CN108473540A - 突变的hev多肽及其用于测定抗hev抗体的用途 - Google Patents
突变的hev多肽及其用于测定抗hev抗体的用途 Download PDFInfo
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Abstract
本发明涉及戊型肝炎病毒p‑ORF2蛋白的多肽,其包含至少氨基酸序列394‑660(相对于660个氨基酸的p‑ORF2蛋白编号),其中位置627、630和638的三个半胱氨酸已经被突变,或对于不同长度的p‑ORF2蛋白,至少对应于660个氨基酸的p‑ORF2蛋白的氨基酸394‑660的氨基酸序列,其中位于对应于660个氨基酸的p‑ORF2蛋白的位置627、630和638的三个位置的三个半胱氨酸已被突变。本发明还涉及使用这些多肽测定针对p‑ORF2蛋白的体液应答的存在或抗体效价的方法,还涉及其在感染戊型肝炎病毒的情况中的用途。无附图。
Description
本发明涉及戊型肝炎病毒(HEV)感染领域。具体而言,本发明涉及检测由戊型肝炎病毒引起的肝炎。
肝炎是肝脏的炎性病变,其中可能有许多原因:传染、药物相关、自身免疫等。病毒起源的急性肝损伤是常见的,通常无症状。这是由于病毒的直接致细胞病变作用,或者通常是由于针对感染的肝细胞的免疫反应。当症状存在时,这些症状结合发热、瘙痒性黄疸、粪便变色、尿液变褐以及或多或少的转氨酶大幅增加,证明细胞溶解和肝功能异常。
许多病毒能够引起肝病变,例如Epstein-Barr病毒(EBV)或巨细胞病毒(CMV),但只有六种病毒被认为是通常被称作“病毒性肝炎”的原因。这些病毒属于不同的科,包括甲型肝炎病毒、乙型肝炎病毒、丙型肝炎病毒、丁型肝炎病毒、戊型肝炎病毒和庚型肝炎病毒。
庚型肝炎病毒还没有被广泛描述。
甲型肝炎病毒或HAV属于小核糖核酸病毒科(famille des Picornaviridae),并且是唯一代表肝病毒属的病毒。它是裸RNA病毒。病毒宿主是被感染的对象,其可能会生病也可能不会生病。传播方式取决于病毒超常的抗性、及其在粪便中的高浓度。主要的传播方式基本上是粪口路径。特定的风险与食用贝类和不洁生蔬菜相关。
乙型肝炎病毒或HBV,属于肝脱氧核糖核酸病毒科(famille deshepadnaviridae)。它是一种环状DNA病毒,在其周长的3/4都是双链结构。这种病毒使暴露于暴发性肝炎、活动性慢性肝炎、肝硬化和肝癌的风险。病毒的主要载体是血液,但它也可以通过性传播。全球范围内,长期感染此病毒的个体数估计为3.5亿,并且是每年估计超过100万死亡的原因。
丙型肝炎病毒,或HCV、或NANBH(“非甲非乙型肝炎”),其是具有正极的RNA基因组的病毒,与黄病毒的结构接近,其具有9500个核苷酸(9.5kb)、非编码5'和3'末端、并且从5'末端开始是衣壳(C)、包膜(E1和E2)和非结构蛋白(NS1至NS5)基因。HCV是严格的人类病毒。污染方式主要是静脉途径,例如通过使用未灭菌的针头,在没有筛查供体的发展中国家仍然存在输血污染。丙型肝炎最令人担忧的因素是除了一般无症状的原发性感染(90%的病例)之外,70%至80%的病例发展为慢性病,20%的慢性感染个体有肝硬化和原发性肝癌的风险,在潜伏平均20年后有肝硬化的风险、30年后有原发性肝癌的风险。
丁型肝炎病毒或HDV,是一种非常小的RNA病毒,如果没有HBV它就不能复制,所述HBV将其HBs表面抗原借给它。丁型肝炎病毒感染仅与HBV感染同时发生,其预后因此恶化:增加了暴发性肝炎的风险,并进展为活动性慢性肝炎。
戊型肝炎病毒或HEV或ET-NANBH(“肠道传播的非甲非乙型肝炎”),是一种小型无包膜的裸病毒,其基因组是正极的单链RNA。最初被分类在与其相似的杯状病毒科(familledes Caliciviridae),在得知它的全基因组信息后,如今已将其单独分类作为戊型肝炎病毒属(genre Hepevirus)、戊型肝炎病毒科(famille des Hepeviridae)的唯一成员(Emerson,S.U.,&Purcell,R.H.,2007)。这种病毒在人类间传播主要是通过粪口途径(脏水和食物)发生。感染在亚洲、非洲和中南美洲的某些地区呈地方性流行。戊型肝炎病毒被认为是在卫生水平低的国家的急性肝炎流行病的主要因素。最近,它已被明确定义为工业化国家病人急性肝炎实际散发性病例的原因,这些病人从未花时间在地方性流行区。目前清楚地表明,戊型肝炎是一种人畜共患病,许多家畜和野生动物物种都感染了HEV,构成了病毒宿主。除了某些类型的患者,如那些接受过实体器官移植的患者,戊型肝炎像甲型肝炎一样,一般不会进展为慢性。然而,它有一个很难解释的特殊性:虽然它通常是自发解决的,但据观察,在印度,随着胎龄的增加,孕妇的死亡率可能达到20%,这可能使得HEV感染成为怀孕期间所有类型的病毒性肝炎中最为严重的肝炎。因此,必须有可用的有效和可靠的工具来检测HEV感染。
戊型肝炎病毒的基因组长度大约有7.5kb,并且具有3个部分重叠的阅读框(ORF1、ORF2和ORF3),其由在5'末端27至32个核苷酸的非编码序列和在3'末端65至74个核苷酸的序列构架,随后是取决于病毒的可变长度的聚腺苷酸化末端。ORF1编码约186kDa的多聚蛋白,称为p-ORF1蛋白,其随后将剪切成非结构蛋白,包括甲基转移酶(证明该病毒在其5'末端被加帽)以及RNA依赖性RNA聚合酶。根据迄今为止所描述的变体,ORF2编码具有659至674个氨基酸的糖基化衣壳蛋白,称为p-ORF2蛋白,变体的大部分p-ORF2蛋白具有660个氨基酸。该p-ORF2蛋白具有几个免疫原性位点,包括氨基酸394和457(相对于660个氨基酸的蛋白编号)之间的构象免疫显性表位,并且包括具有相同编号的位于氨基酸452和617之间的也是构象的中和抗体的靶表位(Meng J等人,2001)。它还包含称为表位406.3-2的另一免疫显性表位,其对应于660个氨基酸的ORF2变体的氨基酸613-654(WO 93/14116)。由ORF3编码的称为p-ORF3蛋白的具有分子量为13kDa的磷蛋白,取决于病毒是非常多变的。这种蛋白质的作用仍有待明确,似乎涉及病毒复制调节功能或核衣壳的组装。
目前的诊断基于通过粪便和血清样本的基因扩增来检测病毒,或甚至胆汁或肝脏活组织检查,或基于检测抗HEV血清抗体应答。
基因扩增使用根据基因型的几对引物自基因组最保守区域通过RT-PCR、巢式PCR或实时PCR来进行。取决于技术,检测阈值为10至103个cDNA分子/反应,粪便中的病毒分泌可达106个cDNA分子。基因型可以在第二步中表征。在症状和抗体出现之前这些技术相对于感染基本上用于早期检测血液中的病毒血症。然而,这些靶向检测病毒核苷酸的技术的缺点是,病毒血症时间短(血液中1-2周,粪便中3-4周),并且需要昂贵的不能非常靠近患者使用的设备。
HEV感染的血清学诊断基于检测IgM和/或IgG类型的特异性抗HEV抗体,其主要靶标是p-ORF2。有几种试剂盒可以购买。因此,MP DiagnosticTM公司提出了HEVIgM试剂盒,其是一种免疫色谱检测装置,旨在快速检测针对戊型肝炎病毒p-ORF2蛋白的IgM抗体。为此,试剂盒使用重组多肽,多肽394-660,相对于p-ORF2的序列1-660编号,或者称为p-ORF2.1多肽,对应于蛋白的最后267个氨基酸。针对人IgM的小鼠抗体被固定在免疫色谱膜上,从而可以捕获样品中存在的各种人类IgM。通过使用作为检测配偶体的络合至金-标记的抗HEV单克隆抗体的重组多肽394-660来显示特异性针对HEV的IgM的存在。在专利申请WO95/08632中公开了使用394-660重组多肽而不是整个蛋白的原因。根据本专利申请的教导,在大肠杆菌中表达的完整p-ORF2蛋白的免疫反应性不是最佳的,分子的一部分可能降低或甚至抑制该分子另一部分的免疫反应性。为了克服这种抑制效应,专利申请WO95/08632提出使用缺失或截短的p-ORF2蛋白。在测试的各种构建体中,缺失前393个氨基酸的重组多肽394-660表现出最好的免疫反应性。
在Riddell MA等人,2000中描述了多肽394-660的抗原结构的详细特征,以及其与由体外自组装、与HEV病毒颗粒抗原性接近的类病毒样颗粒或VLP的对比。
使用多肽394-660的缺点是其C-末端部分含有至少会部分抑制多肽自组装成寡聚体和VLP的结构域。这会干扰构象表位的正确呈递。
为了克服这些缺点,Wantai公司通过缺失干扰寡聚化和自组装能力的氨基酸607-660(相对于p-ORF2的序列1-660编号)修饰了多肽394-660。如此获得的多肽称为多肽pE2,如专利申请WO 01/22916中所述。序列394-606的这种多肽pE2的优点是其天然二聚化并且二聚体pE2的免疫反应性比单体pE2高得多,促进了构象表位的正确呈递。它的缺点是这种截短的多肽不包含大的表位,如专利申请WO 93/14116中所示的对应于660个氨基酸的ORF2变体的氨基酸613-654的表位406.3-2。因此,这种缺失会导致使用这种截短的多肽的诊断测试的灵敏度降低。
出乎意料的,申请人已经发现,有可能通过在HEV ORF2多肽394-660的位置627、630、638进行3次突变(相对于660个氨基酸的p-ORF2蛋白编号),来克服现有技术多肽的缺点,这同时提高其抗原性和免疫反应性。因此,称为p-ORF2-MUT的突变多肽具有大表位,以非共价方式天然二聚体化,能够在没有任何聚集的情况下寡聚化,并且比未突变的重组多肽394-660具有更高的免疫反应性。
因此,本发明涉及衍生自戊型肝炎病毒p-ORF2蛋白的多肽,其包含(i)至少氨基酸序列394-660(相对于660个氨基酸的p-ORF2蛋白编号),其中位置627、630和638的三个半胱氨酸已经被突变,或(ii)对于不同长度的p-ORF2蛋白,至少对应于660个氨基酸的p-ORF2蛋白的氨基酸394-660的氨基酸序列,其中位于对应于660个氨基酸的p-ORF2蛋白的位置627、630和638的三个位置的三个半胱氨酸已被突变。
本发明的另一个主题涉及包含编码本发明多肽的核苷酸序列、或与所述编码序列互补的序列的分离的核酸,以及包含这些序列的表达载体。
另一个主题涉及包含这些相同核酸序列(直接***或通过表达载体的方式***)的宿主细胞。
此外,涉及本发明的多肽用于测定针对戊型肝炎病毒的p-ORF2蛋白的抗体应答的存在或者用于测定这些抗体的效价的用途。
因此,本发明的另一个主题涉及通过免疫测定测定来自对象的生物样品中针对戊型肝炎病毒的p-ORF2蛋白的抗体应答的存在的方法,所述来自对象的生物样品可能含有所述应答的抗体,该方法包括以下步骤:
-使所述生物样品与本发明的多肽接触,
-使用能够发出可检测信号的标签,检测由所述多肽和所述抗体(如果存在的话)之间的结合发出的信号,
-比较通过此法获得的信号与预先测定的两个群体对照(一个群体已经发展出所述抗体而另一群体未发展出所述抗体)的参考信号S,
-低于所述参考信号S的信号表示样品不含所述抗体,
-高于所述参考信号S的信号表示样品含有所述抗体。
另一个主题还涉及通过免疫测定测定来自对象的生物样品中针对戊型肝炎病毒p-ORF2蛋白的抗体的效价的方法,所述来自对象的生物样品可能含有所述抗体,该方法包括以下步骤:
-使所述生物样品与本发明的多肽接触,
-使用能够发出可检测信号的标签,检测由所述多肽和所述抗体(如果存在的话)之间的结合发出的信号,
-将检测到的信号转换成抗体效价。
另一个主题涉及这些方法的以下用途:用于协助体外诊断,用于体外诊断可能被感染的对象中的戊型肝炎病毒的感染,用于治疗性监测感染了戊型肝炎病毒的对象,用于在人群或特定地理区域中进行抗HEV抗体的血清阳性率的流行病学研究,或测定对象是否需要针对戊型肝炎病毒接种疫苗或重新接种疫苗。
最后一个主题涉及通过免疫测定测定对象中针对戊型肝炎病毒p-ORF2蛋白的体液应答的存在或抗体的效价的试剂盒,所述对象可能已产生这些抗体,所述试剂盒包含本发明的多肽。
通过阅读下文非限制性描述以及附图1至6,可以更清楚地理解本发明,其中:
-图1给出了得自Uniprot数据库的主要HEV病毒变体的各种p-ORF2蛋白的氨基酸序列比对,第一列对应于UNIPROT参考,第二列对应于HEV毒株的名称,最后一列对应于序列比对。使用UNIPROT网站可用的Clustal Omega程序进行序列比对。每个序列比对下的最后一行显示每个变体之间的氨基酸相同性或非相同性,“*”指示完全保守位置,在所有变体中具有完全相同的氨基酸,“:”指示非常保守的位置,氨基酸具有强的相似的性质,并且在Gonnet PAM 250矩阵中得分>0.5,“.”表示比较保守的位置,其中氨基酸具有弱的相似的性质,并且Gonnet PAM 250基质中得分=<0.5。其他位置标有“°”。比对的各个部分分布于图1A到1R。图1A至1L给出了不同变体的全部蛋白的比对。其中下划线的660个氨基酸的Q81871变体(SEQ ID No.11)的序列394-660作为参考。图1G中的箭头表示本发明多肽的最小序列的第一个氨基酸,图1K中的矩形显示了Q81871变体的12个氨基酸的序列,其中3个半胱氨酸被突变。图1M至1R给出了由箭头开始的从图1A至1L提取的不同变体的本发明多肽的最小序列的比对。为Q81871变体参考多肽的序列394-660(SEQ ID No.26)下划线。
-图2显示了天然氨基酸侧链电子密度图的图示,由X射线衍射获得,以1.5埃分辨率计算,从网站(2015年11月13日引用)http://people.mbi.ucla.edu/sawaya/m230d/Modelbuilding/modelbuilding.html打印:
-图3是用考马斯蓝染色的(4-12%)SDS-PAGE分析凝胶的照片,以显现本发明的多肽ORF2-MUT和非突变多肽ORF2-REF(其对应于在申请WO95/08632中公开的多肽p-ORF2.1(氨基酸394-660))。在凝胶分析之前,纯化和透析的多肽ORF2-REF和ORF2-MUT通过添加二硫苏糖醇(DTT)进行还原,或通过加热(75℃10分钟)进行变性,或同时进行处理或都不处理,如凝胶上的表所示。M泳道对应于Page Ruler分子量标记(Pierce),条带的表观分子量在左侧以千道尔顿(kDa)表示。
-图4展示了通过在280nm处的UV吸光度后获得的现有技术多肽ORF2-REF(图4A)和本发明的多肽ORF2-MUT(图4B)的尺寸排阻色谱图。为了使图4A的各个峰的可视化良好,两个色谱图不以相同比例的y轴来呈现。
-图5展示了给出通过使用AsFlFFF-MALS(“非对称流场流分级-多角度光散射”)技术获得的本发明多肽ORF2-MUT结果的图。在280nm的UV吸光度(细实线)、多角度光散射信号(MALS,阴影线)和摩尔质量估计(粗实线)重叠在y轴上表示作为分析时间(分钟)的函数。
-图6的箱形图展示了使用作为捕获抗原的现有技术多肽ORF2-REF或本发明的多肽ORF2-MUT用免疫测定(自动化装置,bioMérieux)在不含抗-ORF2抗体(阴性)的样品和含有抗-ORF2抗体(阳性)的HEV阳性样品中获得的RFV信号分布。根据Tukey方法绘制箱形图:箱子的上限和下限分别对应于分布的第25和第75百分位。在箱子大约一半绘制的数值是中位数。高点对应于第75百分位+1.5×四分间距,而低点对应于第25百分位-1.5×四分间距。图上方和下方的值以单个点的形式表示,因为它们是不常见的极端值。
出乎意料的,申请人已经表明就治疗患有戊型肝炎感染的对象而言,可能使用衍生自戊型肝炎病毒p-ORF2蛋白的多肽,该多肽至少包含氨基酸序列394-660(相对于660个氨基酸的p-ORF2蛋白编号),同时避免了现有技术中当多肽中包含氨基酸607-660的缺点,即它们都具有大表位、以非共价方式天然二聚化,并且能够在没有任何聚集的情况下寡聚化。此外,与现有技术多肽相反,本发明的多肽是均一产生的。事实上,在它们的生产过程中,最终产品可再产生地展现超过75%的非共价二聚体,其余部分由十二聚体组成,然而现有技术多肽的非共价二聚体、共价二聚体、和聚集体的比例在各个群体变化。此外,本发明的多肽具有比未突变的重组多肽394-660更高的免疫反应性。最后,本发明的多肽当其用于免疫测定时可提高测试的诊断特异性,而不会改变其诊断敏感性,这对于检测戊型肝炎病毒的测试是必需的。
如前所述,如图1所示,HEV病毒的p-ORF2蛋白具有不同的长度,从659到674个氨基酸(参见图1L给出p-ORF2蛋白的最后几个氨基酸)。由于大多数蛋白具有660个氨基酸,因此通常认为由660个氨基酸的蛋白可作为参考。在本申请中,660个氨基酸的参考序列是Q81871变体的序列(SEQ ID No.11)。然而,尽管其他变体的蛋白质具有不同的氨基酸序列,例如674个氨基酸(SEQ ID Nos.1至7)、672个氨基酸(SEQ ID No.8)、671个氨基酸(SEQ IDNo.9)、668个氨基酸(SEQ ID No.10)或659个氨基酸(SEQ ID No.24),并且还有那些具有相同长度的蛋白质的变体(SEQ ID No.12至23)实际上也包括在本发明的范围内。
因此,为了找到本发明的所有多肽,其定义为包含:
-当p-ORF2蛋白具有660个氨基酸,至少氨基酸序列394-660(相对于660个氨基酸的p-ORF2蛋白编号),其中位置627、630和638的三个半胱氨酸被突变,以及
-当p-ORF2蛋白质具有不同长度,至少对应于660个氨基酸的p-ORF2蛋白的氨基酸394-660的氨基酸序列,其中位于对应于660个氨基酸的p-ORF2蛋白的位置627、630和638的三个位置的三个半胱氨酸被突变,这对于本领域技术人员而言足以进行相对于660个氨基酸的蛋白的比对。因此,例如,如果参考图1,无论将属于Q81871变体(其中序列394-660在图1中用下划线表示)的蛋白作为660个氨基酸的参考蛋白,并且例如,考虑672、671、659、668和674个氨基酸的变体蛋白,本发明的多肽至少包含:
-氨基酸序列394-660(SEQ ID No.26和SEQ ID No.38至49),其中位置627、630和638的半胱氨酸被突变(衍生自变体Q81871、P29326、Q6J8F7、Q04611、Q68965、Q9YLQ9、P33426、Q9YLR2、Q0QC51、Q69411、A0A024D9U6、A0A024D9R2、Q8V729),或
-氨基酸序列408-674(SEQ ID No.28至34),其中位置641、644和652的半胱氨酸被突变(衍生自变体Q8JJN2、Q80IR5、Q806D7、Q6BD83、Q6BD78、B6VC89、Q6PMR3),
-氨基酸序列406-672(SEQ ID No.35),其中位置639、642和650的半胱氨酸被突变(衍生自Q9IVZ8变体),或
-氨基酸序列405-671(SEQ ID No.36),其中位置638、641和649的半胱氨酸被突变(衍生自Q8JJM1变体),或
