leu Tyr Asn Pro Asp Thr Asp Arg Leu Val Trp Gly Cys Val Gly Val
85 90 95
Glu Val Gly Arg Gly Gln Pro Leu Gly Val Gly Leu Ser Gly His Pro
100 105 110
Leu Phe Asn Lys Tyr Asp Asp Thr Glu Asn Ser Arg Ile Ala Asn Gly
115 120 125
Asn Ala Gln Gln Asp Val Arg Asp Asn Thr Ser Val Asp Asn Lys Gln
130 135 140
Thr Gln Leu Cys Ile Ile Gly Cys Ala Pro Pro Ile Gly Glu His Trp
145 150 155 160
Gly Ile Gly Thr Ile Cys Lys Asn Thr Gln Thr Gln Arg Gly Asp Cys
165 170 175
Pro Pro Leu Glu Leu Val Ser Ser Val Ile Gln Asp Gly Asp Met Ile
180 185 190
Asp Thr Gly Phe Gly Ala Met Asp Phe Ala Ala Leu Gln Ala Thr Lys
195 200 205
Ser Asp Val Pro Leu Asp Ile Ser Gln Ser Val Cys Lys Tyr Pro Asp
210 215 220
Tyr Leu Lys Met Ser Ala Asp Thr Tyr Gly Asn Ser Met Phe Phe His
225 230 235 240
Leu Arg Arg Glu Gln Ile Phe Ala Arg His Phe Phe Asn Lys Ala Gly
245 250 255
Thr Ile Gly Asp Pro Val Pro Val Ser Met Tyr Ile Lys Gly Ala Gly
260 265 270
Gln Gly Arg Glu Pro Pro Thr Thr Ser Ile Tyr Ser Ala Thr Pro Ser
275 280 285
Gly Ser Met Ile Thr Ser Asp Ser Gln Ile Phe Asn Lys Pro Tyr Trp
290 295 300
Leu His Arg Ala Gln Gly His Asn Asn Gly Ile Cys Trp Asn Asn Gln
305 310 315 320
Leu Phe Ile Thr Cys Val Asp Thr Thr Arg Ser Thr Asn Leu Thr Ile
325 330 335
Ser Thr Ala Thr Ala Ala Val Ser Pro Thr Phe Thr Pro Ser Asn Phe
340 345 350
Lys Gln Tyr Ile Arg His Gly Glu Glu Tyr Glu Leu Gln Phe Ile Phe
355 360 365
Gln Leu Cys Lys Ile Thr Leu Thr Thr Glu Val Met Ala Tyr Leu His
370 375 380
Thr Met Asp Pro Thr Ile Leu Glu Gln Trp Asn Phe Gly Leu Thr Leu
385 390 395 400
Pro Pro Ser Ala Ser Leu Glu Asp Ala Tyr Arg Phe Val Arg Asn Ala
405 410 415
Ala Thr Ser Cys Gln Lys Asp Thr Pro Pro Gln Ala Lys Pro Asp Pro
420 425 430
Leu Ala Lys Tyr Lys Phe Trp Asp Val Asp Leu Lys Glu Arg Phe Ser
435 440 445
Leu Asp Leu Asp Gln Phe Ala Leu Gly Arg Lys Phe Leu Leu Gln Val
450 455 460
Gly Val Gln Arg Lys Pro Arg Pro Gly Leu Lys Arg Pro Ala Ser Ser
465 470 475 480
Ala Ser Ser Ser Ser Ser Ser Ser Ala Lys Arg Lys Arg Val Lys Lys
485 490 495
<210> 47
<211> 497
<212> PRT
<213> Artificial Sequence
<220>
<223> H51N9-69T4-26S5
<400> 47
Met Lys Val Tyr Leu Pro Pro Ala Pro Val Ser Arg Ile Val Asn Thr
1 5 10 15
Glu Glu Tyr Ile Thr Arg Thr Gly Ile Tyr Tyr Tyr Ala Gly Ser Ser
20 25 30
Arg Leu Ile Thr Leu Gly His Pro Tyr Phe Pro Leu Pro Lys Thr Ser
35 40 45
Thr Arg Ala Ala Ile Pro Lys Val Ser Ala Phe Gln Tyr Arg Val Phe
50 55 60
Arg Val Gln Leu Pro Asp Pro Asn Lys Phe Gly Leu Pro Asp Pro Asn
65 70 75 80
Leu Tyr Asn Pro Asp Thr Asp Arg Leu Val Trp Gly Cys Val Gly Val
85 90 95
Glu Val Gly Arg Gly Gln Pro Leu Gly Val Gly Leu Ser Gly His Pro
100 105 110
Leu Phe Asn Lys Tyr Asp Asp Thr Glu Asn Ser Arg Ile Ala Asn Gly
115 120 125
Asn Ala Gln Gln Asp Val Arg Asp Asn Thr Ser Val Asp Asn Lys Gln
130 135 140
Thr Gln Leu Cys Ile Ile Gly Cys Ala Pro Pro Ile Gly Glu His Trp
145 150 155 160
Gly Ile Gly Thr Thr Cys Lys Asn Thr Pro Val Pro Pro Gly Asp Cys
165 170 175
Pro Pro Leu Glu Leu Val Ser Ser Val Ile Gln Asp Gly Asp Met Ile
180 185 190
Asp Thr Gly Phe Gly Ala Met Asp Phe Ala Ala Leu Gln Ala Thr Lys
195 200 205
Ser Asp Val Pro Leu Asp Ile Ser Gln Ser Val Cys Lys Tyr Pro Asp
210 215 220
Tyr Leu Lys Met Ser Ala Asp Thr Tyr Gly Asn Ser Met Phe Phe His
225 230 235 240
Leu Arg Arg Glu Gln Ile Phe Ala Arg His Phe Phe Asn Lys Ala Gly
245 250 255
Thr Ile Gly Asp Pro Val Pro Val Ser Met Tyr Ile Lys Gly Ala Gly
260 265 270
Gln Gly Arg Glu Pro Pro Thr Thr Ser Ile Tyr Ser Ala Thr Pro Ser
275 280 285
Gly Ser Met Ile Thr Ser Asp Ser Gln Ile Phe Asn Lys Pro Tyr Trp
290 295 300
Leu His Arg Ala Gln Gly His Asn Asn Gly Ile Cys Trp Asn Asn Gln
305 310 315 320
Leu Phe Ile Thr Cys Val Asp Thr Thr Arg Ser Thr Asn Leu Thr Ile
325 330 335
Ser Thr Ala Ser Ala Ala Ser Ala Ser Thr Pro Phe Lys Pro Ser Asp
340 345 350
Phe Lys Gln Tyr Ile Arg His Gly Glu Glu Tyr Glu Leu Gln Phe Ile
355 360 365
Phe Gln Leu Cys Lys Ile Thr Leu Thr Thr Glu Val Met Ala Tyr Leu
370 375 380
His Thr Met Asp Pro Thr Ile Leu Glu Gln Trp Asn Phe Gly Leu Thr
385 390 395 400
Leu Pro Pro Ser Ala Ser Leu Glu Asp Ala Tyr Arg Phe Val Arg Asn
405 410 415
Ala Ala Thr Ser Cys Gln Lys Asp Thr Pro Pro Gln Ala Lys Pro Asp