-氨基酸序列405-668(SEQ ID No.37),其中位置638、641和649的半胱氨酸被突变(衍生自Q2PYP3变体),或
-氨基酸序列393-659(SEQ ID No.50),其中位置626、629和637的半胱氨酸被突变(衍生自Q03500变体)。
因此,从图1M至1R中描述的以及从图1G的箭头开始在图1G至1L中提取的变体的各种片段394-660、408-674、406-672、405-671、405-668和393-659,对应于以下序列:
片段394-660
Q8V729
SEQ ID No.49
片段408-674
Q6PMR3
SEQ ID No.34
片段406-672
Q9IVZ8
SEQ ID No.35
片段405-671
Q8JJM1
SEQ ID No.36
片段405-668
Q2PYP3
SEQ ID No.37
片段393-659
Q03500
SEQ ID No.50
图1还显示,如果将Q81871变体的氨基酸序列394-660用作660个氨基酸的所有蛋白质的参考序列(SEQ ID No.26),则其他变体的氨基酸序列394-660(SEQ ID No.38至49)与序列SEQ ID No.26具有90.64%和99.25%之间的相同性,而如果用该相同变体的660个氨基酸的蛋白总序列(SEQ ID No.11)用作参考,其他变体的660个氨基酸的序列(SEQ IDNo.12至23)与该序列SEQ ID No.11具有90.45%和99.09%之间的相同性。
同样,如果变体Q8JJN2的氨基酸序列408-674用作所有674个氨基酸的蛋白质的参考序列(SEQ ID No.28),则其他变体的氨基酸序列408-674(SEQ ID No.29至34)与序列SEQID No.28具有98.50%和98.88%之间的相同性,而如果用该相同变体的674个氨基酸的蛋白质的总序列(SEQ ID No.1)用作参考,则其他变体的674个氨基酸序列(SEQ ID No.2至7)与该序列SEQ ID No.1具有98.22%和98.37%之间的相同性。
更全面地,如果Q81871变体的氨基酸序列394-660用作参考序列(SEQ ID No.26),则其他变体的相应氨基酸序列(SEQ ID No.28至50)与序列SEQ ID No.26具有90.64%和99.25%之间的相同性,因此具有至少90%的相同性,而如果用该相同变体的660个氨基酸的蛋白质的总序列(SEQ ID No.11)用作参考,其他变体的蛋白总序列(SEQ ID No.1至10和12至24)与该序列SEQ ID No.11具有89.97%和99.09%之间的相同性,因此具有至少89%的相同性。
从多个序列比对中计算2个序列之间的百分比相同性。从EMBL-EMI网站(http://www.ebi.ac.uk/Tools/msa/clustalo/)上获得的更加参数化版本的Clustal Omega程序,与多重比对同时生成比对分数。如图1所示,该分数与2个比较序列之间的相似程度相关,适用于所有序列。
如图1K所示,待突变的3个半胱氨酸位于如下定义的12个氨基酸的序列中:CPECRX1LGX2QGC(SEQ ID No.25),其中X1代表P、T、S或A且X2代表L或F。
上述三个半胱氨酸上的突变通过用本领域技术人员熟知的半胱氨酸以外的任何氨基酸取代所述半胱氨酸来进行,例如蛋白原氨基酸如组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、苏氨酸、色氨酸、缬氨酸、丙氨酸、精氨酸、天冬氨酸、天冬酰胺、谷氨酸、谷氨酰胺、甘氨酸、脯氨酸、丝氨酸和酪氨酸。
然而,优选根据以下两个标准选择取代氨基酸:
1)通过依赖于由X射线衍射获得的电子密度图的展示的氨基酸侧链的“大小或体积”,例如如图2给出了这样的展示,在1.5埃的分辨率计算并衍生自以下网站(2013年11月13日打印):http://people.mbi.ucla.edu/sawaya/m230d/Modelbuilding/modelbuilding.html。的确,基于这些图,选择电子密度与半胱氨酸电子密度最相似的氨基酸(例如丝氨酸、缬氨酸和苏氨酸),或比半胱氨酸“更小”的氨基酸(例如甘氨酸、丙氨酸)。优选丢弃太“大”的氨基酸(例如赖氨酸、组氨酸、苯丙氨酸、酪氨酸、精氨酸和色氨酸)。
2)可能的反应性。不期望取代的氨基酸容易地与其他周围的氨基酸反应。优选地,丢弃带电荷的氨基酸如碱性氨基酸(第一标准已经排除)和酸性氨基酸。
根据一个实施方案,本发明多肽中的突变通过用除了脯氨酸、侧链带电荷的氨基酸如赖氨酸、精氨酸、组氨酸、天冬氨酸酸或谷氨酸,以及侧链包含芳香族苯环的氨基酸如酪氨酸、苯丙氨酸或色氨酸以外的任何氨基酸置换三个半胱氨酸来进行。
优选地,本发明多肽中的突变是通过用选自丙氨酸、甘氨酸、苏氨酸、缬氨酸和丝氨酸的氨基酸置换三个半胱氨酸来进行。
3个半胱氨酸可以用相同的氨基酸或用不同的氨基酸取代,优选根据上述标准。
根据另一个实施方案,进行的突变包括用相同的氨基酸并优选丝氨酸取代3个半胱氨酸。
本发明的多肽至少包含氨基酸序列394-660(相对于660个氨基酸的p-ORF2蛋白编号),对于不同长度的p-ORF2蛋白,它们至少包含对应于660个氨基酸的p-ORF2蛋白的氨基酸394-660,所述序列如前所述被突变。
表达“衍生自戊型肝炎病毒的p-ORF2蛋白的多肽”,旨在表示衍生自戊型肝炎病毒p-ORF2蛋白位置394-660或等价位置的连续系列氨基酸。还可以不加区分地提及衍生自p-ORF2蛋白的多肽、p-ORF2蛋白的多肽、p-ORF2多肽、突变的p-ORF2多肽、衍生自p-ORF2蛋白的蛋白质、源自p-ORF2蛋白分蛋白质或突变的p-ORF2蛋白。
表达“至少包含序列”旨在表示该多肽具有所述衍生自p-ORF2蛋白的连续系列氨基酸,或者其具有可添加以下的该系列氨基酸:
(i)位于所述序列之前的属于p-ORF2蛋白的一个或多个氨基酸,和/或
(ii)不属于p-ORF2蛋白的一个或多个氨基酸,例如多聚组氨酸尾、多聚赖氨酸尾或融合蛋白,例如GST(谷胱甘肽S转移酶)、MBP(麦芽糖结合蛋白)、CBP(钙调蛋白结合肽)、CBD(几丁质结合结构域)、蛋白A,硫氧还蛋白和/或
(iii)标记,例如(a)通过与本领域技术人员已知的标记分子偶联,如生物素、酶、荧光标记、放射性分子或如下定义的任何其他标记,或(b)磷酸化标记。
因此,根据一个实施方案,本发明的多肽包含以下一个或多个特征:
-它们由氨基酸序列394-660(相对于660个氨基酸的p-ORF2蛋白编号)的多肽组成,其中位置627、630和638的三个半胱氨酸已被突变,或者对于不同长度的p-ORF2,氨基酸序列对应于660个氨基酸的p-ORF2蛋白的氨基酸394-660的氨基酸,其中三个位于对应于660个氨基酸的p-ORF2的位置627、630和638的三个位置的半胱氨酸已被突变;
-它们包含一个或多个不属于p-ORF2蛋白的氨基酸;
-它们被标记,例如如上所示。
本发明的多肽可以通过本领域技术人员熟知的技术生产。例如,本发明的多肽可以通过使用本领域技术人员已知的常规的遗传工程步骤所获得,所述步骤包括:
-提供编码本发明多肽的DNA
-将该DNA通过克隆***到表达载体,如质粒、粘粒、λ噬菌体或病毒载体(杆状病毒(苜蓿银纹夜蛾核多角体病毒)、痘苗病毒、塞姆利基森林病毒、腺病毒、慢病毒等),所述载体还包含复制起点(质粒或粘粒)、或允许其在宿主细胞中扩增的复制***、和一个或多个允许RNA信使转录的启动子,所述RNA信使将被翻译成蛋白质,
-将表达载体引入宿主细胞,例如通过转化或感染原核细胞(例如细菌如大肠杆菌(Escherichia coli)、枯草芽孢杆菌(Bacillus subtilis)),或者例如通过瞬时或永久转染、或者其它病毒感染真核细胞(例如酵母(酿酒酵母(Saccharomyces cerevisiae)、巴斯德毕赤酵母(Pichia pastoris))、昆虫细胞(Sf9、Sf21、High5细胞)、哺乳动物细胞(CHO、293、Per.C6、BHK-21、Vero等)。
-培养并任选地使含有表达载体的宿主细胞繁殖,任选地扩增在宿主细胞中的载体,
-根据需要,诱导用于生产本发明的重组多肽的转录和蛋白质合成,
-纯化以提取所述多肽,例如通过多聚组氨酸尾的方式。然后这些多肽被认为是重组的。
因此,本发明的主题还是:
-分离的核酸,其包含编码如先前所定义的本发明的多肽的核苷酸序列,或与所述编码序列互补的序列;
-包含如上定义的核酸序列的表达载体,
-原核或真核宿主细胞,其包含编码如上定义的本发明多肽的核苷酸序列,或与所述编码序列或上文定义的表达载体互补的序列。
当本发明的多肽包含如上所述的其他组分,如天然多肽或融合蛋白的标签时,编码这些组分的核酸序列也可***载体中的相同阅读框中以允许融合产生。
可以通过本领域技术人员已知的技术,使用由标签和本发明的多肽的-NH2和-COOR基团形成的-NH-OC-键(R为例如活化的酯基)来进行向本发明的多肽添加非蛋白质标签。因此,例如,当标签是生物素时,本领域技术人员可以使用市售试剂,例如EZ-NHS-生物素试剂(ThermoScientific No.20217、21333和21343),根据供应商的推荐,其包含可以与根据本发明的多肽的-NH2基团反应的-COO-活化的酯基。
如前所述,本发明的多肽特别用于测定检测针对戊型肝炎病毒p-ORF2蛋白的抗体应答的存在。
测定来自对象的生物样品中针对戊型肝炎病毒的p-ORF2蛋白的抗体应答的存在,其可以通过免疫测定进行,并且包含或由以下步骤组成:
-使所述生物样品与本发明的多肽接触,
-使用能够发出可检测信号的标签,检测由所述多肽和所述抗体(如果存在的话)之间的结合发出的信号,
-比较通过此法获得的信号与预先测定的两个群体对照(一个群体已经发展出所述抗体而另一群体未发展出所述抗体)的参考信号S,
-低于所述参考信号S的信号表示样品不含所述抗体,
-高于所述参考信号S的信号表示样品含有所述抗体。
在可能感染HEV病毒的对象中,进行测定抗体应答的存在或抗体效价,所述对象可以是任何对象,特别是:
o患有急性肝炎症状的患者,例如皮肤和眼睛呈黄色(黄疸)、尿色暗淡、变色的粪便、极度疲劳、恶心、呕吐、发烧、腹痛或“流感样”综合征。这些症状可能伴有或不伴有升高的肝酶(ALAT/ASAT)。这些对象可能已经或者可能不会对HAV、HBV或HCV病毒检测呈阳性;
o肝酶(ALAT/ASAT)升高的无症状患者。这些对象可能已经或可能不会对HAV、HBV或HCV病毒检测呈阳性;
o属于处于变成慢性的病况的“风险”或处于暴发严重形式的“风险”的人群个体,如:
·出于任何原因发生免疫抑制的个体,包括经历过移植的对象、接受一种或多种免疫调节或免疫抑制疗法(如化疗、抗TNFα治疗、或皮质疗法)的对象、共感染HIV的对象,老年个体(免疫衰老),
·怀孕的妇女
·先前患有慢性肝病的对象。
对象可以是哺乳动物,例如人、家畜(狗、猫、马等)和农场动物(绵羊种族的成员、牛、山羊科的成员),优选人类。
通过可能含有抗戊型肝炎病毒p-ORF2抗体的对象的生物样品,可以提及的生物液体如全血或其衍生物,例如血清或血浆、尿液、唾液和渗出物,以及还有粪便。血液或其衍生物是优选的,同样粪便也是。这些样品在本发明的方法中使用或可以根据本领域技术人员已知的方法进行预处理。
表达“测定来自对象的生物样品中针对戊型肝炎病毒的p-ORF2蛋白的抗体应答”,旨在表示测定对象在感染HEV病毒的情况下产生的抗体存在或不存在,这些抗体针对p-ORF2蛋白。
该测定是通过免疫测定进行的,这是本领域技术人员已知的测定。简而言之,它包括使用至少一个结合分析物的配偶体来测定分析物,在本情况中为抗p-ORF2抗体的抗体应答(也称为体液应答)。
当然,术语“免疫测定”中的前缀“免疫”,例如在本申请中不应该被认为是严格地指示结合的配偶体必须是免疫起源的配偶体,例如抗体或抗体片段。实际上,如本领域技术人员所熟知的,该术语还更广泛地用于表示测试和方法中非免疫学起源/天然配偶体的结合配偶体,但是所述结合配偶体例如由期望检测和/或量化的分析物的受体组成。重要的条件是,所讨论的结合配偶体能够结合所寻求的分析物,在目前的抗体性质的情况下,优选特异性地。因此,已知的实践是参照ELISA测定进行使用严格意义上非免疫的结合配偶体的测定更广泛地被称为“配体结合测定”,而术语“免疫”包括在与首字母缩写ELISA相对应的标题中。为了清楚和统一,在本申请中使用术语“免疫”来表示使用至少一种适于结合所寻求和所检测和/或所量化的分析物的结合配偶体,优选特异性地,即使当所述结合配偶体在严格意义上不具有免疫特性或来源。
表达“与抗-p-ORF2抗体结合的配偶体”,意在表示能够结合这些抗体的任何分子。作为这种结合配偶体的实例,可以提及的抗原如天然或重组的p-ORF2蛋白,该蛋白的片段,特别是如前所述的多肽,抗体,如抗Ig抗体,例如给定物种的抗总Ig的抗体,或抗IgG或抗IgM,取决于是否寻求IgG或IgM(使用抗该物种IgG或抗该物种IgM用于检测该物种中的IgG或IgM),抗体类似物(能够模拟抗体的分子),例如nanofitin、适配体或“DARPins”,或已知与抗体具有相互作用的任何其他分子。使用根据本发明进行测定抗体应答的存在的方法的基本条件是使用至少如前所述的本发明多肽作为结合配偶体。
抗体结合配偶体可以例如是多克隆抗体或单克隆抗体,其得是本领域技术人员广泛已知的。
抗体片段举例来说,可以提及的是Fab、Fab'和F(ab')2片段,以及scFv(单链可变片段)和dsFv(双链可变片段)。这些功能性片段尤其可以通过遗传工程获得。
nanofitin抗体类似物是小的蛋白质,它与抗体一样,能够与生物靶标结合,因此可以检测到它,捕获它或很简单地在生物体内靶向它。
适配体抗体类似物是寡核苷酸,通常是在含有多达1015个不同序列的文库中通过称为SELEX(Systematic Evolution of Ligands by Exponetial Enrichment(EllingtonAD和Szostak JW.,1990))的体外选择的组合方法鉴定的RNA或DNA。大多数适配体是RNA化合物,由于RNA采用不同的复杂结构的能力,从而可以在其表面创造不同几何形状的空腔,进而可以结合各种配体。它们是感兴趣的生物化学工具,可用于生物技术、诊断或治疗的应用。它们的选择性和它们的配体结合特性与抗体相当。
“DARPins”抗体类似物是另一类蛋白,DARPins代表Designed Ankyrin RepeatProteINS(Boersma YL和PlütckthunA,2011),它可以模拟抗体并能够以高亲和力和高选择性与靶蛋白结合。它们衍生自锚蛋白家族,是衔接蛋白,使得整合膜蛋白与构成细胞质膜“骨架”的血影蛋白/肌动蛋白网络的结合成为可能。锚蛋白的结构是基于重复的约33个氨基酸的基序,对于DARPins也是如此。每个基序都具有螺旋-转角-螺旋型的二级结构。DARPins含有至少三个,优选四至五个重复单元,并通过筛选组合文库获得。
包括在测定抗体应答的免疫测定是定性、半定量、或定量测定,这是本领域技术人员广泛已知的技术,其优选使用两种抗体结合配偶体。两个配偶体中的一个可以与标签偶联以形成缀合物或示踪剂。另一个结合配偶体可以在固相支持体上被捕获。于是提及捕获配偶体是后者,检测配偶体是前者。
使用两种结合配偶体的形式是本领域技术人员熟知的夹心形式,即:
-通常称为双抗原夹心的形式,其在捕获和检测中使用两种相同或不同性质的抗原,其能够被所寻求的抗体识别,应理解为至少有一种抗原是本发明的多肽;
-通常称为免疫捕获的形式,其在捕获中使用如前所述抗体、抗体片段或抗体类似物,并且在检测中使用本发明的多肽;和
-通常称为间接夹心的形式,其在捕获中使用本发明的多肽,并且在检测中使用抗体、抗体片段或抗体类似物。
优选地,捕获配偶体是本发明的多肽,并且检测配偶体是抗人IgG或抗人IgM抗体(间接夹心形式)。
在免疫测定期间发射的测量信号则与生物样品的抗体量成比例。
术语“标签”旨在特别表示含有与一组结合配偶体反应的基团的任何分子,直接没有化学修饰或在化学修饰后以包括这样的基团,所述分子能够直接或间接产生可检测信号。这些直接检测标签的非限制性列表由以下组成:
·产生可通过例如比色法、荧光、发光检测的信号的酶,如辣根过氧化物酶、碱性磷酸酶、半乳糖苷酶或葡萄糖-6-磷酸脱氢酶,
·生色基团如荧光、发光或染料化合物,
·放射性分子,如32P、35S或125I,
·荧光分子如Alexa或藻蓝蛋白,和
·电化学发光盐,如吖啶基或钌基有机金属衍生物。
也可以使用间接检测***,例如能够与抗配体反应的配体。然后配体对应于标签用于与结合配偶体形成缀合物。
配体/抗配体对在本领域技术人员是熟知的,例如使用以下对的情况:生物素/链霉亲和素、半抗原/抗体、抗原/抗体、肽/抗体、糖/凝集素、多核苷酸/与多核苷酸互补的序列。
然后抗配体可以使用先前描述的直接检测标签直接检测,或者其本身可以通过另一配体/抗配体对检测,等等。
这些间接检测***可以在某些条件下导致信号的放大。该信号放大技术对于本领域技术人员来说是熟知的,可以参考本申请人的现有专利申请FR 2781802或WO 95/08000。
如前所述,这些不同的标签可以与本发明的多肽偶联。
取决于所使用标签的类型,本领域技术人员将添加试剂,其允许标签的可视化、或发出通过任何类型的适当测量装置(例如分光光度计、分光荧光计、密度计、光度计或高清摄像头)可检测的信号。
免疫测定还可以包括本领域技术人员已知的其他步骤,例如洗涤步骤和孵育步骤。
如本领域技术人员所熟知的,免疫测定可以是一步或两步测定。简而言之,一步免疫测定包括将待测试的样品同时与两种结合配偶体(包括如前所定义的本发明的多肽)接触,而两步免疫测定包括首先将待测试样品与第一结合配偶体接触,然后将如此形成的分析物-第一结合配偶体复合物与第二结合配偶体接触,两结合配偶体中的一个是如之前所定义的本发明的多肽。
在根据本发明的方法中使用的参考信号S是事先用两个对照群体获得的信号,一个群体已经在HEV病毒感染之后发展出针对p-ORF2蛋白的抗体应答,另一个群体还未发展出这样的抗体反应。这种确定对于本领域技术人员来说是广为已知的。其特别包括进行与本发明的方法中实施的、在这两个群体(性质与将用于测定测试对象中抗体应答的存在的方法中的样品相同)的生物样品中进行的免疫测定相同的免疫测定,以及包括测定测试(信号)的值使得有可能区分这两个群体。
与参考信号相比,用于指定样品中是否含有所寻求的抗体的检测信号可以对应于由标签发出的信号,或者可以将其转化为指标,该指标是检测到的信号/参考信号的比率。根据一个简单的实例,其中不存在灰色区域,如果参考指数固定为“1”,则高于“1”的被测试样品的指数表示样品含有所述抗体,并且指数低于“1”的表示样品不含有所述抗体。
或者当然,先前给出的关于多肽的所有定义适用于测定针对上述戊型肝炎病毒p-ORF2蛋白的抗体应答的存在的方法。
本发明的多肽也可用于测定来自可能含有所述抗体的对象的生物样品中针对戊型肝炎病毒p-ORF2蛋白的抗体的效价。该测定可以通过免疫测定来进行,并且包括或由以下步骤组成:
-使所述生物样品与本发明的多肽接触,
-使用能够发出可检测信号的标签,检测由所述多肽和所述抗体(如果存在的话)之间的结合发出的信号,
-将检测到的信号转换成抗体效价。
当然,再一次地,先前给出的关于多肽的所有定义、以及与测定抗体应答的存在的方法相关的定义,可适用于测定抗体效价的方法。唯一的区别由给出的结果组成,它不是在检测到的信号与参考信号进行比较之后得到的“是”/“否”这样类型的结果,而是在将检测到的信号转化为抗体效价的最后一步之后的浓度、效价或数量型的结果。
将检测到的信号转换成抗体效价的步骤对于本领域技术人员来说是广泛已知的。它包括使用基于标准范围预先建立的数学模型。此标准范围将以已知方式预先获得。简而言之,标准范围的获得包括测量由增加和已知靶抗体的量或浓度产生的信号,绘制曲线,给出信号作为抗体效价的函数,并找到尽可能准确表示这种关系的数学模型。该数学模型将用于测定待测试生物样品中所含的抗p-ORF2抗体的未知量、效价或浓度。
来自对象的生物样品中寻求的抗体具有各种性质:IgM、IgG、IgA、IgE、IgG和IgM型的抗体是优选的。可以寻找相同性质的抗体,例如单独的IgG、或单独的IgM,或者可以以组合的方式来检索不同性质的抗体,例如同时IgG和IgM,或者同时所有类型的抗-ORF2免疫球蛋白(总Ig)。
无论所寻求的抗体的性质如何,并且优选当它们是IgG或IgM时,用于测定如前所述的抗体应答的存在或抗体效价的方法特别用于治疗与戊型肝炎病毒感染有关的对象。
术语“戊型肝炎病毒感染”意指当前感染,也就是说进行免疫测定的对象正处于感染过程中,并且意指过去的感染,也就是说进行免疫测定的对象不再有任何症状,但是之前已经与病毒接触过,或者接种过抗病毒疫苗。
因此,本发明的另一主题涉及如先前所定义的方法的用途,用于协助体外诊断,用于体外诊断可能被感染的对象中的戊型肝炎病毒的感染,用于治疗性监测感染了戊型肝炎病毒的对象,用于在人群或特定地理区域中进行抗HEV抗体的血清阳性率的流行病学研究。
所有这些用途对于本领域技术人员来说都是熟知的,唯一的条件是它们是用前述方法进行的,并因此是前述的多肽。
当所寻求的抗体是IgG时,如先前所定义的方法也特别用于测定对象是否需要针对戊型肝炎病毒接种疫苗或重新接种疫苗,这构成了本发明的另一主题。
具体而言,为了测定对象是否需要针对戊型肝炎病毒接种疫苗或重新接种疫苗,可以执行以下步骤:
1.根据之前定义的方法,在健康对象中、或优选处于风险中的患者的生物样品(如先前描述的那些)中,特别是在血液或血液衍生物样品中,测定抗HEV的IgG抗体的效价,
2.将获得的反应与阈值进行比较,根据现有的需求事先确定该阈值,
3.如果获得的反应低于阈值,则表示对象应接种疫苗或重新接种疫苗,
4.如果获得的反应高于阈值,则表示对象不需要接种疫苗或重新接种。
当然,先前在用于测定抗体应答的存在或抗体效价的方法的上下文中描述的特征,适用于这些方法的用途,例如多肽及其各种长度和突变,生物样品和涉及的主题。
为了实施特别根据上述用途使用的本发明的方法,本发明的多肽可以包含在试剂盒中。
因此,本发明的另一个主题涉及通过免疫测定测定对象中针对戊型肝炎病毒p-ORF2蛋白的体液应答的存在或抗体的效价的试剂盒,所述对象可能已产生这些抗体,所述试剂盒包含如前所定义的多肽。
再次,先前在本发明的多肽和方法的上下文中描述的特征,适用于本发明的试剂盒。
根据一个具体实施方案,试剂盒还包含或含有至少一种阳性对照。该阳性对照包含能够结合试剂盒使用期间采用的结合配偶体的化合物,所述化合物以预定量存在。
作为这种化合物的非限制性实例,可以提及的是天然抗ORF2免疫球蛋白(在这种情况下,阳性对照可以是ORF2阳性血清生物样品)、非天然的例如人源化的抗ORF2免疫球蛋白,或者抗ORF2单克隆抗体,例如小鼠单克隆抗体。
所述试剂盒还可以包含在结合配偶体和靶抗体之间进行反应所需的所有化合物,例如洗涤缓冲剂,或允许可视化标签或发射可检测信号的试剂。
本发明通过以非限制性说明的方式给出的以下实施例,将被更清楚地理解。
实施例
实施例1:构建、表达和纯化突变或未突变的戊型肝炎病毒的ORF2衣壳蛋白的394-
660片段
所表达的ORF2序列是人类/中国/河北/1987分离株的戊型肝炎病毒,其为基因型1(Uniprot登录号Q81871-参见图1-SEQ ID No.11)。对于参考构建体(ORF2REF),对应于ORF2氨基酸394-660(SEQ ID No.26)的序列在N末端融合了多聚组氨酸标签(8-HIS)。对于根据本发明的的构建体(ORF2-MUT),在ORF2 394-660片段位置627、630和638的3个半胱氨酸进行3个非保守突变(半胱氨酸到丝氨酸)(SEQ ID No.27)。如ORF2-REF,ORF2-MUT亦在其N末端包括8-his标签。
SEQ ID No.26:
SEQ ID No.27:
对应于ORF2-REF和ORF2-MUT构建体的DNA片段是以合成基因的形式从公司(Life Technologies)获取的。它们被克隆到pET3d载体(Novagen,EMDMillipore)中的NcoⅠ(5')和BamH I(3')位点间,在IPTG(异丙基-β-D-1硫代半乳糖苷)诱导性T7启动子的控制下。获得的质粒通过测序在***的水平验证,以确保它们不含错误。
表达质粒通过热休克转化引入大肠杆菌BL21DE3细菌中(Stratagene,AgilentTechnologies)。在含有氨苄青霉素的LB琼脂培养皿中分离菌落后,取出对应于ORF2-REF的一个菌落及对应于ORF2-MUT的一个菌落并接种到200毫升含有0.5%葡萄糖的2×YT培养基中,该培养基存在100μg/ml的氨苄青霉素,以250rpm搅拌在37℃过夜。在每个预培养物中取出16ml的体积用于接种400ml的2×YT-0.5%葡萄糖-100μg/ml氨苄青霉素培养基。这些培养物在37℃以250rpm搅拌孵育。当在600nm处测量的光密度(OD)达到约1OD单位时,加入1mMIPTG诱导该蛋白质的表达。培养物的生长是通过定期测量光密度来监测的。孵育约3小时后,当培养物达到稳定期,停止培养,通过离心(5000g,20分钟,+2/8℃)收集该细菌。称重细菌沉淀,然后在-80℃下冷冻直至纯化。
对于纯化,取沉淀(2至2.2克)于30ml裂解缓冲剂(20mM Tris HCl,100Mm NaCl,5%甘油,5U/mlNuclease(Novagen),0.48g/l MgCl2,,无EDTA的完全蛋白酶抑制剂(Roche,Ref 045 66462)1片/50ml,pH7.4)中。使用细胞破碎***(ConstantSystems Ltd,Northants,United Kingdom)在1600bar通过分解裂解细菌,同时保持***在+2/8℃冷藏。为了回收所有的裂解物,用另外30ml的裂解缓冲剂冲洗分解器。然后将裂解物在10000g,40分钟,+2/8℃离心并回收沉淀。
为了溶解包涵体,取每个沉淀于30ml含有100mM NaCl、5%甘油和5M尿素、pH7.4的20mM Tris HCl缓冲剂,并在+18/25℃搅拌1小时30分。通过在10000g,20分钟,环境温度离心回收上清液,然后依次通过1.2μm和0.8μm硝酸纤维素过滤器过滤。
ORF2-REF和ORF2-MUT蛋白利用其多聚组氨酸标签通过一步金属螯合亲和层析纯化。纯化在型自动化***(GE Healthcare Lifesciences)上进行。将离心后获得的上清液加载到Ni NTA树脂柱(Roche,Ref058-93682001)上,其已用含有100mM NaCl,5%甘油和5M尿素(pH 7.4)的20mM Tris HCl缓冲剂(平衡缓冲剂,与上述溶解缓冲剂相同)平衡。洗脱缓冲剂是含有300mM咪唑的平衡缓冲剂,其pH值已重新调整至7.4。用含有40mM咪唑的平衡缓冲剂进行洗涤循环。然后通过平台(plateau)的方式用100%洗脱缓冲剂,即300mM咪唑洗脱蛋白质。用考马斯蓝染色的SDS-PAGE凝胶分析纯化的部分。该分析可以验证进行纯化的方法和选择含有感兴趣的蛋白质部分。
汇集所选部分并在含有250mM NaCl、10%甘露醇、0.4M精氨酸和2M尿素(pH7.4)的40mM Tris HCl缓冲剂中透析。在+18/25℃用比样品体积大100倍的缓冲剂对样品进行两次连续透析。通过测量280nm处的光密度来分析透析的蛋白质的总蛋白质,然后储存在-80℃。
实施例2:通过SDS-PAGE分析ORF2-REF和ORF2-MUT蛋白的鉴定
纯化的ORF2-REF和ORF2-MUT蛋白的第一次表征通过在MES SDS缓冲剂(Life Technologies)中的Bis-Tris 4-12%凝胶上进行SDS-PAGE分析。在加载到凝胶上(10μL/孔)之前,将蛋白质在4XNuPAGE LDS样品缓冲剂(Life Technologies)(3/1,体积/体积)中稀释并进行各种处理。通过加入终浓度为50mM的二硫苏糖醇(DTT)进行还原。75℃加热10分钟。测试的组合如下:
加热和还原(使用DTT)
加热和不还原(没有DTT)
非加热和还原(使用DTT)
非加热和不还原(不含DTT)。
图3中显示了用考马斯蓝染色的SDS-PAGE凝胶以显现总蛋白质的图片。还原和加热(+符号下的条带以及表中+符号下的列),ORF2-REF和ORF2-MUT蛋白质具有相同的分子量,略高于30kDa。该分析条件使得可以看到两种蛋白质的单体形式。
在未还原和加热的条件下(-符号下的条带以及表中-符号下的列),ORF2-REF具有4条带,包括大部分分子量明显小于70kDa的条带。该带对应于ORF2-REF蛋白的二聚体形式:两个单体通过至少一个未被热变性破坏并且需要添加还原剂的共价键(二硫键)连接。在相同的分析条件下,ORF2-MUT具有单一条带,因此是单体。
在非加热条件下,存在或不存在还原剂(-下的条带表示加热,表中+或-分别表示还原),ORF2-REF具有复杂的迁移信号和多个条带,强调了单体之间发生相互作用的多样性。存在于ORF2-REF中的寡聚体形式异质性,在非变性条件(即未加热和未还原)下分析的条带中被清楚地证明了。除了对应于共价和非共价二聚体的条带以外,还观察到至少5条高分子量的条带的存在。相反,非加热的ORF2-MUT无论还原还是不还原(-下的条带表示加热,表中+或-分别表示还原),具有非常简单的迁移特征,具有对应于非共价二聚体的主要优势条带。也注意到单体的痕迹和以大约80kDa迁移的带,这很可能是非共价四聚体形式。
因此,ORF2-MUT蛋白明显比ORF2-REF蛋白更均一,并且基本上是非共价二聚体的形式。ORF2-REF非常异质,同时含有共价二聚体(主要形式)、非共价二聚体和各种高分子量形式。
实施例3:通过荧光标记游离半胱氨酸分析ORF2-REF和ORF2-MUT蛋白特性
为了改进先前的结果,需要测定针对每种蛋白质制剂游离半胱氨酸和参与二硫键的半胱氨酸的比例。蛋白质样品分为两部分:第一部分经过可及的半胱氨酸游离巯基的直接烷基化;第二部分在还原和加热后经历烷基化,该处理使得所有半胱氨酸都可及。
使用具有与荧光素非常相似的光谱特征的FL碘代乙酰胺荧光试剂(Life Technologies,Ref.D-6003)进行烷基化。标签按照制造商的说明进行。非常简要说明,需要临场制备1或10mM的BODIPY FL碘乙酰胺储备溶液,并将蛋白质稀释至100μM。在黑暗中,将FL碘乙酰胺逐滴加入待标记的蛋白质溶液中(每摩尔蛋白质10至20摩尔的FL碘代乙酰胺),混合物在黑暗中孵育30至60分钟。如此标记的蛋白质在SDS-PAGE凝胶上迁移,以将其从过量的荧光团中分离出来。然后在荧光成像***(ChemiDocTM XRS+,Bio-Rad)上可视化凝胶,并在蛋白质条带的水平上测量荧光强度。这种荧光是特异性的,与标记的半胱氨酸数量成正比。
以加热还原后获得的ORF2-REF单体的荧光强度为参照,以相对量进行分析。在这个分子中,有3个半胱氨酸,理论上在这些条件下,所有的半胱氨酸都被标记(100%荧光)。ORF2-MUT蛋白不用FL碘乙酰胺标记。ORF2-MUT蛋白检测到大约1%的荧光;它是非特异性的背景噪音。关于ORF2-REF蛋白质,在未加热的非还原样品中没有检测到荧光。这表明烷化剂不可及半胱氨酸,这与在SDS-PAGE中观察到的图谱一致(图3)。对于加热的ORF2-REF样品,单体条带对应于5%的荧光强度,这表明5%的ORF2-REF半胱氨酸不参与二硫键,但埋藏在蛋白质的核心中,因此当样品不被加热时不可及。
该分析可以明确的确认ORF2-REF蛋白质主要是非单体的。ORF2-REF蛋白无论是形成共价二聚体还是非共价二聚体,都比ORF2-MUT蛋白更加异质。
实施例4:通过尺寸排阻色谱法(SEC)研究ORF2-REF和ORF2-MUT蛋白质的性质
尺寸排阻色谱法可以根据其大小分离分子。每种排除色谱树脂的特征在于以分子量表示的特定的分级范围,在分级范围内可以分离分子。尺寸低于分级范围的下限或高于其上限的分子不能有效地分级。尺寸超过排除限制(也以分子量表示)的分子不分级,并与柱子残存的体积一起洗脱。
尺寸排阻色谱分析是在装备有PBS(磷酸盐缓冲盐水)缓冲剂中的Superdex20010/300GL柱(GE Healthcare)的Waters Alliance HPLC(高效液相色谱)***上进行的。Superdex 200树脂的有效分级范围为10至600kDa,排除极限为1300kDa。对于每种ORF2蛋白质,以0.5ml/分钟注射100μl样品(大约175μg)。通过测量280nm处的吸光度进行检测。ORF2REF色谱图(图4A)显示了3个群体,一个主要群体代表观察到的形式的86.9%,另外两个群体占观察到的形式的8.5%和4.2%,分别是在主峰略微之前和略微之后洗脱。另一方面,在ORF2MUT色谱图上(图4B),存在单个峰,其代表99.9%所观察到的形式。
对于每个色谱图,在峰值水平的280nm处吸光度信号的整合可以测定分析期间分级的蛋白质的总量。对于ORF2-REF蛋白,3个峰中每个峰下的面积总和为6800mU*干。对于ORF2-MUT蛋白,单峰下面积为16100mU*干。在分析过程中,ORF2-REF分级的量仅代表ORF2-MUT分级的量(面积比)的42%,而最初,每种蛋白质的注射量是相同的。由此可以推出,大部分的ORF2-REF没有进入树脂中,因此是以沉淀物的形式保留在柱子的预过滤器中。由于与SDS-PAGE电泳不同,SEC凝胶层析分析的试剂不含有SDS或可能有助于溶解蛋白质的其他洗涤剂,因此促进了沉淀的聚集。
总之,尺寸排阻色谱分析使得可以通过一个独立的技术确认ORF2-MUT蛋白(观察到1种形式)比ORF2-REF蛋白(观察到3种形式)更加均一。在分析条件下,大部分ORF2-REF蛋白呈沉淀形式,因此不能研究。此外,不能排除ORF2-MUT蛋白也会发生类似的沉淀现象或自组装现象,以至于无法分析至少一小部分蛋白。为了补充SEC分析,并能够更明确地证明ORF2-MUT蛋白不含聚集体,有必要使用其他的生物物理表征技术,使得可以在很宽范围的分子大小上进行分析。
实施例5:通过AsFlFFF-MALS(非对称流场流分级-多角度光散射)技术来研究
ORF2-REF和ORF2-MUT蛋白质的性质
为了能够在天然条件下研究ORF2-REF和ORF2-MUT蛋白质的聚集状态,使用了一种新技术,其能够分离5kDa至10μm的宽范围的分子。该技术是偶联到多角度光散射(MALS)的不对称流场流分级(AsFlFFF或AF4)。在Cross Flow、没有任何固定相、和天然条件的情况下,根据其散射系数分离大分子。不存在固定相是一个相当大的优势,因为后者可以与寻求要分离的一种或一些分子物种相互作用,从而出现分析偏差。
AsFlFFF-MALS分析由Toulouse INP(Ecole d’ingénieurs[GraduateEngineering School]Purpan,Toulouse)的“Biological and Technological Qualitiesof Plant Raw Materials”团队进行。分析进行的实验条件如下:
由于分析难以解释,因此没有展示ORF2-REF蛋白获得的fractogram图谱。这是因为第一个峰超载整个分析的MALS信号,使分子量的估计不精确和不可靠。然而,有可能得出存在非常大的聚集体的结论,其大小目前估计为105-106kDa。
在图5中,给出了ORF2-MUT蛋白的UV(细实线)和MALS(阴影线)信号获得的fractogram图谱。在UV(细实线)下观察到了在9至15分钟洗脱的带肩峰的主峰(un picmajoritaire avec unépaulement)。在UV下,该峰的双峰性质在MALS(阴影线)中显得非常清楚。在后者中,存在摩尔质量估计月为70kDA的第一群体(样品的75%,在9.2和11.7分钟之间洗脱)和摩尔质量估计月为356kDA的第二群体(样品的25%,在11.7和15.0分钟之间洗脱)。对于ORF2-MUT蛋白的单体,由其序列计算的理论摩尔质量为31kDa。该理论计算通过实验在实施例2中展示的SDS-PAGE分析中确认。因此,观察到的约70kDa的摩尔质量对应于二聚体,而356kDa则对应于ORF2-MUT的十二聚体(12-mer)。最后,与ORF2-REF相反,在fractogram开始时的空间模式的洗脱下,ORF2-MUT不包含大量可检测的聚集体。
总之,AsFlFFF-MALS分析是一种能够在天然条件下表征分子种类,而不与固定相发生任何相互作用的复杂方法,可以证明ORF2-MUT蛋白i)是75%的非共价二聚体和25%的非共价十二聚体的混合物,ii)在天然状态下不含聚集体,并且iii)比ORF2-REF更加均一。ORF2-REF蛋白质中分子种类的异质性非常大,即使是与AsFlFFF-MALS一样复杂和分辨的技术也不能可靠地描述各种形式的分布。
实施例6:比较ORF2-REF和ORF2-MUT抗原的免疫反应性,以及比较使用这些抗原用
于检测抗ORF2 IgM的免疫测定的诊断性能水平
使用自动免疫分析仪(bioMérieux)通过免疫测定比较ORF2-REF和ORF2-MUT蛋白的抗原性。一次性使用的吸头既可以作为反应的固相也可以作为移液***。该盒由10个孔(X0至X9)组成,其上覆盖有密封并贴有标签的铝箔。第一个孔(X0)包含一个便于引入样品的预切部分。最后一个孔(X9)是测量底物荧光的光学比色杯。分析所需的各种试剂包含在中间孔(X1至X8)中。仪器自动进行测试的所有步骤。它们由一系列吸入/释放反应基质的循环组成。
a)吸头的敏化和钝化(涂层)