420 425 430
Pro Leu Ala Lys Tyr Lys Phe Trp Asp Val Asp Leu Lys Glu Arg Phe
435 440 445
Ser Leu Asp Leu Asp Gln Phe Ala Leu Gly Arg Lys Phe Leu Leu Gln
450 455 460
Val Gly Val Gln Arg Lys Pro Arg Pro Gly Leu Lys Arg Pro Ala Ser
465 470 475 480
Ser Ala Ser Ser Ser Ser Ser Ser Ser Ala Lys Arg Lys Arg Val Lys
485 490 495
Lys
<210> 48
<211> 1491
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码H51N9-69T2-26S1的DNA序列
<400> 48
atgaaggtgt acctgccccc cgcccccgtg agcaggatcg tgaacaccga ggagtacatc 60
accaggaccg gcatctacta ctacgccggc agcagcaggc tgatcaccct gggccacccc 120
tacttctcta tcccgaaaac cggtcagaaa gctgaaatcc cgaaagtttc tgccttccag 180
tacagggtgt tcagggtgca gctccccgac cccaacaagt tcggcctgcc cgaccccaac 240
ctgtacaacc ccgacaccga caggctggtg tggggctgcg tgggcgtgga ggtgggtcgt 300
ggtcagccgc tgggtgtcgg tctgtctggt cacccgctgt tcaacaaact ggacgacacc 360
gaaaactctc acctggctac cgctaacgct gacaccgaca accgtgacaa cgtttgcgtt 420
gacaacaagc agacccagct gtgcatcatc ggctgcgccc cccccatcgg cgagcactgg 480
ggcatcggca ccacctgcaa gaacaccccc gtgccccccg gcgactgccc ccccctggag 540
ctggtgagca gcgtgatcca ggacggcgac atgatcgaca ccggcttcgg cgccatggac 600
ttcgccgccc tgcaggccac caagagcgac gtgcccctgg acatcagcca gagcgtgtgc 660
aagtaccccg actacctgaa gatgagcgcc gacacctacg gcaacagcat gttcttccac 720
ctgaggaggg agcagatctt cgccaggcac tactacaaca agctgggcag cgtgggcgag 780
gacatcccca ccgactacta catcaagggc agcggcaacg gcagggaccc catcgagagc 840
tacatctaca gcgccacccc cagcggcagc atgatcacca gcgacagcca gatcttcaac 900
aagccctact ggctgcacag ggcccagggc cacaacaacg gcatctgctg gaacaaccag 960
ctgttcatca cctgcgtgga caccaccagg agcaccaacc tgaccatcag caccgccacc 1020
gccgccgtga gccccacctt cacccccagc aacttcaagc agtacatcag gcacggcgag 1080
gagtacgagc tgcagttcat cttccagctg tgcaagatca ccctgaccac cgaggtgatg 1140
gcctacctgc acaccatgga ccccaccatc ctggagcagt ggaacttcgg cctgaccctg 1200
ccccccagcg ccagcctgga ggacgcctac aggttcgtga ggaacgccgc caccagctgc 1260
cagaaggaca ccccccccca ggccaagccc gaccccctgg ccaagtacaa gttctgggac 1320
gtggacctga aggagaggtt cagcctggac ctggaccagt tcgccctggg caggaagttc 1380
ctgctgcagg tgggcgtgca gaggaagccc aggcccggcc tgaagaggcc cgctagcagc 1440
gccagctcca gcagctccag cagcgccaag aggaagaggg tgaagaagta a 1491
<210> 49
<211> 1491
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码H51N9-69T2-26S3的DNA序列
<400> 49
atgaaggtgt acctgccccc cgcccccgtg agcaggatcg tgaacaccga ggagtacatc 60
accaggaccg gcatctacta ctacgccggc agcagcaggc tgatcaccct gggccacccc 120
tacttccccc tgcccaagac cagcaccagg gccgccatcc ccaaggtgag cgccttccag 180
tacagggtgt tcagggtgca gctccccgac cccaacaagt tcggcctgcc cgaccccaac 240
ctgtacaacc ccgacaccga caggctggtg tggggctgcg tgggcgtgga ggtgggtcgt 300
ggtcagccgc tgggtgtcgg tctgtctggt cacccgctgt tcaacaaact ggacgacacc 360
gaaaactctc acctggctac cgctaacgct gacaccgaca accgtgacaa cgtttgcgtt 420
gacaacaagc agacccagct gtgcatcatc ggctgcgccc cccccatcgg cgagcactgg 480
ggtatcggta ccatctgcaa aaacacccag acccagcgtg gtgactgccc gccgctggag 540
ctggtgagca gcgtgatcca ggacggcgac atgatcgaca ccggcttcgg cgccatggac 600
ttcgccgccc tgcaggccac caagagcgac gtgcccctgg acatcagcca gagcgtgtgc 660
aagtaccccg actacctgaa gatgagcgcc gacacctacg gcaacagcat gttcttccac 720
ctgaggaggg agcagatctt cgccaggcac tactacaaca agctgggcag cgtgggcgag 780
gacatcccca ccgactacta catcaagggc agcggcaacg gcagggaccc catcgagagc 840
tacatctaca gcgccacccc cagcggcagc atgatcacca gcgacagcca gatcttcaac 900
aagccctact ggctgcacag ggcccagggc cacaacaacg gcatctgctg gaacaaccag 960
ctgttcatca cctgcgtgga caccaccagg agcaccaacc tgaccatcag caccgccacc 1020
gccgccgtga gccccacctt cacccccagc aacttcaagc agtacatcag gcacggcgag 1080
gagtacgagc tgcagttcat cttccagctg tgcaagatca ccctgaccac cgaggtgatg 1140
gcctacctgc acaccatgga ccccaccatc ctggagcagt ggaacttcgg cctgaccctg 1200
ccccccagcg ccagcctgga ggacgcctac aggttcgtga ggaacgccgc caccagctgc 1260
cagaaggaca ccccccccca ggccaagccc gaccccctgg ccaagtacaa gttctgggac 1320
gtggacctga aggagaggtt cagcctggac ctggaccagt tcgccctggg caggaagttc 1380
ctgctgcagg tgggcgtgca gaggaagccc aggcccggcc tgaagaggcc cgctagcagc 1440
gccagctcca gcagctccag cagcgccaag aggaagaggg tgaagaagta a 1491
<210> 50
<211> 1491