吸头用300μL溶于77mM碳酸盐缓冲剂中,pH9.2的2μg/ml的ORF2-REF或ORF2MUT溶液来敏化。在+18/25℃与敏化溶液孵育大约20小时后,吸头被清空。然后加入300μL含有5g/L牛白蛋白的200mM Tris溶液。继续在+18/25℃过夜进行钝化。将吸头清空,干燥,然后在+4℃保存,防潮,直至使用。
b)免疫测定步骤
自动装置将600μL含20mM Tris、pH7.4、300mM NaCl和5g/l血清白蛋白的样品稀释液与38.3μl待测血清或血浆样品混合。一旦吸头与样品接触,免疫反应的第一步开始。该步骤能够使抗-ORF2IgM(可能存在或不存在于血清或血浆样品中)的抗体与吸附在吸头上的ORF2蛋白特异性结合。在37℃孵育4分钟后,用含300mM NaCl和0.275%Triton X-100的200mM Tris缓冲剂(pH9)洗涤除去未结合的组分。在第二步中,将吸头与含有约60ng/mL的碱性磷酸酶偶联的抗人IgM小鼠IgG(bioMérieux)溶于含有300mMNaCl和5g/l的牛血清白蛋白的10mM磷酸盐缓冲剂中的缀合物溶液孵育。X5孔含有400μl的该溶液,仍然在37℃,吸头吸入/释放5分钟。第二步导致样品中存在的抗ORF2IgM与碱性磷酸酶偶联的抗IgM之间形成复合物。此步骤后接2次连续洗涤以除去未结合的化合物。
在最后的揭示步骤中,吸头吸入4-甲基伞形酮磷酸酯底物,然后释放;缀合物的碱性磷酸酶催化该底物水解反应为4-甲基伞形酮,在450nm测量其发射的荧光。荧光信号的值(RFV=相对荧光值)与样品中存在的抗ORF2IgM的浓度成正比。
在18个HEV阳性IgM样品和21个HEV阴性IgM样品中,进行免疫测定步骤检测抗ORF2IgM。这些样品(血清或血浆)主要是是从Etablissementsdu Sang(EFS))[French Blood Bank]获得,并已通过预先使用以下各种商业化测试表征:Wantai HEV-IgMELISA(Ref.WE-7196),recomWell HEV IgM(Ref.5005,Mikrogen Diagnostik)或EIAgenHEV IgM试剂盒(Ref.071050Adaltis)。如果样品至少在上述测试中的一个为阳性,则定义此样品为HEV IgM阳性状态。所述“HEV阴性”样品对于所使用的所有商业化测试技术来说是部分阴性的。
免疫反应性。等量的ORF2-MUT蛋白具有比ORF2-REF蛋白高得多的抗原反应性。该优越性在统计学上非常显著(P<0.0001,单侧配对Wilcoxon检验),并在图6中显示了通过使用ORF2-REF抗原(随后称为ORF2-REFIgM测试)或ORF2-MUT抗原(随后称为ORF2-MUT IgM测试)对HEV阳性样品(表1)和HEV阴性样品(表2)进行的IgM免疫测定获得的RFV信号的分布。对于所有阳性样品,用ORF2-MUT抗原获得的RFV信号高于用ORF2-REF抗原获得的RFV信号。对于样本155797、154183、154053和154050,RFV的增加非常显著地达到大约1000RFV。此外,通过ORF2-REF和ORF2-MUT IgM测试获得的HEV阴性样本的RFV信号相当并且保持非常低(图6)。
诊断敏感度。在表1所示的分析的阳性样品组中,根据现有技术的ORF2-REF IgM测试显示两个假阴性(样品155118和136997),其对应于仅88.9%的灵敏度,而ORF2-MUT IgM测试没有假阴性,这导致灵敏度提高到100%。
此外,使用Wantai测试之前测试分析组,以能够鉴定样品对于所述测试的哪种是阴性的,但通过两种其他IgM试剂盒证实为阳性。该选择的目的是证明本发明的多肽394-660的优点。Wantai IgM试剂盒是唯一仅包含称为pE2的ORF2抗原的商业IgM试剂盒,因此可直接与使用ORF2-REF或ORF2-MUT的IgM免疫测定相比较。然而,与多肽394-660不同,pE2抗原的序列不包含C末端表位(氨基酸613-654)。在测试的阳性样品组中,Wantai测试显示有6个假阴性,也就是说灵敏度仅为66.6%。在这些样品中,通过ORF2-REF IgM检测,4/6被ORF2-REF IgM测试检测为阳性,说明C末端表位的诊断优势,并且特别是6/6被ORF2-MUTIgM测试检测到,这再次证明了此多肽的优越性,以及其对提高免疫测定灵敏度的贡献。
表1.在确定的急性戊型肝炎感染患者的血清中检索抗ORF2IgM。对确认的阳性样品进行敏感性研究
Neg=阴性 Pos=阳性
诊断特异性。在所分析的阴性样品组(表2)中,ORF2-REF IgM测试显示两个假阳性(样品129534和137163),其对应于仅为88.9%的特异性,而ORF2-MUT IgM测试没有假阳性,这是通过使特异性增加到100%来反映的。
应该注意的是ORF2-MUT IgM测试的灵敏度提高不会损害其特异性。
表2.在确定的戊型肝炎感染患者的血清中检索抗ORF2 IgM。确认阴性样本的特异性研究。
总之,ORF2-MUT抗原表现出比ORF2-REF抗原更好的免疫反应性,这在灵敏度和特异性方面导致更好的诊断性能水平。如实施例2(更多非共价二聚体)和实施例5(十二聚体的形成)所示,ORF2-MUT蛋白这种更佳的免疫反应性可以通过更好的免疫显性构象表位呈递来解释,这是由于其更均一和更低聚的结构,这也使得它总体上显示出与病毒颗粒更接近的抗原结构。
实施例7:使用ORF2-REF或ORF2-MUT检测抗戊型肝炎病毒IgM的测试的重复性
根据实施例6中描述的步骤,在两个不同的系列中以3天为一行使用ORF2-REF IgM测试和ORF2-MUT IgM测试分析相同的阳性样品,两次重复。结果列于表3中。变异系数(CV)是标准偏差与平均值的比率,并允许比较测量尺度不相当的值的分布。变异系数的值越小,平均值附近的分散就越小,因此测量的可重复性越高。ORF2-REF IgM测试的变异系数为5.4%,ORF2-MUT IgM测试的变异系数为2.1%。两种免疫测定明显是可重复的;ORF2-MUTIgM测试似乎更好。
表3.使用ORF2-REF或ORF2-MUT蛋白检测抗-ORF2IgM的测试的重复性。
为了能够确定2个CV之间观察到的差异是否是统计学显著的,估计每个不确定性。接受α=0.05的风险(置信区间CI为95%),并假设风险对称和双边分布(即因为低估CV,风险被高估),上限CV应用以下公式推导出来:
Chi2(0.025,ddl)是Chi2定律风险为0.025(α=0.05的一半)和给定自由度(ddl)的值。对于所呈现的系列,重复次数是n=12,dd1=n-1,即11。Chi2定律值(0.025,11)是21.92。该公式的95%CI的上限由公式给出。通过从观察到的CV减去观察到的上限和CV之间的差值来推断95%CI的下限。因此获得以下估计值:
根据这些计算,ORF2-REF IgM测试的CV可在3.2%和7.7%之间,而ORF2-MUT IgM测试的CV可在1.3%和3.0%之间。两个区间不重叠,观察到的两个CV分别为5.4%和2.1%,因此差异显著。
因此,ORF2-MUT IgM测试比ORF2-REF IgM测试更具有更佳的重复性。
参考文献
-Boersma YL,Plückthun A,2011,Curr.Opin.Biotechnol,22:849-857
-Ellington AD and Szostak JW.,1990,Nature,346:818-822
-Emerson,S.U.,&Purcell,R.H.,2007,Hepatitis E Virus.In D.M.Knipe,P.M.Howley,D.E.Griffin,R.A.Lamb,M.A.Martin&B.a.S.Roizman S.E.(Eds.),FieldsVirology(5th ed.,pp.3047-3058).Philadelphia,USA:Lippincott Williams&Wilkins
-Fields and Noble,1990,Int J Pept Protein Res.,35:161-214
-Meng J,et al.,2001,Virology,288:203-211
-Merrifield 1963,J Am Chem Soc.85:2149-2154
-Riddell M.A.,et al.,2000,Journal of Virology,74(17):8011-8017
序列表
<110> 生物梅里埃公司
<120> 突变的HEV多肽及其用于测定抗HEV抗体的用途
<130> Mutacys
<150> FR1561596
<151> 2015-11-30
<160> 50
<170> PatentIn version 3.5
<210> 1
<211> 674
<212> PRT
<213> Hepatitis E virus
<400> 1
Met Asn Asn Met Phe Phe Cys Ser Val His Gly Asp Ala Thr Met Arg
1 5 10 15
Ser Arg Ala Phe Leu Phe Leu Phe Leu Val Leu Leu Pro Met Leu Pro
20 25 30
Ala Pro Pro Ala Gly Gln Pro Ser Gly Arg Arg Arg Gly Arg Arg Ser
35 40 45
Gly Gly Ala Gly Gly Gly Phe Trp Gly Asp Arg Val Asp Ser Gln Pro
50 55 60
Phe Ala Leu Pro Tyr Ile His Pro Thr Asn Pro Phe Ala Ser Asp Ile
65 70 75 80
Pro Ala Ala Ala Gly Ala Gly Ala Arg Pro Arg Gln Pro Ala Arg Pro
85 90 95
Leu Gly Ser Ala Trp Arg Asp Gln Ser Gln Arg Pro Ala Thr Ser Ala
100 105 110
Arg Arg Arg Ser Ala Pro Ala Gly Ala Ser Pro Leu Thr Ala Val Ala
115 120 125
Pro Ala Pro Asp Thr Ala Pro Val Pro Asp Val Asp Ser Arg Gly Ala
130 135 140
Ile Leu Arg Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr Ser Thr
145 150 155 160
Ile Ala Thr Gly Thr Asn Leu Val Leu Tyr Ala Ala Pro Leu Ser Pro
165 170 175
Leu Leu Pro Leu Gln Asp Gly Thr Asn Thr His Ile Met Ala Thr Glu
180 185 190
Ala Ser Asn Tyr Ala Gln Tyr Arg Val Val Arg Ala Thr Ile Arg Tyr
195 200 205
Arg Pro Leu Val Pro Asn Ala Val Gly Gly Tyr Ala Ile Ser Ile Ser
210 215 220
Phe Trp Pro Gln Thr Thr Thr Thr Pro Thr Ser Val Asp Met Asn Ser
225 230 235 240
Ile Thr Ser Thr Asp Val Arg Ile Leu Val Gln Pro Gly Ile Ala Ser
245 250 255
Glu Leu Val Ile Pro Ser Glu Arg Leu His Tyr Arg Asn Gln Gly Trp
260 265 270
Arg Ser Val Glu Thr Ser Gly Val Ala Glu Glu Glu Ala Thr Ser Gly
275 280 285
Leu Val Met Leu Cys Ile His Gly Ser Pro Val Asn Ser Tyr Thr Asn
290 295 300
Thr Pro Tyr Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu Glu Leu
305 310 315 320
Glu Phe Arg Asn Leu Thr Pro Gly Asn Thr Asn Thr Arg Val Ser Arg
325 330 335
Tyr Ser Ser Ser Ala Arg His Lys Leu Arg Arg Gly Pro Asp Gly Thr
340 345 350
Ala Glu Leu Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp Leu His
355 360 365
Phe Thr Gly Thr Asn Gly Val Gly Glu Val Gly Arg Gly Ile Ala Leu
370 375 380
Thr Leu Phe Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro Thr Glu
385 390 395 400
Leu Ile Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro Val Val
405 410 415
Ser Ala Asn Gly Glu Pro Thr Val Lys Leu Tyr Thr Ser Val Glu Asn
420 425 430
Ala Gln Gln Asp Lys Gly Ile Ala Ile Pro His Asp Ile Asp Leu Gly
435 440 445
Glu Ser Arg Val Val Ile Gln Asp Tyr Asp Asn Gln His Glu Gln Asp
450 455 460
Arg Pro Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val Leu Arg
465 470 475 480
Ala Asn Asp Val Leu Trp Leu Ser Leu Thr Ala Ala Glu Tyr Asp Gln
485 490 495
Thr Thr Tyr Gly Ser Ser Thr Asn Pro Met Tyr Val Ser Asp Thr Val
500 505 510
Thr Phe Val Asn Val Ala Thr Gly Ala Gln Gly Val Ser Arg Ser Leu
515 520 525
Asp Trp Ser Lys Val Thr Leu Asp Gly Arg Pro Leu Met Thr Ile Gln
530 535 540
Gln Tyr Ser Lys Thr Phe Phe Val Leu Pro Leu Arg Gly Lys Leu Ser
545 550 555 560
Phe Trp Glu Ala Gly Thr Thr Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn
565 570 575
Thr Thr Ala Ser Asp Gln Ile Leu Ile Glu Asn Ala Ala Gly His Arg
580 585 590
Val Cys Ile Ser Thr Tyr Thr Thr Asn Leu Gly Ser Gly Pro Val Ser
595 600 605
Ile Ser Ala Val Gly Val Leu Ala Pro His Ser Ala Leu Ala Ala Leu
610 615 620
Glu Asp Thr Val Asp Tyr Pro Ala Arg Ala His Thr Phe Asp Asp Phe
625 630 635 640
Cys Pro Glu Cys Arg Ala Leu Gly Leu Gln Gly Cys Ala Phe Gln Ser
645 650 655
Thr Val Ala Glu Leu Gln Arg Leu Lys Met Lys Val Gly Lys Thr Arg
660 665 670
Glu Tyr
<210> 2
<211> 674
<212> PRT
<213> Hepatitis E virus
<400> 2
Met Asn Asn Met Phe Phe Cys Ser Val His Gly Asp Ala Thr Met Arg
1 5 10 15
Ser Arg Ala Leu Leu Phe Leu Leu Phe Val Leu Leu Pro Met Leu Pro
20 25 30
Ala Pro Pro Ala Gly Gln Pro Ser Gly Arg Arg Arg Gly Arg Arg Ser
35 40 45
Gly Gly Ala Gly Gly Gly Phe Trp Gly Asp Arg Val Asp Ser Gln Pro
50 55 60
Phe Ala Leu Pro Tyr Ile His Pro Thr Asn Pro Phe Ala Ser Asp Ile
65 70 75 80
Pro Thr Ala Ala Gly Ser Gly Ala Arg Pro Arg Gln Pro Ala Arg Pro
85 90 95
Leu Gly Ser Ala Trp Arg Asp Gln Ser Gln Arg Pro Ala Ala Pro Ala
100 105 110
Arg Arg Arg Ser Ala Pro Ala Gly Ala Ser Pro Leu Thr Ala Val Ala
115 120 125
Pro Ala Pro Asp Thr Ala Pro Val Pro Asp Val Asp Ser Arg Gly Ala
130 135 140
Ile Leu Arg Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr Ser Thr
145 150 155 160
Ile Ala Thr Gly Thr Asn Leu Val Leu Tyr Ala Ala Pro Leu Ser Pro
165 170 175
Leu Leu Pro Leu Gln Asp Gly Thr Asn Thr His Ile Met Ala Thr Glu
180 185 190
Ala Ser Asn Tyr Ala Gln Tyr Arg Val Val Arg Ala Thr Ile Arg Tyr
195 200 205
Arg Pro Leu Val Pro Asn Ala Val Gly Gly Tyr Ala Ile Ser Ile Ser
210 215 220
Phe Trp Pro Gln Thr Thr Thr Thr Pro Thr Ser Val Asp Met Asn Ser
225 230 235 240
Ile Thr Ser Thr Asp Val Arg Ile Leu Val Gln Pro Gly Ile Ala Ser
245 250 255
Glu Leu Val Ile Pro Ser Glu Arg Leu His Tyr Arg Asn Gln Gly Trp
260 265 270
Arg Ser Val Glu Thr Ser Gly Val Ala Glu Glu Glu Ala Thr Ser Gly
275 280 285
Leu Val Met Leu Cys Ile His Gly Ser Pro Val Asn Ser Tyr Thr Asn
290 295 300
Thr Pro Tyr Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu Glu Leu
305 310 315 320
Glu Phe Arg Asn Leu Thr Pro Gly Asn Thr Asn Thr Arg Val Ser Arg
325 330 335
Tyr Ser Ser Ser Ala Arg His Lys Leu Arg Arg Gly Pro Asp Gly Thr
340 345 350
Ala Glu Leu Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp Leu His
355 360 365
Phe Thr Gly Thr Asn Gly Val Gly Glu Val Gly Arg Gly Ile Ala Leu
370 375 380
Thr Leu Phe Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro Thr Glu
385 390 395 400
Leu Ile Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro Val Val
405 410 415
Ser Ala Asn Gly Glu Pro Thr Val Lys Leu Tyr Thr Ser Val Glu Asn
420 425 430
Ala Gln Gln Asp Lys Gly Ile Ala Ile Pro His Asp Ile Asp Leu Gly
435 440 445
Glu Ser Arg Val Val Ile Gln Asp Tyr Asp Asn Gln His Glu Gln Asp
450 455 460
Arg Pro Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val Leu Arg
465 470 475 480
Ala Asn Asp Val Leu Trp Leu Ser Leu Thr Ala Ala Glu Tyr Asp Gln
485 490 495
Thr Thr Tyr Gly Ser Ser Thr Asn Pro Met Tyr Val Ser Asp Thr Val
500 505 510
Thr Phe Val Asn Val Ala Thr Gly Ala Gln Gly Val Ser Arg Ser Leu
515 520 525
Asp Trp Ser Lys Val Thr Leu Asp Gly Arg Pro Leu Thr Thr Ile Gln
530 535 540
Gln Tyr Ser Lys Thr Phe Phe Val Leu Pro Leu Arg Gly Lys Leu Ser
545 550 555 560
Phe Trp Glu Ala Gly Thr Thr Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn
565 570 575
Thr Thr Ala Ser Asp Gln Ile Leu Ile Glu Asn Ala Ala Gly His Arg
580 585 590
Val Cys Ile Ser Thr Tyr Thr Thr Asn Leu Gly Ser Gly Pro Val Ser
595 600 605
Ile Ser Ser Val Gly Val Leu Ala Pro His Ser Ala Leu Ala Ala Leu
610 615 620
Glu Asp Thr Val Asp Tyr Pro Ala Arg Ala His Thr Phe Asp Asp Phe
625 630 635 640
Cys Pro Glu Cys Arg Thr Leu Gly Leu Gln Gly Cys Ala Phe Gln Ser
645 650 655
Thr Val Ala Glu Leu Gln Arg Leu Lys Met Lys Val Gly Lys Thr Arg
660 665 670
Glu Tyr
<210> 3
<211> 674
<212> PRT
<213> Hepatitis E virus
<400> 3
Met Asn Asn Met Phe Phe Cys Ser Val His Gly Asp Ala Thr Met Arg
1 5 10 15
Ser Arg Ala Leu Leu Phe Leu Leu Phe Val Leu Leu Pro Met Leu Pro
20 25 30
Ala Pro Pro Ala Gly Gln Pro Ser Gly Arg Arg Arg Gly Arg Arg Ser
35 40 45
Gly Gly Ala Gly Gly Gly Phe Trp Gly Asp Arg Val Asp Ser Gln Pro
50 55 60
Phe Ala Leu Pro Tyr Ile His Pro Thr Asn Pro Phe Ala Ser Asp Ile
65 70 75 80
Pro Thr Ala Ala Gly Ser Gly Ala Arg Pro Arg Gln Pro Ala Arg Pro
85 90 95
Leu Gly Ser Ala Trp Arg Asp Gln Ser Gln Arg Pro Ala Ala Ser Ala
100 105 110
Arg Arg Arg Ser Ala Pro Ala Gly Ala Ser Pro Leu Thr Ala Val Ala
115 120 125
Pro Ala Pro Asp Thr Ala Pro Val Pro Asp Val Asp Ser Arg Gly Ala
130 135 140
Ile Leu Arg Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr Ser Thr
145 150 155 160
Ile Ala Thr Gly Thr Asn Leu Val Leu Tyr Ala Ala Pro Leu Ser Pro
165 170 175
Leu Leu Pro Leu Gln Asp Gly Thr Asn Thr His Ile Met Ala Thr Glu
180 185 190
Ala Ser Asn Tyr Ala Gln Tyr Arg Val Val Arg Ala Thr Ile Arg Tyr
195 200 205
Arg Pro Leu Val Pro Asn Ala Val Gly Gly Tyr Ala Ile Ser Ile Ser
210 215 220
Phe Trp Pro Gln Thr Thr Thr Thr Pro Thr Ser Val Asp Met Asn Ser
225 230 235 240
Ile Thr Ser Thr Asp Val Arg Ile Leu Val Gln Pro Gly Ile Ala Ser
245 250 255
Glu Leu Val Ile Pro Ser Glu Arg Leu His Tyr Arg Asn Gln Gly Trp
260 265 270
Arg Ser Val Glu Thr Ser Gly Val Ala Glu Glu Glu Ala Thr Ser Gly
275 280 285
Leu Val Met Leu Cys Ile His Gly Ser Pro Val Asn Ser Tyr Thr Asn
290 295 300
Thr Pro Tyr Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu Glu Leu
305 310 315 320
Glu Phe Arg Asn Leu Thr Pro Gly Asn Thr Asn Thr Arg Val Ser Arg
325 330 335
Tyr Ser Ser Ser Ala Arg His Lys Leu Arg Arg Gly Pro Asp Gly Thr
340 345 350
Ala Glu Leu Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp Leu His
355 360 365
Phe Thr Gly Thr Asn Gly Val Gly Glu Val Gly Arg Gly Ile Ala Leu
370 375 380
Thr Leu Phe Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro Thr Glu
385 390 395 400
Leu Ile Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro Val Val
405 410 415
Ser Ala Asn Gly Glu Pro Thr Val Lys Leu Tyr Thr Ser Val Glu Asn
420 425 430
Ala Gln Gln Asp Lys Gly Ile Ala Ile Pro His Asp Ile Asp Leu Gly
435 440 445
Glu Ser Arg Val Val Ile Gln Asp Tyr Asp Asn Gln His Glu Gln Asp
450 455 460
Arg Pro Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val Leu Arg
465 470 475 480
Ala Asn Asp Val Leu Trp Leu Ser Leu Thr Ala Ala Glu Tyr Asp Gln
485 490 495
Thr Thr Tyr Gly Ser Ser Thr Asn Pro Met Tyr Val Ser Asp Thr Val
500 505 510
Thr Phe Val Asn Val Ala Thr Gly Ala Gln Gly Val Ser Arg Ser Leu
515 520 525
Asp Trp Ser Lys Val Thr Leu Asp Gly Arg Pro Leu Thr Thr Ile Gln
530 535 540
Gln Tyr Ser Lys Thr Phe Phe Val Leu Pro Leu Arg Gly Lys Leu Ser
545 550 555 560
Phe Trp Glu Ala Gly Thr Thr Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn
565 570 575
Thr Thr Ala Ser Asp Gln Ile Leu Ile Glu Asn Ala Ala Gly His Arg
580 585 590
Val Cys Ile Ser Thr Tyr Thr Thr Asn Leu Gly Ser Gly Pro Val Ser
595 600 605
Ile Ser Ser Val Gly Val Leu Ala Pro His Ser Ala Leu Ala Ala Leu
610 615 620
Glu Asp Thr Val Asp Tyr Pro Ala Arg Ala His Thr Phe Asp Asp Phe
625 630 635 640
Cys Pro Glu Cys Arg Thr Leu Gly Leu Gln Gly Cys Ala Phe Gln Ser
645 650 655
Thr Val Ala Glu Leu Gln Arg Leu Lys Met Lys Val Gly Lys Thr Arg
660 665 670
Glu Tyr
<210> 4
<211> 674
<212> PRT
<213> Hepatitis E virus
<400> 4
Met Asn Asn Met Phe Phe Cys Ser Val His Gly Asp Ala Thr Met Arg
1 5 10 15
Ser Arg Ala Phe Leu Phe Leu Phe Leu Val Leu Leu Pro Met Leu Pro
20 25 30
Ala Pro Pro Ala Gly Gln Pro Ser Gly Arg Arg Arg Gly Arg Arg Ser
35 40 45
Gly Gly Ala Gly Gly Gly Phe Trp Gly Asp Arg Val Asp Ser Gln Pro
50 55 60
Phe Ala Leu Pro Tyr Ile His Pro Thr Asn Pro Phe Ala Ser Asp Ile
65 70 75 80
Pro Ala Ala Ala Gly Ala Gly Ala Arg Pro Arg Gln Pro Ala Arg Pro
85 90 95
Leu Gly Ser Ala Trp Arg Asp Gln Ser Gln Arg Pro Ala Thr Ser Ala
100 105 110
Arg Arg Arg Ser Ala Pro Ala Gly Ala Ser Pro Leu Thr Ala Val Ala
115 120 125
Pro Ala Pro Asp Thr Ala Pro Val Pro Asp Val Asp Ser Arg Gly Ala
130 135 140
Ile Leu Arg Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr Ser Thr
145 150 155 160
Ile Ala Thr Gly Thr Asn Leu Val Leu Tyr Ala Ala Pro Leu Ser Pro
165 170 175
Leu Leu Pro Leu Gln Asp Gly Thr Asn Thr His Ile Met Ala Thr Glu
180 185 190
Ala Ser Asn Tyr Ala Gln Tyr Arg Val Val Arg Ala Thr Ile Arg Tyr
195 200 205
Arg Pro Leu Val Pro Asn Ala Val Gly Gly Tyr Ala Ile Ser Ile Ser
210 215 220
Phe Trp Pro Gln Thr Thr Thr Thr Pro Thr Ser Val Asp Met Asn Ser
225 230 235 240
Ile Thr Ser Thr Asp Val Arg Ile Leu Val Gln Pro Gly Ile Ala Ser
245 250 255
Glu Leu Val Ile Pro Ser Glu Arg Leu His Tyr Arg Asn Gln Gly Trp
260 265 270
Arg Ser Val Glu Thr Ser Gly Val Ala Glu Glu Glu Ala Thr Ser Gly
275 280 285
Leu Val Met Leu Cys Ile His Gly Ser Pro Val Asn Ser Tyr Thr Asn
290 295 300
Thr Pro Tyr Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu Glu Leu
305 310 315 320
Glu Phe Arg Asn Leu Thr Pro Gly Asn Thr Asn Thr Arg Val Ser Arg
325 330 335
Tyr Ser Ser Ser Ala Arg His Lys Leu Arg Arg Gly Pro Asp Gly Thr
340 345 350
Ala Glu Leu Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp Leu His
355 360 365
Phe Thr Gly Thr Asn Gly Val Gly Glu Val Gly Arg Gly Ile Ala Leu
370 375 380
Thr Leu Phe Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro Thr Glu
385 390 395 400
Leu Ile Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro Val Val
405 410 415
Ser Ala Asn Gly Glu Pro Thr Val Lys Leu Tyr Thr Ser Val Glu Asn
420 425 430
Ala Gln Gln Asp Lys Gly Ile Ala Ile Pro His Asp Ile Asp Leu Gly
435 440 445
Glu Ser Arg Val Val Ile Gln Asp Tyr Asp Asn Gln His Glu Gln Asp
450 455 460
Arg Pro Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val Leu Arg