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码H51N9-69T2-26S4的DNA序列
<400> 50
atgaaggtgt acctgccccc cgcccccgtg agcaggatcg tgaacaccga ggagtacatc 60
accaggaccg gcatctacta ctacgccggc agcagcaggc tgatcaccct gggccacccc 120
tacttccccc tgcccaagac cagcaccagg gccgccatcc ccaaggtgag cgccttccag 180
tacagggtgt tcagggtgca gctccccgac cccaacaagt tcggcctgcc cgaccccaac 240
ctgtacaacc ccgacaccga caggctggtg tggggctgcg tgggcgtgga ggtgggtcgt 300
ggtcagccgc tgggtgtcgg tctgtctggt cacccgctgt tcaacaaact ggacgacacc 360
gaaaactctc acctggctac cgctaacgct gacaccgaca accgtgacaa cgtttgcgtt 420
gacaacaagc agacccagct gtgcatcatc ggctgcgccc cccccatcgg cgagcactgg 480
ggcatcggca ccacctgcaa gaacaccccc gtgccccccg gcgactgccc ccccctggag 540
ctggtgagca gcgtgatcca ggacggcgac atgatcgaca ccggcttcgg cgccatggac 600
ttcgccgccc tgcaggccac caagagcgac gtgcccctgg acatcagcca gagcgtgtgc 660
aagtaccccg actacctgaa gatgagcgcc gacacctacg gcaacagcat gttcttccac 720
ctgaggaggg agcagatctt cgccaggcac ttctacaaca aagctggtgc tgttggtgac 780
gctatcccga ccaccctgta catcaaaggt gctgaatctg gtcgtgaacc gccgacctct 840
tctatctact ctgccacccc cagcggcagc atgatcacca gcgacagcca gatcttcaac 900
aagccctact ggctgcacag ggcccagggc cacaacaacg gcatctgctg gaacaaccag 960
ctgttcatca cctgcgtgga caccaccagg agcaccaacc tgaccatcag caccgccacc 1020
gccgccgtga gccccacctt cacccccagc aacttcaagc agtacatcag gcacggcgag 1080
gagtacgagc tgcagttcat cttccagctg tgcaagatca ccctgaccac cgaggtgatg 1140
gcctacctgc acaccatgga ccccaccatc ctggagcagt ggaacttcgg cctgaccctg 1200
ccccccagcg ccagcctgga ggacgcctac aggttcgtga ggaacgccgc caccagctgc 1260
cagaaggaca ccccccccca ggccaagccc gaccccctgg ccaagtacaa gttctgggac 1320
gtggacctga aggagaggtt cagcctggac ctggaccagt tcgccctggg caggaagttc 1380
ctgctgcagg tgggcgtgca gaggaagccc aggcccggcc tgaagaggcc cgctagcagc 1440
gccagctcca gcagctccag cagcgccaag aggaagaggg tgaagaagta a 1491
<210> 51
<211> 1494
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码H51N9-69T2-26S5的DNA序列
<400> 51
atgaaggtgt acctgccccc cgcccccgtg agcaggatcg tgaacaccga ggagtacatc 60
accaggaccg gcatctacta ctacgccggc agcagcaggc tgatcaccct gggccacccc 120
tacttccccc tgcccaagac cagcaccagg gccgccatcc ccaaggtgag cgccttccag 180
tacagggtgt tcagggtgca gctccccgac cccaacaagt tcggcctgcc cgaccccaac 240
ctgtacaacc ccgacaccga caggctggtg tggggctgcg tgggcgtgga ggtgggtcgt 300
ggtcagccgc tgggtgtcgg tctgtctggt cacccgctgt tcaacaaact ggacgacacc 360
gaaaactctc acctggctac cgctaacgct gacaccgaca accgtgacaa cgtttgcgtt 420
gacaacaagc agacccagct gtgcatcatc ggctgcgccc cccccatcgg cgagcactgg 480
ggcatcggca ccacctgcaa gaacaccccc gtgccccccg gcgactgccc ccccctggag 540
ctggtgagca gcgtgatcca ggacggcgac atgatcgaca ccggcttcgg cgccatggac 600
ttcgccgccc tgcaggccac caagagcgac gtgcccctgg acatcagcca gagcgtgtgc 660
aagtaccccg actacctgaa gatgagcgcc gacacctacg gcaacagcat gttcttccac 720
ctgaggaggg agcagatctt cgccaggcac tactacaaca agctgggcag cgtgggcgag 780
gacatcccca ccgactacta catcaagggc agcggcaacg gcagggaccc catcgagagc 840
tacatctaca gcgccacccc cagcggcagc atgatcacca gcgacagcca gatcttcaac 900
aagccctact ggctgcacag ggcccagggc cacaacaacg gcatctgctg gaacaaccag 960
ctgttcatca cctgcgtgga caccaccagg agcaccaacc tgaccatcag caccgcctct 1020
gctgcttctg cttctacccc gttcaaaccg tctgacttca agcagtacat caggcacggc 1080
gaggagtacg agctgcagtt catcttccag ctgtgcaaga tcaccctgac caccgaggtg 1140
atggcctacc tgcacaccat ggaccccacc atcctggagc agtggaactt cggcctgacc 1200
ctgcccccca gcgccagcct ggaggacgcc tacaggttcg tgaggaacgc cgccaccagc 1260
tgccagaagg acaccccccc ccaggccaag cccgaccccc tggccaagta caagttctgg 1320
gacgtggacc tgaaggagag gttcagcctg gacctggacc agttcgccct gggcaggaag 1380
ttcctgctgc aggtgggcgt gcagaggaag cccaggcccg gcctgaagag gcccgctagc 1440
agcgccagct ccagcagctc cagcagcgcc aagaggaaga gggtgaagaa gtaa 1494
<210> 52
<211> 1491
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码H51N9-69T4-26S1的DNA序列
<400> 52
atgaaggtgt acctgccccc cgcccccgtg agcaggatcg tgaacaccga ggagtacatc 60
accaggaccg gcatctacta ctacgccggc agcagcaggc tgatcaccct gggccacccc 120
tacttctcta tcccgaaaac cggtcagaaa gctgaaatcc cgaaagtttc tgccttccag 180
tacagggtgt tcagggtgca gctccccgac cccaacaagt tcggcctgcc cgaccccaac 240
ctgtacaacc ccgacaccga caggctggtg tggggctgcg tgggcgtgga ggtgggcagg 300