465 470 475 480
Ala Asn Asp Val Leu Trp Leu Ser Leu Thr Ala Ala Glu Tyr Asp Gln
485 490 495
Thr Thr Tyr Gly Ser Ser Thr Asn Pro Met Tyr Val Ser Asp Thr Val
500 505 510
Thr Phe Val Asn Val Ala Thr Gly Ala Gln Gly Val Ser Arg Ser Leu
515 520 525
Asp Trp Ser Lys Val Thr Leu Asp Gly Arg Pro Leu Met Thr Ile Gln
530 535 540
Gln Tyr Ser Lys Thr Phe Phe Val Leu Pro Leu Arg Gly Lys Leu Ser
545 550 555 560
Phe Trp Glu Ala Gly Thr Thr Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn
565 570 575
Thr Thr Ala Ser Asp Gln Ile Leu Ile Glu Asn Ala Ala Gly His Arg
580 585 590
Val Cys Ile Ser Thr Tyr Thr Thr Asn Leu Gly Ser Gly Pro Val Ser
595 600 605
Ile Ser Ala Val Gly Val Leu Ala Pro His Ser Ala Leu Ala Ala Leu
610 615 620
Glu Asp Thr Val Asp Tyr Pro Ala Arg Ala His Thr Phe Asp Asp Phe
625 630 635 640
Cys Pro Glu Cys Arg Thr Leu Gly Leu Gln Gly Cys Ala Phe Gln Ser
645 650 655
Thr Val Ala Glu Leu Gln Arg Leu Lys Met Lys Val Gly Lys Thr Arg
660 665 670
Glu Tyr
<210> 5
<211> 674
<212> PRT
<213> Hepatitis E virus
<400> 5
Met Asn Asn Met Phe Phe Cys Ser Val His Gly Asp Ala Thr Met Arg
1 5 10 15
Ser Arg Ala Phe Leu Phe Leu Phe Leu Val Leu Leu Pro Met Leu Pro
20 25 30
Ala Pro Pro Ala Gly Gln Pro Ser Gly Arg Arg Arg Gly Arg Arg Ser
35 40 45
Gly Gly Ala Gly Gly Gly Phe Trp Gly Asp Arg Val Asp Ser Gln Pro
50 55 60
Phe Ala Leu Pro Tyr Ile His Pro Thr Asn Pro Phe Ala Ser Asp Ile
65 70 75 80
Pro Ala Ala Ala Gly Ala Gly Ala Arg Pro Arg Gln Pro Ala Arg Pro
85 90 95
Leu Gly Ser Ala Trp Arg Asp Gln Ser Gln Arg Pro Ala Thr Ser Ala
100 105 110
Arg Arg Arg Ser Ala Pro Ala Gly Ala Ser Pro Leu Thr Ala Val Ala
115 120 125
Pro Ala Pro Asp Thr Ala Pro Val Pro Asp Val Asp Ser Arg Gly Ala
130 135 140
Ile Leu Arg Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr Ser Thr
145 150 155 160
Ile Ala Thr Gly Thr Asn Leu Val Leu Tyr Ala Ala Pro Leu Ser Pro
165 170 175
Leu Leu Pro Leu Gln Asp Gly Thr Asn Thr His Ile Met Ala Thr Glu
180 185 190
Ala Ser Asn Tyr Ala Gln Tyr Arg Val Val Arg Ala Thr Ile Arg Tyr
195 200 205
Arg Pro Leu Val Pro Asn Ala Val Gly Gly Tyr Ala Ile Ser Ile Ser
210 215 220
Phe Trp Pro Gln Thr Thr Thr Thr Pro Thr Ser Val Asp Met Asn Ser
225 230 235 240
Ile Thr Ser Thr Asp Val Arg Ile Leu Val Gln Pro Gly Val Ala Ser
245 250 255
Glu Leu Val Ile Pro Ser Glu Arg Leu His Tyr Arg Asn Gln Gly Trp
260 265 270
Arg Ser Val Glu Thr Ser Gly Val Ala Glu Glu Glu Ala Thr Ser Gly
275 280 285
Leu Val Met Leu Cys Ile His Gly Ser Pro Val Asn Ser Tyr Thr Asn
290 295 300
Thr Pro Tyr Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu Glu Leu
305 310 315 320
Glu Phe Arg Asn Leu Thr Pro Gly Asn Thr Asn Thr Arg Val Ser Arg
325 330 335
Tyr Ser Ser Ser Ala Arg His Lys Leu Arg Arg Gly Pro Asp Gly Thr
340 345 350
Ala Glu Leu Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp Leu His
355 360 365
Phe Thr Gly Thr Asn Gly Val Gly Glu Val Gly Arg Gly Ile Ala Leu
370 375 380
Thr Leu Phe Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro Thr Glu
385 390 395 400
Leu Ile Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro Val Val
405 410 415
Ser Ala Asn Gly Glu Pro Thr Val Lys Leu Tyr Thr Ser Val Glu Asn
420 425 430
Ala Gln Gln Asp Lys Gly Ile Ala Ile Pro His Asp Ile Asp Leu Gly
435 440 445
Glu Ser Arg Val Val Ile Gln Asp Tyr Asp Asn Gln His Glu Gln Asp
450 455 460
Arg Pro Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val Leu Arg
465 470 475 480
Ala Asn Asp Val Leu Trp Leu Ser Leu Thr Ala Ala Glu Tyr Asp Gln
485 490 495
Thr Thr Tyr Gly Ser Ser Thr Asn Pro Met Tyr Val Ser Asp Thr Val
500 505 510
Thr Phe Val Asn Val Ala Thr Gly Ala Gln Gly Val Ser Arg Ser Leu
515 520 525
Asp Trp Ser Lys Val Thr Leu Asp Gly Arg Pro Leu Met Thr Ile Gln
530 535 540
Gln Tyr Ser Lys Thr Phe Phe Val Leu Pro Leu Arg Gly Lys Leu Ser
545 550 555 560
Phe Trp Glu Ala Gly Thr Thr Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn
565 570 575
Thr Thr Ala Ser Asp Gln Ile Leu Ile Glu Asn Ala Ala Gly His Arg
580 585 590
Val Cys Ile Ser Thr Tyr Thr Thr Asn Leu Gly Ser Gly Pro Val Ser
595 600 605
Ile Ser Ala Val Gly Val Leu Ala Pro His Ser Ala Leu Ala Ala Leu
610 615 620
Glu Asp Thr Val Asp Tyr Pro Ala Arg Ala His Thr Phe Asp Asp Phe
625 630 635 640
Cys Pro Glu Cys Arg Ala Leu Gly Leu Gln Gly Cys Ala Phe Gln Ser
645 650 655
Thr Val Ala Glu Leu Gln Arg Leu Lys Met Lys Val Gly Lys Thr Arg
660 665 670
Glu Tyr
<210> 6
<211> 674
<212> PRT
<213> Hepatitis E virus
<400> 6
Met Asn Asn Met Phe Phe Cys Ser Leu His Gly Asp Ala Thr Met Arg
1 5 10 15
Ser Arg Ala Leu Leu Phe Leu Leu Leu Leu Leu Leu Pro Met Leu Pro
20 25 30
Ala Pro Pro Ala Gly Gln Pro Ser Gly Arg Arg Arg Gly Arg Arg Ser
35 40 45
Gly Gly Ala Gly Ser Gly Phe Trp Gly Asp Arg Val Asp Ser Gln Pro
50 55 60
Phe Ala Leu Pro Tyr Ile His Pro Thr Asn Pro Phe Ala Ser Asp Ile
65 70 75 80
Pro Ala Ala Ala Gly Ala Gly Ala Arg Pro Arg Gln Pro Ala Arg Pro
85 90 95
Leu Gly Ser Ala Trp Arg Asp Gln Ser Gln Arg Pro Ala Ala Pro Ala
100 105 110
Arg Arg Arg Ser Ala Pro Ala Gly Ala Ser Pro Leu Thr Ala Val Ala
115 120 125
Pro Ala Pro Asp Thr Ala Pro Val Pro Asp Val Asp Ser Arg Gly Ala
130 135 140
Ile Leu Arg Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr Ser Thr
145 150 155 160
Ile Ala Thr Gly Thr Asn Leu Val Leu Tyr Ala Ala Pro Leu Ser Pro
165 170 175
Leu Leu Pro Leu Gln Asp Gly Thr Asn Thr His Ile Met Ala Thr Glu
180 185 190
Ala Ser Asn Tyr Ala Gln Tyr Arg Val Val Arg Ala Thr Ile Arg Tyr
195 200 205
Arg Pro Leu Val Pro Asn Ala Val Gly Gly Tyr Ala Ile Ser Ile Ser
210 215 220
Phe Trp Pro Gln Thr Thr Thr Thr Pro Thr Ser Val Asp Met Asn Ser
225 230 235 240
Ile Thr Ser Thr Asp Val Arg Ile Leu Val Gln Pro Gly Ile Ala Ser
245 250 255
Glu Leu Val Ile Pro Ser Glu Arg Leu His Tyr Arg Asn Gln Gly Trp
260 265 270
Arg Ser Val Glu Thr Ser Gly Val Ala Glu Glu Glu Ala Thr Ser Gly
275 280 285
Leu Val Met Leu Cys Ile His Gly Ser Pro Val Asn Ser Tyr Thr Asn
290 295 300
Thr Pro Tyr Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu Glu Leu
305 310 315 320
Glu Phe Arg Asn Leu Thr Pro Gly Asn Thr Asn Thr Arg Val Ser Arg
325 330 335
Tyr Ser Ser Ser Ala Arg His Lys Leu Arg Arg Gly Ala Asp Gly Thr
340 345 350
Ala Glu Leu Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp Leu His
355 360 365
Phe Thr Gly Thr Asn Gly Val Gly Glu Val Gly Arg Gly Ile Ala Leu
370 375 380
Thr Leu Phe Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro Thr Glu
385 390 395 400
Leu Ile Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro Val Val
405 410 415
Ser Ala Asn Gly Glu Pro Thr Val Lys Leu Tyr Thr Ser Val Glu Asn
420 425 430
Ala Gln Gln Asp Lys Gly Ile Ala Ile Pro His Asp Ile Asp Leu Gly
435 440 445
Glu Ser Arg Val Val Ile Gln Asp Tyr Asp Asn Gln His Glu Gln Asp
450 455 460
Arg Pro Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val Leu Arg
465 470 475 480
Ala Asn Asp Val Leu Trp Leu Ser Leu Thr Ala Ala Glu Tyr Asp Gln
485 490 495
Thr Thr Tyr Gly Ser Ser Thr Asn Pro Met Tyr Val Ser Asp Thr Val
500 505 510
Thr Phe Val Asn Val Ala Thr Gly Ala Gln Gly Val Ser Arg Ser Leu
515 520 525
Asp Trp Ser Lys Val Thr Leu Asp Gly Arg Pro Leu Thr Thr Ile Gln
530 535 540
Gln Tyr Ser Lys Thr Phe Tyr Val Leu Pro Leu Arg Gly Lys Leu Ser
545 550 555 560
Phe Trp Glu Ala Gly Thr Thr Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn
565 570 575
Thr Thr Ala Ser Asp Gln Ile Leu Ile Glu Asn Ala Ala Gly His Arg
580 585 590
Val Cys Ile Ser Thr Tyr Thr Thr Asn Leu Gly Ser Gly Pro Val Ser
595 600 605
Ile Ser Ala Val Gly Val Leu Ala Pro His Ser Ala Leu Ala Val Leu
610 615 620
Glu Asp Thr Val Asp Tyr Pro Ala Arg Ala His Thr Phe Asp Asp Phe
625 630 635 640
Cys Pro Glu Cys Arg Ala Leu Gly Leu Gln Gly Cys Ala Phe Gln Ser
645 650 655
Thr Val Ala Glu Leu Gln Arg Leu Lys Met Lys Val Gly Lys Thr Arg
660 665 670
Glu Tyr
<210> 7
<211> 674
<212> PRT
<213> Hepatitis E virus
<400> 7
Met Asn Asn Met Phe Phe Cys Ser Ala His Gly Asp Ala Thr Met Arg
1 5 10 15
Ser Arg Ala Leu Leu Phe Leu Leu Leu Val Phe Leu Pro Met Leu Pro
20 25 30
Ala Pro Pro Ala Gly Gln Pro Ser Gly Arg Arg Arg Gly Arg Arg Ser
35 40 45
Gly Gly Ala Gly Ser Gly Phe Trp Gly Asp Arg Val Asp Ser Gln Pro
50 55 60
Phe Ala Leu Pro Tyr Ile His Pro Thr Asn Pro Phe Ala Ser Asp Ile
65 70 75 80