ggccagcccc tgggcgtggg cctgagcggc caccccctgt tcaacaagta cgacgacacc 360
gagaacagca ggatcgccaa cggcaacgcc cagcaggacg tgagggacaa caccagcgtg 420
gacaacaagc agacccagct gtgcatcatc ggctgcgccc cccccatcgg cgagcactgg 480
ggcatcggca ccacctgcaa gaacaccccc gtgccccccg gcgactgccc ccccctggag 540
ctggtgagca gcgtgatcca ggacggcgac atgatcgaca ccggcttcgg cgccatggac 600
ttcgccgccc tgcaggccac caagagcgac gtgcccctgg acatcagcca gagcgtgtgc 660
aagtaccccg actacctgaa gatgagcgcc gacacctacg gcaacagcat gttcttccac 720
ctgaggaggg agcagatctt cgccaggcac ttcttcaaca aagctggtac catcggtgac 780
cctgttccgg tttctatgta catcaaaggt gctggtcagg gtcgtgaacc gccgaccaca 840
tccatctact ctgccacccc cagcggcagc atgatcacca gcgacagcca gatcttcaac 900
aagccctact ggctgcacag ggcccagggc cacaacaacg gcatctgctg gaacaaccag 960
ctgttcatca cctgcgtgga caccaccagg agcaccaacc tgaccatcag caccgccacc 1020
gccgccgtga gccccacctt cacccccagc aacttcaagc agtacatcag gcacggcgag 1080
gagtacgagc tgcagttcat cttccagctg tgcaagatca ccctgaccac cgaggtgatg 1140
gcctacctgc acaccatgga ccccaccatc ctggagcagt ggaacttcgg cctgaccctg 1200
ccccccagcg ccagcctgga ggacgcctac aggttcgtga ggaacgccgc caccagctgc 1260
cagaaggaca ccccccccca ggccaagccc gaccccctgg ccaagtacaa gttctgggac 1320
gtggacctga aggagaggtt cagcctggac ctggaccagt tcgccctggg caggaagttc 1380
ctgctgcagg tgggcgtgca gaggaagccc aggcccggcc tgaagaggcc cgctagcagc 1440
gccagctcca gcagctccag cagcgccaag aggaagaggg tgaagaagta a 1491
<210> 53
<211> 1491
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码H51N9-69T4-26S2的DNA序列
<400> 53
atgaaggtgt acctgccccc cgcccccgtg agcaggatcg tgaacaccga ggagtacatc 60
accaggaccg gcatctacta ctacgccggc agcagcaggc tgatcaccct gggccacccc 120
tacttccccc tgcccaagac cagcaccagg gccgccatcc ccaaggtgag cgccttccag 180
tacagggtgt tcagggtgca gctccccgac cccaacaagt tcggcctgcc cgaccccaac 240
ctgtacaacc ccgacaccga caggctggtg tggggctgcg tgggcgtgga ggtgggtcgt 300
ggtcagccgc tgggtatcgg tctgtctggt cacccgctgt tcaacaaact ggacgacacc 360
gaaaactctc acctggctac cgttaacgct gacaccgaca accgtgacaa cgtttctgtt 420
gacaacaagc agacccagct gtgcatcatc ggctgcgccc cccccatcgg cgagcactgg 480
ggcatcggca ccacctgcaa gaacaccccc gtgccccccg gcgactgccc ccccctggag 540
ctggtgagca gcgtgatcca ggacggcgac atgatcgaca ccggcttcgg cgccatggac 600
ttcgccgccc tgcaggccac caagagcgac gtgcccctgg acatcagcca gagcgtgtgc 660
aagtaccccg actacctgaa gatgagcgcc gacacctacg gcaacagcat gttcttccac 720
ctgaggaggg agcagatctt cgccaggcac ttcttcaaca aagctggtac catcggtgac 780
cctgttccgg tttctatgta catcaaaggt gctggtcagg gtcgtgaacc gccgaccaca 840
tccatctact ctgccacccc cagcggcagc atgatcacca gcgacagcca gatcttcaac 900
aagccctact ggctgcacag ggcccagggc cacaacaacg gcatctgctg gaacaaccag 960
ctgttcatca cctgcgtgga caccaccagg agcaccaacc tgaccatcag caccgccacc 1020
gccgccgtga gccccacctt cacccccagc aacttcaagc agtacatcag gcacggcgag 1080
gagtacgagc tgcagttcat cttccagctg tgcaagatca ccctgaccac cgaggtgatg 1140
gcctacctgc acaccatgga ccccaccatc ctggagcagt ggaacttcgg cctgaccctg 1200
ccccccagcg ccagcctgga ggacgcctac aggttcgtga ggaacgccgc caccagctgc 1260
cagaaggaca ccccccccca ggccaagccc gaccccctgg ccaagtacaa gttctgggac 1320
gtggacctga aggagaggtt cagcctggac ctggaccagt tcgccctggg caggaagttc 1380
ctgctgcagg tgggcgtgca gaggaagccc aggcccggcc tgaagaggcc cgctagcagc 1440
gccagctcca gcagctccag cagcgccaag aggaagaggg tgaagaagta a 1491
<210> 54
<211> 1491
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码H51N9-69T4-26S3的DNA序列
<400> 54
atgaaggtgt acctgccccc cgcccccgtg agcaggatcg tgaacaccga ggagtacatc 60
accaggaccg gcatctacta ctacgccggc agcagcaggc tgatcaccct gggccacccc 120
tacttccccc tgcccaagac cagcaccagg gccgccatcc ccaaggtgag cgccttccag 180
tacagggtgt tcagggtgca gctccccgac cccaacaagt tcggcctgcc cgaccccaac 240
ctgtacaacc ccgacaccga caggctggtg tggggctgcg tgggcgtgga ggtgggcagg 300
ggccagcccc tgggcgtggg cctgagcggc caccccctgt tcaacaagta cgacgacacc 360
gagaacagca ggatcgccaa cggcaacgcc cagcaggacg tgagggacaa caccagcgtg 420
gacaacaagc agacccagct gtgcatcatc ggctgcgccc cccccatcgg cgagcactgg 480
ggtatcggta ccatctgcaa aaacacccag acccagcgtg gtgactgccc gccgctggag 540
ctggtgagca gcgtgatcca ggacggcgac atgatcgaca ccggcttcgg cgccatggac 600
ttcgccgccc tgcaggccac caagagcgac gtgcccctgg acatcagcca gagcgtgtgc 660
aagtaccccg actacctgaa gatgagcgcc gacacctacg gcaacagcat gttcttccac 720
ctgaggaggg agcagatctt cgccaggcac ttcttcaaca aagctggtac catcggtgac 780
cctgttccgg tttctatgta catcaaaggt gctggtcagg gtcgtgaacc gccgaccaca 840
tccatctact ctgccacccc cagcggcagc atgatcacca gcgacagcca gatcttcaac 900
aagccctact ggctgcacag ggcccagggc cacaacaacg gcatctgctg gaacaaccag 960
ctgttcatca cctgcgtgga caccaccagg agcaccaacc tgaccatcag caccgccacc 1020
gccgccgtga gccccacctt cacccccagc aacttcaagc agtacatcag gcacggcgag 1080
gagtacgagc tgcagttcat cttccagctg tgcaagatca ccctgaccac cgaggtgatg 1140
gcctacctgc acaccatgga ccccaccatc ctggagcagt ggaacttcgg cctgaccctg 1200
ccccccagcg ccagcctgga ggacgcctac aggttcgtga ggaacgccgc caccagctgc 1260
cagaaggaca ccccccccca ggccaagccc gaccccctgg ccaagtacaa gttctgggac 1320
gtggacctga aggagaggtt cagcctggac ctggaccagt tcgccctggg caggaagttc 1380
ctgctgcagg tgggcgtgca gaggaagccc aggcccggcc tgaagaggcc cgctagcagc 1440
gccagctcca gcagctccag cagcgccaag aggaagaggg tgaagaagta a 1491
<210> 55
<211> 1494
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码H51N9-69T4-26S5的DNA序列
<400> 55
atgaaggtgt acctgccccc cgcccccgtg agcaggatcg tgaacaccga ggagtacatc 60
accaggaccg gcatctacta ctacgccggc agcagcaggc tgatcaccct gggccacccc 120
tacttccccc tgcccaagac cagcaccagg gccgccatcc ccaaggtgag cgccttccag 180
tacagggtgt tcagggtgca gctccccgac cccaacaagt tcggcctgcc cgaccccaac 240
ctgtacaacc ccgacaccga caggctggtg tggggctgcg tgggcgtgga ggtgggcagg 300
ggccagcccc tgggcgtggg cctgagcggc caccccctgt tcaacaagta cgacgacacc 360
gagaacagca ggatcgccaa cggcaacgcc cagcaggacg tgagggacaa caccagcgtg 420
gacaacaagc agacccagct gtgcatcatc ggctgcgccc cccccatcgg cgagcactgg 480
ggcatcggca ccacctgcaa gaacaccccc gtgccccccg gcgactgccc ccccctggag 540
ctggtgagca gcgtgatcca ggacggcgac atgatcgaca ccggcttcgg cgccatggac 600
ttcgccgccc tgcaggccac caagagcgac gtgcccctgg acatcagcca gagcgtgtgc 660
aagtaccccg actacctgaa gatgagcgcc gacacctacg gcaacagcat gttcttccac 720
ctgaggaggg agcagatctt cgccaggcac ttcttcaaca aagctggtac catcggtgac 780
cctgttccgg tttctatgta catcaaaggt gctggtcagg gtcgtgaacc gccgaccaca 840
tccatctact ctgccacccc cagcggcagc atgatcacca gcgacagcca gatcttcaac 900
aagccctact ggctgcacag ggcccagggc cacaacaacg gcatctgctg gaacaaccag 960
ctgttcatca cctgcgtgga caccaccagg agcaccaacc tgaccatcag caccgcctct 1020
gctgcttctg cttctacccc gttcaaaccg tctgacttca agcagtacat caggcacggc 1080
gaggagtacg agctgcagtt catcttccag ctgtgcaaga tcaccctgac caccgaggtg 1140
atggcctacc tgcacaccat ggaccccacc atcctggagc agtggaactt cggcctgacc 1200
ctgcccccca gcgccagcct ggaggacgcc tacaggttcg tgaggaacgc cgccaccagc 1260
tgccagaagg acaccccccc ccaggccaag cccgaccccc tggccaagta caagttctgg 1320
gacgtggacc tgaaggagag gttcagcctg gacctggacc agttcgccct gggcaggaag 1380
ttcctgctgc aggtgggcgt gcagaggaag cccaggcccg gcctgaagag gcccgctagc 1440
agcgccagct ccagcagctc cagcagcgcc aagaggaaga gggtgaagaa gtaa 1494
<210> 56
<211> 10
<212> PRT
<213> Human papillomavirus type 26
<400> 56
Ser Ile Pro Lys Thr Gly Gln Lys Ala Glu
1 5 10
<210> 57
<211> 33
<212> PRT
<213> Human papillomavirus type 26
<400> 57
Ile Gly Leu Ser Gly His Pro Leu Phe Asn Lys Leu Asp Asp Thr Glu
1 5 10 15
Asn Ser His Leu Ala Thr Val Asn Ala Asp Thr Asp Asn Arg Asp Asn
20 25 30
Val
<210> 58
<211> 9
<212> PRT
<213> Human papillomavirus type 26
<400> 58
Ile Cys Lys Asn Thr Gln Thr Gln Arg
1 5
<210> 59
<211> 31
<212> PRT
<213> Human papillomavirus type 26
<400> 59
Phe Tyr Asn Lys Ala Gly Ala Val Gly Asp Ala Ile Pro Thr Thr Leu
1 5 10 15
Tyr Ile Lys Gly Ala Glu Ser Gly Arg Glu Pro Pro Thr Ser Ser
20 25 30
<210> 60
<211> 13
<212> PRT
<213> Human papillomavirus type 26
<400> 60
Ser Ala Ala Ser Ala Ser Thr Pro Phe Lys Pro Ser Asp
1 5 10
<210> 61
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 61
gtaggggtgg cccagggtga tcag 24
<210> 62
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 62
gccttccagt acagggtgtt cagg 24
<210> 63
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 63
cacctccacg cccacgcagc ccca 24
<210> 64
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 64
acaagcagac ccagctgtgc atca 24
<210> 65
<211> 39