Pro Ala Ala Ala Gly Ala Gly Ala Arg Pro Arg Gln Pro Ala Arg Pro
85 90 95
Leu Gly Ser Ala Trp Arg Asp Gln Ser Gln Arg Pro Ala Ala Ser Thr
100 105 110
Arg Arg Arg Pro Ala Pro Ala Gly Ala Ser Pro Leu Thr Ala Val Ala
115 120 125
Pro Ala Pro Asp Thr Ala Pro Val Pro Asp Val Asp Ser Arg Gly Ala
130 135 140
Ile Leu Arg Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr Ser Thr
145 150 155 160
Ile Ala Thr Gly Thr Asn Leu Val Leu Tyr Ala Ala Pro Leu Ser Pro
165 170 175
Leu Leu Pro Leu Gln Asp Gly Thr Asn Thr His Ile Met Ala Thr Glu
180 185 190
Ala Ser Asn Tyr Ala Gln Tyr Arg Val Val Arg Ala Thr Ile Arg Tyr
195 200 205
Arg Pro Leu Val Pro Asn Ala Val Gly Gly Tyr Ala Ile Ser Ile Ser
210 215 220
Phe Trp Pro Gln Thr Thr Thr Thr Pro Thr Ser Val Asp Met Asn Ser
225 230 235 240
Ile Thr Ser Thr Asp Val Arg Ile Leu Val Gln Pro Gly Ile Ala Ser
245 250 255
Glu Leu Val Ile Pro Ser Glu Arg Leu His Tyr Arg Asn Gln Gly Trp
260 265 270
Arg Ser Val Glu Thr Ser Gly Val Ala Glu Glu Glu Ala Thr Ser Gly
275 280 285
Leu Val Met Leu Cys Ile His Gly Ser Pro Val Asn Ser Tyr Thr Asn
290 295 300
Thr Pro Tyr Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu Glu Leu
305 310 315 320
Glu Phe Arg Asn Leu Thr Pro Gly Asn Thr Asn Thr Arg Val Ser Arg
325 330 335
Tyr Ser Ser Ser Ala Arg His Lys Leu Arg Arg Gly Pro Asp Gly Thr
340 345 350
Val Glu Leu Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp Leu His
355 360 365
Phe Thr Gly Thr Asn Gly Val Gly Glu Val Gly Arg Gly Ile Ala Leu
370 375 380
Thr Leu Phe Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro Thr Glu
385 390 395 400
Leu Ile Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro Val Val
405 410 415
Ser Ala Asn Gly Glu Pro Thr Val Lys Leu Tyr Thr Ser Val Glu Asn
420 425 430
Ala Gln Gln Asp Lys Gly Ile Ala Ile Pro His Asp Ile Asp Leu Gly
435 440 445
Glu Ser Arg Val Val Ile Gln Asp Tyr Asp Asn Gln His Glu Gln Asp
450 455 460
Arg Pro Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val Leu Arg
465 470 475 480
Ala Asn Asp Val Leu Trp Leu Ser Leu Thr Ala Ala Glu Tyr Asp Gln
485 490 495
Thr Thr Tyr Gly Ser Ser Thr Asn Pro Met Tyr Val Ser Asp Thr Val
500 505 510
Thr Phe Val Asn Val Ala Thr Gly Ala Gln Gly Val Ser Arg Ser Leu
515 520 525
Asp Trp Ser Lys Val Thr Leu Asp Gly Arg Pro Leu Thr Thr Ile Gln
530 535 540
Gln Tyr Ser Lys Thr Phe Tyr Val Leu Pro Leu Arg Gly Lys Leu Ser
545 550 555 560
Phe Trp Glu Ala Gly Thr Thr Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn
565 570 575
Thr Thr Ala Ser Asp Gln Ile Leu Ile Glu Asn Ala Ala Gly His Arg
580 585 590
Val Cys Ile Ser Thr Tyr Thr Thr Asn Leu Gly Ser Gly Pro Val Ser
595 600 605
Ile Ser Ala Val Gly Val Leu Ala Pro His Ser Ala Leu Ala Ile Leu
610 615 620
Glu Asp Thr Ala Asp Tyr Pro Ala Arg Ala His Thr Phe Asp Asp Phe
625 630 635 640
Cys Pro Glu Cys Arg Ser Leu Gly Leu Gln Gly Cys Ala Phe Gln Ser
645 650 655
Thr Val Ala Glu Leu Gln Arg Leu Lys Met Lys Val Gly Lys Thr Arg
660 665 670
Glu Tyr
<210> 8
<211> 672
<212> PRT
<213> Hepatitis E virus
<400> 8
Met Asn Asn Met Phe Phe Cys Ser Val His Gly Asp Ala Thr Met Arg
1 5 10 15
Ser Arg Ala Leu Leu Phe Leu Leu Phe Val Leu Leu Pro Met Leu Pro
20 25 30
Ala Pro Pro Ala Gly Gln Pro Ser Gly Arg Arg Arg Gly Gln Ala Gly
35 40 45
Cys Gly Gly Gly Phe Trp Gly Asp Arg Val Asp Ser Gln Pro Phe Ala
50 55 60
Leu Pro Tyr Ile His Pro Thr Asn Pro Phe Ala Ser Asp Ile Pro Ala
65 70 75 80
Ala Ala Gly Thr Gly Ala Arg Pro Arg Gln Pro Ile Arg Pro Leu Gly
85 90 95
Ser Ala Trp Arg Asp Gln Ser Gln Arg Pro Ala Ala Ser Thr Arg Arg
100 105 110
Arg Pro Ala Pro Ala Gly Ala Ser Pro Leu Thr Ala Val Ala Pro Ala
115 120 125
Pro Asp Thr Ala Pro Val Pro Asp Ala Asp Ser Arg Gly Ala Ile Leu
130 135 140
Arg Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr Ser Thr Ile Ala
145 150 155 160
Thr Gly Thr Asn Phe Val Leu Tyr Ala Ala Pro Leu Ser Pro Leu Leu
165 170 175
Pro Leu Gln Asp Gly Thr Asn Thr His Ile Met Ala Thr Glu Ala Ser
180 185 190
Asn Tyr Ala Gln Tyr Arg Val Val Arg Ala Thr Ile Arg Tyr Arg Pro
195 200 205
Leu Val Pro Asn Ala Val Gly Gly Tyr Ala Ile Ser Ile Ser Phe Trp
210 215 220
Pro Gln Thr Thr Thr Thr Pro Thr Ser Val Asp Met Asn Ser Ile Thr
225 230 235 240
Ser Thr Asp Val Arg Ile Leu Val Gln Pro Gly Ile Ala Ser Glu Leu
245 250 255
Val Thr Pro Ser Glu Arg Leu His Tyr Arg Asn Gln Gly Trp Arg Ser
260 265 270
Val Glu Thr Ser Gly Val Ala Glu Glu Glu Ala Thr Ser Gly Leu Val
275 280 285
Met Leu Cys Ile His Gly Ser Pro Val Asn Ser Tyr Thr Asn Thr Pro
290 295 300
Tyr Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu Glu Leu Glu Phe
305 310 315 320
Arg Asn Leu Thr Pro Gly Asn Thr Asn Thr Arg Val Ser Arg Tyr Ser
325 330 335
Ser Ser Ala Arg His Lys Leu Arg Arg Gly Pro Asp Gly Thr Ala Glu
340 345 350
Leu Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp Leu His Phe Thr
355 360 365
Gly Thr Asn Gly Val Gly Glu Val Gly Arg Gly Ile Ala Leu Thr Leu
370 375 380
Phe Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro Thr Glu Leu Ile
385 390 395 400
Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala
405 410 415
Asn Gly Glu Leu Thr Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln
420 425 430
Gln Asp Lys Gly Val Ala Ile Pro His Asp Ile Asp Leu Gly Glu Ser
435 440 445
Arg Val Val Ile Gln Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro
450 455 460
Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn
465 470 475 480
Asp Val Leu Trp Leu Ser Leu Thr Ala Ala Glu Tyr Asp Gln Thr Thr
485 490 495
Tyr Gly Ser Ser Thr Asn Pro Met Tyr Val Ser Asp Thr Val Thr Phe
500 505 510
Val Asn Val Ala Thr Gly Ala Gln Gly Val Ser Arg Ser Leu Asp Trp
515 520 525
Ser Lys Val Thr Leu Asp Gly Arg Pro Leu Thr Thr Ile Gln Gln Tyr
530 535 540
Ser Lys Thr Phe Tyr Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp
545 550 555 560
Glu Ala Gly Thr Thr Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr
565 570 575
Ala Ser Asp Gln Ile Leu Ile Glu Asn Ala Ala Gly His Arg Val Cys
580 585 590
Ile Ser Thr Tyr Thr Thr Asn Leu Gly Ser Gly Pro Val Ser Val Ser
595 600 605
Ala Val Gly Val Leu Ala Pro His Ser Ala Leu Ala Ala Leu Glu Asp
610 615 620
Thr Ala Asp Tyr Pro Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro
625 630 635 640
Glu Cys Arg Ala Leu Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Val
645 650 655
Gly Glu Leu Gln Arg Leu Lys Met Lys Val Gly Lys Thr Arg Glu Tyr
660 665 670
<210> 9
<211> 671
<212> PRT
<213> Hepatitis E virus
<400> 9
Met Phe Phe Cys Ser Val His Gly Asp Ala Thr Met Arg Ser Arg Ala
1 5 10 15
Leu Leu Phe Leu Leu Phe Val Leu Leu Pro Met Leu Pro Ala Pro Pro
20 25 30
Ala Gly Gln Pro Ser Gly Arg Arg Arg Gly Arg Arg Ser Gly Gly Ala
35 40 45
Gly Gly Gly Phe Trp Gly Asp Arg Val Asp Ser Gln Pro Phe Ala Leu
50 55 60
Pro Tyr Ile His Pro Thr Asn Pro Phe Ala Ser Asp Ile Pro Thr Ala
65 70 75 80
Ala Gly Ser Gly Ala Arg Pro Arg Gln Pro Val Arg Pro Leu Gly Ser
85 90 95
Ala Trp Arg Asp Gln Ser Gln Arg Pro Ala Ala Ser Ala Arg Arg Arg
100 105 110
Pro Ala Pro Ala Gly Ala Ser Pro Leu Thr Ala Val Ala Pro Ala Pro
115 120 125
Asp Thr Ala Pro Val Pro Asp Val Asp Ser Arg Gly Ala Ile Leu Arg
130 135 140
Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr Ser Thr Ile Ala Thr
145 150 155 160
Gly Thr Asn Leu Val Leu Tyr Ala Ala Pro Leu Ser Pro Leu Leu Pro
165 170 175
Leu Gln Asp Gly Thr Asn Thr His Ile Met Ala Thr Glu Ala Ser Asn
180 185 190
Tyr Ala Gln Tyr Arg Val Val Arg Ala Thr Ile Arg Tyr Arg Pro Leu
195 200 205
Val Pro Asn Ala Val Gly Gly Tyr Ala Ile Ser Ile Ser Phe Trp Pro
210 215 220
Gln Thr Thr Thr Thr Pro Thr Ser Val Asp Met Asn Ser Ile Thr Ser
225 230 235 240
Thr Asp Val Arg Ile Leu Val Gln Pro Gly Ile Ala Ser Glu Leu Val
245 250 255
Ile Pro Ser Glu Arg Leu His Tyr Arg Asn Gln Gly Trp Arg Ser Val
260 265 270
Glu Thr Ser Gly Val Ala Glu Glu Glu Ala Thr Ser Gly Leu Val Met
275 280 285
Leu Cys Ile His Gly Ser Pro Val Asn Ser Tyr Thr Asn Thr Pro Tyr
290 295 300
Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu Glu Leu Glu Phe Arg
305 310 315 320
Asn Leu Thr Pro Gly Asn Thr Asn Thr Arg Val Ser Arg Tyr Ser Ser
325 330 335
Ser Ala Arg His Lys Leu Arg Arg Gly Pro Asp Gly Thr Ala Glu Leu
340 345 350
Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp Leu His Phe Thr Gly