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 65
ctcgccgatg gggggggcgc agccgatgat gcacagctg 39
<210> 66
<211> 39
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 66
ccctggagct ggtgagcagc gtgatccagg acggcgaca 39
<210> 67
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 67
gtgcctggcg aagatctgct ccct 24
<210> 68
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 68
gccaccccca gcggcagcat gatc 24
<210> 69
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 69
ggcggtgctg atggtcaggt tggt 24
<210> 70
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 70
acttcaagca gtacatcagg cacg 24
<210> 71
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 71
ctgatcaccc tgggccaccc ctacttcccg atcccgaaat ctggt 45
<210> 72
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 72
cctgaacacc ctgtactgga aggcagagac cttcgggatt tcagc 45
<210> 73
<211> 42
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 73
tggggctgcg tgggcgtgga ggtgggtcgt ggtcagccgc tg 42
<210> 74
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 74
tgatgcacag ctgggtctgc ttgttgtcaa cgcaaacgtt gtcac 45
<210> 75
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 75
ggctgcgccc cccccatcgg cgagcactgg ggtgtcggta ccgtt 45
<210> 76
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 76
tcacgctgct caccagctcc aggggcgggc agtcaccacg ctgaa 45
<210> 77
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 77
agggagcaga tcttcgccag gcacttcttc aacaaagctg gtacc 45
<210> 78
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 78
gatcatgctg ccgctggggg tggcagagta gatggatgtg gtcgg 45
<210> 79
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 79
accaacctga ccatcagcac cgcctctgct cagtctgctt ctgct 45
<210> 80
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 80
cgtgcctgat gtactgcttg aagtcagacg gtttgaaggt agcag 45
<210> 81
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 81
tggggctgcg tgggcgtgga ggtgggtcgt ggtcagccgc tgggt 45
<210> 82
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 82
gggggcgcag ccgatgatgc acagctgggt ctgtttgttg tcaac 45
<210> 83
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 83
cacctccacg cccacgcagc ccca 24
<210> 84
<211> 31
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 84
ctgtgcatca tcggctgcgc tccccccatc g 31
<210> 85
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 85
atcatcggct gcgccccccc catcggtgaa cactggggta tcggt 45
<210> 86
<211> 42
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 86
gccgtcctgg atcacgctgc tcaccagttc cagcggcggg ca 42
<210> 87
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 87
gatggggggg gcgcagccga tgat 24
<210> 88
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 88
gtgagcagcg tgatccagga cggc 24
<210> 89
<211> 54
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 89
tacggcaaca gcatgttctt ccacctgcgt cgtgaacaga tcttcgctcg tcac 54
<210> 90
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 90
gctgtcgctg gtgatcatgc tgccagacgg ggtagcagag tagat 45
<210> 91
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 91
gtggaagaac atgctgttgc cgta 24
<210> 92
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 92
ggcagcatga tcaccagcga cagc 24
<210> 93
<211> 54
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 93
ttcatcacct gcgtggacac cacccgttct accaacctga ccatctctac cgcg 54
<210> 94
<211> 57
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 94
cagctggaag atgaactgca gctcgtattc ttcaccgtga cggatgtact gtttgaa 57
<210> 95
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 95
ggtggtgtcc acgcaggtga tgaacag 27
<210> 96
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 96
gagctgcagt tcatcttcca gctg 24
<210> 97
<211> 42
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 97
tacgccggca gcagcaggct gatcaccctg ggtcacccgt ac 42
<210> 98
<211> 42
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 98
caccctgaac accctgtact ggaaagcaga aactttcggg at 42
<210> 99
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 99
gatcagcctg ctgctgccgg cgta 24
<210> 100
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 100
ttccagtaca gggtgttcag ggtg 24
<210> 101
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 101
tggggctgcg tgggcgtgga ggtgggtcgt ggtcagccgc tgggt 45
<210> 102
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 102
gggggcgcag ccgatgatgc acagctgggt ctgtttgttg tcaac 45
<210> 103
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 103
cacctccacg cccacgcagc ccca 24
<210> 104
<211> 31
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 104
ctgtgcatca tcggctgcgc tccccccatc g 31
<210> 105
<211> 54
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 105
tacggcaaca gcatgttctt ccacctgcgt cgtgaacaga tcttcgctcg tcac 54
<210> 106
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 106
gctgtcgctg gtgatcatgc tgccagacgg ggtagcagag tagat 45
<210> 107
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 107
gtggaagaac atgctgttgc cgta 24
<210> 108
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 108
ggcagcatga tcaccagcga cagc 24
<210> 109
<211> 51
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 109
ttcatcacct gcgtggacac cacccgttct accaacctga ccatctctac c 51
<210> 110
<211> 57
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 110
cagctggaag atgaactgca gctcgtattc ttcaccgtga cggatgtact gtttgaa 57
<210> 111
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 111
ggtggtgtcc acgcaggtga tgaacag 27
<210> 112
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 112
gagctgcagt tcatcttcca gctg 24
<210> 113
<211> 42
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 113
tacgccggca gcagcaggct gatcaccctg ggtcacccgt ac 42
<210> 114
<211> 42
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 114
caccctgaac accctgtact ggaaagcaga aactttcggg at 42
<210> 115
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 115
gatcagcctg ctgctgccgg cgta 24
<210> 116
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 116
ttccagtaca gggtgttcag ggtg 24
<210> 117
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 117
atcatcggct gcgccccccc catcggtgaa cactggggta tcggt 45
<210> 118
<211> 42
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 118
gccgtcctgg atcacgctgc tcaccagttc cagcggcggg ca 42
<210> 119
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 119
gatggggggg gcgcagccga tgat 24
<210> 120
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 120
gtgagcagcg tgatccagga cggc 24
<210> 121
<211> 54
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 121
tacggcaaca gcatgttctt ccacctgcgt cgtgaacaga tcttcgctcg tcac 54
<210> 122
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 122
gctgtcgctg gtgatcatgc tgccagacgg ggtagcagag tagat 45
<210> 123
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 123
gtggaagaac atgctgttgc cgta 24
<210> 124
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 124
ggcagcatga tcaccagcga cagc 24
<210> 125
<211> 51
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 125
ttcatcacct gcgtggacac cacccgttct accaacctga ccatctctac c 51
<210> 126
<211> 57
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 126
cagctggaag atgaactgca gctcgtattc ttcaccgtga cggatgtact gtttgaa 57
<210> 127
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 127
ggtggtgtcc acgcaggtga tgaacag 27
<210> 128
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 128
gagctgcagt tcatcttcca gctg 24
<210> 129
<211> 42
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 129
tacgccggca gcagcaggct gatcaccctg ggtcacccgt ac 42
<210> 130
<211> 42
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 130
caccctgaac accctgtact ggaaagcaga aactttcggg at 42
<210> 131
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 131
gatcagcctg ctgctgccgg cgta 24
<210> 132
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 132
ttccagtaca gggtgttcag ggtg 24
<210> 133
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 133
tggggctgcg tgggcgtgga ggtgggtcgt ggtcagccgc tgggt 45
<210> 134
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 134
gggggcgcag ccgatgatgc acagctgggt ctgtttgttg tcaac 45
<210> 135
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 135
cacctccacg cccacgcagc ccca 24
<210> 136
<211> 31
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 136
ctgtgcatca tcggctgcgc tccccccatc g 31
<210> 137
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 137
atcatcggct gcgccccccc catcggtgaa cactggggta tcggt 45
<210> 138
<211> 42
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 138
gccgtcctgg atcacgctgc tcaccagttc cagcggcggg ca 42
<210> 139
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 139
gatggggggg gcgcagccga tgat 24
<210> 140
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 140
gtgagcagcg tgatccagga cggc 24
<210> 141
<211> 51
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 141
ttcatcacct gcgtggacac cacccgttct accaacctga ccatctctac c 51
<210> 142
<211> 57
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 142
cagctggaag atgaactgca gctcgtattc ttcaccgtga cggatgtact gtttgaa 57
<210> 143
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 143
ggtggtgtcc acgcaggtga tgaacag 27
<210> 144
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 引物
<400> 144
gagctgcagt tcatcttcca gctg 24

Claims (10)

1.一种突变的HPV51L1蛋白或其变体，其中，所述突变的HPV51L1蛋白与野生型HPV51L1蛋白相比，具有下述突变：
(1)N端截短了0-15个氨基酸，例如N端截短了0、1、2、3、4、5、6、7、8、9、10、11、12、13、14或15个氨基酸；以及(2)(a)、(2)(b)、(2)(c)或(2)(d)中所述的突变：
(2)(a)位于野生型HPV51L1蛋白第52-60位的氨基酸残基被替换为第二型别的野生型HPV的L1蛋白的相应位置的氨基酸残基；
(2)(b)位于野生型HPV51L1蛋白第125-147位的氨基酸残基被替换为第二型别的野生型HPV的L1蛋白的相应位置的氨基酸残基；
(2)(c)位于野生型HPV51L1蛋白第170-181位的氨基酸残基被替换为第二型别的野生型HPV的L1蛋白的相应位置的氨基酸残基；和
(2)(d)位于野生型HPV51L1蛋白第259-289位的氨基酸残基被替换为第二型别的野生型HPV的L1蛋白的相应位置的氨基酸残基；
并且，所述变体与所述突变的HPV51L1蛋白相异仅在于一个或几个(例如，1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个、15个、16或17个)氨基酸的置换(优选保守置换)、添加或缺失，且保留了所述突变的HPV51L1蛋白的功能，即，能够诱导针对至少两个型别的HPV(例如，HPV51和HPV69)的中和抗体；
优选地，所述突变的HPV51L1蛋白具有(1)和(2)(a)中所定义的突变，并且任选地，还具有(3)(b)中所定义的突变突变；
优选地，所述突变的HPV51L1蛋白具有(1)和(2)(b)中所定义的突变，并且任选地，还具有(3)(c)中所定义的突变；
优选地，所述突变的HPV51L1蛋白具有(1)和(2)(c)中所定义的突变，并且任选地，还具有(3)(a)或(3)(b)中所定义的突变；
优选地，所述突变的HPV51L1蛋白具有(1)和(2)(d)中所定义的突变，并且任选地，还具有(3)(b)中所定义的突变；
所述的(3)(a)、(3)(b)或(3)(c)中所定义的突变如下：
(3)(a)位于野生型HPV51L1蛋白第51-60位的氨基酸残基被替换为第三型别的野生型HPV L1蛋白的相应位置的氨基酸残基；
(3)(b)位于野生型HPV51L1蛋白第114-146位的氨基酸残基被替换为第三型别的野生型HPV L1蛋白的相应位置的氨基酸残基；
(3)(c)位于野生型HPV51L1蛋白第173-181位的氨基酸残基被替换为第三型别的野生型HPV L1蛋白的相应位置的氨基酸残基；
优选地，所述第二型别的野生型HPV为HPV69；优选地，(2)(a)中所述的相应位置的氨基酸残基为野生型HPV69L1蛋白第52-60位的氨基酸残基；优选地，(2)(b)中所述的相应位置的氨基酸残基为野生型HPV69L1蛋白第125-147位的氨基酸残基；优选地，(2)(c)中所述的相应位置的氨基酸残基为野生型HPV69L1蛋白第170-183位的氨基酸残基；优选地，(2)(d)中所述的相应位置的氨基酸残基为野生型HPV69L1蛋白第261-291位的氨基酸残基；
优选地，所述第三型别的野生型HPV为HPV26；优选地，(3)(a)中所述的相应位置的氨基酸残基为野生型HPV26L1蛋白第51-60位的氨基酸残基；优选地，(3)(b)中所述的相应位置的氨基酸残基为野生型HPV26L1蛋白第114-146位的氨基酸残基；优选地，(3)(c)中所述的相应位置的氨基酸残基为野生型HPV26L1蛋白第173-181位的氨基酸残基；例如，所述突变的HPV51L1蛋白与野生型HPV51L1蛋白相比，N端截短了9个氨基酸；
优选地，所述野生型HPV51L1蛋白具有如SEQ ID NO:1所示的氨基酸序列；
优选地，所述野生型HPV69L1蛋白具有如SEQ ID NO:2所示的氨基酸序列；
优选地，所述野生型HPV26L1蛋白具有如SEQ ID NO:22所示的氨基酸序列；
优选地，所述突变的HPV51L1蛋白具有SEQ ID NO:4、5、6或7所示的氨基酸序列；
优选地，所述突变的HPV51L1蛋白具有SEQ ID NO:23、27、28、41或45所示的氨基酸序列。
2.一种分离的核酸，其编码权利要求1所述的突变的HPV51L1蛋白或其变体，
优选地，所述分离的核酸具有SEQ ID NO:12、13、14或15所示的核苷酸序列；
优选地，所述分离的核酸具有SEQ ID NO:32、36、37、49或53所示的核苷酸序列。
3.包含权利要求2所述的分离的核酸的载体。
4.包含权利要求2所述的分离的核酸和/或权利要求3所述的载体的宿主细胞。
5.一种HPV病毒样颗粒，其含有权利要求1所述的突变的HPV51L1蛋白或其变体，或者由权利要求1所述的突变的HPV51L1蛋白或其变体组成或形成。
6.一种组合物，其包含权利要求1所述的突变的HPV51L1蛋白或其变体，或权利要求2所述的分离的核酸，或权利要求3所述的载体，或权利要求4所述的宿主细胞，或权利要求5所述的HPV病毒样颗粒。
7.一种药物组合物或疫苗，其包含权利要求5所述的HPV病毒样颗粒，任选地还包含药学可接受的载体和/或赋形剂，
优选地，所述HPV病毒样颗粒以预防HPV感染或由HPV感染导致的疾病的有效量存在；
优选地，所述HPV感染是一个或多个型别的HPV感染(例如，由HPV51感染、HPV69感染和HPV26感染组成的组中的至少一种感染)；
优选地，所述由HPV感染所导致的疾病选自宫颈癌、尖锐湿疣及其组合。
8.制备权利要求1所述的突变的HPV51L1蛋白或其变体的方法，其包括，在宿主细胞中表达所述突变的HPV51L1蛋白或其变体，然后从所述宿主细胞的培养物中回收所述突变的HPV51L1蛋白或其变体；
优选地，所述宿主细胞为大肠杆菌；
优选地，所述方法包括步骤：在大肠杆菌中表达所述突变的HPV51L1蛋白或其变体，然后从所述大肠杆菌的裂解上清中纯化得到所述突变的HPV51L1蛋白或其变体；优选地，通过色谱法(例如，阳离子交换色谱，羟基磷灰石色谱和/或疏水相互作用色谱)，从所述大肠杆菌的裂解上清中回收所述突变的HPV51L1蛋白或其变体。
9.一种制备疫苗的方法，其包括将权利要求5所述的HPV病毒样颗粒与药学可接受的载体和/或赋形剂混合。
10.权利要求1所述的突变的HPV51L1蛋白或其变体或权利要求5所述的HPV病毒样颗粒在制备药物组合物或疫苗中的用途，所述药物组合物或疫苗用于预防HPV感染或由HPV感染所导致的疾病，
优选地，所述HPV感染是一个或多个型别的HPV感染(例如，由HPV51感染、HPV69感染和HPV26感染组成的组中的至少一种感染)；
优选地，所述由HPV感染所导致的疾病选自宫颈癌、尖锐湿疣及其组合。
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CN113201550A (zh) * 2021-04-23 2021-08-03 上海博唯生物科技有限公司 一种表达hpv 51l1的多核苷酸及其表达载体、宿主细胞和应用
WO2024146614A1 (zh) * 2023-01-06 2024-07-11 北京康乐卫士生物技术股份有限公司 一种人乳头瘤病毒51型l1蛋白突变体及减少重组蛋白降解的方法及应用

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