355 360 365
Thr Asn Gly Val Gly Glu Val Gly Arg Gly Ile Ala Leu Thr Leu Phe
370 375 380
Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro Thr Glu Leu Ile Ser
385 390 395 400
Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala Asn
405 410 415
Gly Glu Pro Thr Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln
420 425 430
Asp Lys Gly Ile Ala Ile Pro His Asp Ile Asp Leu Gly Glu Ser Arg
435 440 445
Val Val Ile Gln Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr
450 455 460
Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp
465 470 475 480
Val Leu Trp Leu Ser Leu Thr Ala Ala Glu Tyr Asp Gln Thr Thr Tyr
485 490 495
Gly Ser Ser Thr Asn Pro Met Tyr Val Ser Asp Thr Val Thr Phe Val
500 505 510
Asn Val Ala Thr Gly Ala Gln Gly Val Ser Arg Ser Leu Asp Trp Ser
515 520 525
Lys Val Thr Leu Asp Gly Arg Pro Leu Thr Thr Ile Gln Gln Tyr Ser
530 535 540
Lys Thr Phe Phe Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu
545 550 555 560
Ala Gly Thr Thr Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala
565 570 575
Ser Asp Gln Ile Leu Ile Glu Asn Ala Ala Gly His Arg Val Cys Ile
580 585 590
Ser Thr Tyr Thr Thr Asn Leu Gly Ser Gly Pro Val Ser Ile Ser Ala
595 600 605
Val Gly Val Leu Ala Pro His Ser Ala Leu Ala Ala Leu Glu Asp Thr
610 615 620
Val Asp Tyr Pro Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu
625 630 635 640
Cys Arg Thr Leu Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Val Ala
645 650 655
Glu Leu Gln Arg Leu Lys Met Lys Val Gly Lys Thr Arg Glu Tyr
660 665 670
<210> 10
<211> 668
<212> PRT
<213> Hepatitis E virus
<400> 10
Met Phe Phe Cys Ser Val His Gly Asp Ala Thr Met Arg Ser Arg Ala
1 5 10 15
Leu Leu Phe Leu Leu Leu Val Phe Leu Pro Met Leu Pro Ala Leu Pro
20 25 30
Ala Gly Gln Pro Ser Gly Arg Arg Arg Gly Arg Arg Ser Gly Ser Ala
35 40 45
Gly Gly Gly Phe Trp Gly Asp Arg Val Asp Ser Gln Pro Phe Ala Leu
50 55 60
Pro Tyr Ile His Pro Thr Asn Pro Phe Ala Ser Asp Ile Pro Thr Ala
65 70 75 80
Ala Gly Ala Gly Ala Arg Pro Arg Gln Pro Ala Arg Pro Leu Gly Ser
85 90 95
Ala Trp Arg Asp Gln Ser Gln Arg Pro Ala Thr Ser Thr Arg Arg Arg
100 105 110
Ser Ala Pro Val Gly Ala Ser Pro Leu Thr Ala Val Ala Pro Ala Pro
115 120 125
Asp Thr Ala Pro Val Pro Asp Val Asp Ser Arg Gly Ala Ile Leu Arg
130 135 140
Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr Ser Thr Ile Ala Thr
145 150 155 160
Gly Thr Asn Leu Val Leu Tyr Ala Ala Pro Leu Ser Pro Leu Leu Pro
165 170 175
Leu Gln Asp Gly Thr Asn Thr His Ile Met Ala Thr Glu Ala Ser Asn
180 185 190
Tyr Ala Gln Tyr Arg Val Val Arg Ala Thr Ile Arg Tyr Arg Pro Leu
195 200 205
Val Pro Asn Ala Val Gly Gly Tyr Ala Ile Ser Ile Ser Phe Trp Pro
210 215 220
Gln Thr Thr Thr Thr Pro Thr Ser Val Asp Met Asn Ser Ile Thr Ser
225 230 235 240
Thr Asp Val Arg Ile Leu Val Gln Ser Gly Ile Ala Ser Glu Leu Val
245 250 255
Ile Pro Ser Glu Arg Leu His Tyr Arg Asn Gln Gly Trp Arg Ser Val
260 265 270
Glu Thr Ser Gly Val Ala Glu Glu Glu Ala Thr Ser Gly Leu Val Met
275 280 285
Leu Cys Ile His Gly Ser Pro Val Asn Ser Tyr Thr Asn Thr Pro Tyr
290 295 300
Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu Glu Leu Glu Phe Arg
305 310 315 320
Asn Leu Thr Pro Gly Asn Thr Asn Met Arg Val Ser Arg His Ser Ser
325 330 335
Ser Ala Arg His Lys Leu Arg Arg Gly Pro Asp Gly Thr Ala Glu Leu
340 345 350
Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp Leu His Phe Thr Gly
355 360 365
Thr Asn Gly Val Gly Glu Val Gly Arg Gly Ile Ala Leu Thr Leu Phe
370 375 380
Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro Thr Glu Leu Ile Ser
385 390 395 400
Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala Asn
405 410 415
Gly Glu Pro Thr Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln
420 425 430
Asp Lys Gly Ile Ala Ile Pro His Asp Ile Asp Leu Gly Glu Ser Arg
435 440 445
Val Gly Ile Gln Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr
450 455 460
Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp
465 470 475 480
Val Leu Trp Leu Ser Leu Thr Ala Ala Glu Tyr Asp Gln Thr Thr Tyr
485 490 495
Gly Ser Ser Thr Asn Pro Met Tyr Val Ser Asp Thr Val Thr Phe Val
500 505 510
Asn Val Ala Thr Gly Ala Gln Gly Val Ser Arg Ser Leu Asp Trp Ser
515 520 525
Lys Val Thr Leu Asp Gly Arg Ser Leu Thr Thr Ile Gln Gln Tyr Ser
530 535 540
Lys Thr Phe Phe Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu
545 550 555 560
Ala Gly Thr Thr Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala
565 570 575
Ser Asp Gln Ile Leu Ile Glu Asn Ala Ala Gly His Arg Val Cys Ile
580 585 590
Ser Thr Tyr Thr Thr Asn Leu Gly Ser Gly Pro Val Ser Ile Ser Ala
595 600 605
Val Gly Val Leu Ala Pro His Ser Ala Leu Ala Val Leu Glu Asp Thr
610 615 620
Val Asp Tyr Pro Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu
625 630 635 640
Cys Arg Ala Leu Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Val Ala
645 650 655
Glu Leu Gln Arg Leu Lys Met Lys Val Gly Asn His
660 665
<210> 11
<211> 660
<212> PRT
<213> Hepatitis E virus
<400> 11
Met Arg Pro Arg Pro Ile Leu Leu Leu Leu Leu Met Phe Leu Pro Met
1 5 10 15
Leu Pro Ala Pro Pro Pro Gly Gln Pro Ser Gly Arg Arg Arg Gly Arg
20 25 30
Arg Ser Gly Gly Ser Gly Gly Gly Phe Trp Gly Asp Arg Ala Asp Ser
35 40 45
Gln Pro Phe Ala Ile Pro Tyr Ile His Pro Thr Asn Pro Phe Ala Pro
50 55 60
Asp Val Thr Ala Ala Ala Gly Ala Gly Pro Arg Val Arg Gln Pro Ala
65 70 75 80
Arg Pro Leu Gly Ser Ala Trp Arg Asp Gln Ala Gln Arg Pro Ala Ala
85 90 95
Ala Ser Arg Arg Arg Pro Thr Thr Ala Gly Ala Ala Pro Leu Thr Ala
100 105 110
Val Ala Pro Ala His Asp Thr Pro Pro Val Pro Asp Val Asp Ser Arg
115 120 125
Gly Ala Ile Leu Arg Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr
130 135 140
Ser Ser Val Ala Thr Gly Thr Asn Leu Val Leu Tyr Ala Ala Pro Leu
145 150 155 160
Ser Pro Leu Leu Pro Leu Gln Asp Gly Thr Asn Thr His Ile Met Ala
165 170 175
Thr Glu Ala Ser Asn Tyr Ala Gln Tyr Arg Val Val Arg Ala Thr Ile
180 185 190
Arg Tyr Arg Pro Leu Val Pro Asn Ala Val Gly Gly Tyr Ala Ile Ser
195 200 205
Ile Ser Phe Trp Pro Gln Thr Thr Thr Thr Pro Thr Ser Val Asp Met
210 215 220
Asn Ser Ile Thr Ser Thr Asp Val Arg Ile Leu Val Gln Pro Gly Ile
225 230 235 240
Ala Ser Glu His Val Ile Pro Ser Glu Arg Leu His Tyr Arg Asn Gln
245 250 255
Gly Trp Arg Ser Val Glu Thr Ser Gly Val Ala Glu Glu Glu Ala Thr
260 265 270
Ser Gly Leu Val Met Leu Cys Ile His Gly Ser Leu Val Asn Ser Tyr
275 280 285
Thr Asn Thr Pro Tyr Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu
290 295 300
Glu Leu Glu Phe Arg Asn Leu Thr Pro Gly Asn Thr Asn Thr Arg Val
305 310 315 320
Ser Arg Tyr Ser Ser Thr Ala Arg His Arg Leu Arg Arg Gly Ala Asp
325 330 335
Gly Thr Ala Glu Leu Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp
340 345 350
Leu Tyr Phe Thr Ser Thr Asn Gly Val Gly Glu Ile Gly Arg Gly Ile
355 360 365
Ala Leu Thr Leu Phe Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro
370 375 380
Thr Glu Leu Ile Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro
385 390 395 400
Val Val Ser Ala Asn Gly Glu Pro Thr Val Lys Leu Tyr Thr Ser Val
405 410 415
Glu Asn Ala Gln Gln Asp Lys Gly Ile Ala Ile Pro His Asp Ile Asp
420 425 430
Leu Gly Glu Ser Arg Val Val Ile Gln Asp Tyr Asp Asn Gln His Glu
435 440 445
Gln Asp Arg Pro Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val
450 455 460
Leu Arg Ala Asn Asp Val Leu Trp Leu Ser Leu Thr Ala Ala Glu Tyr
465 470 475 480
Asp Gln Ser Thr Tyr Gly Ser Ser Thr Gly Pro Val Tyr Val Ser Asp
485 490 495
Ser Val Thr Leu Val Asn Val Ala Thr Gly Ala Gln Ala Val Ala Arg
500 505 510
Ser Leu Asp Trp Thr Lys Val Thr Leu Asp Gly Arg Pro Leu Ser Thr
515 520 525
Thr Gln Gln Tyr Ser Lys Thr Phe Phe Val Leu Pro Leu Arg Gly Lys
530 535 540
Leu Ser Phe Trp Glu Ala Gly Thr Thr Lys Ala Gly Tyr Pro Tyr Asn
545 550 555 560
Tyr Asn Thr Thr Ala Ser Asp Gln Leu Leu Val Glu Asn Ala Ala Gly
565 570 575
His Arg Val Ala Ile Ser Thr Tyr Thr Thr Ser Leu Gly Ala Gly Pro
580 585 590
Val Ser Ile Ser Ala Val Ala Val Leu Ala Pro His Ser Ala Leu Ala
595 600 605
Leu Leu Glu Asp Thr Met Asp Tyr Pro Ala Arg Ala His Thr Phe Asp
610 615 620
Asp Phe Cys Pro Glu Cys Arg Pro Leu Gly Leu Gln Gly Cys Ala Phe
625 630 635 640
Gln Ser Thr Val Ala Glu Leu Gln Arg Leu Lys Met Lys Val Gly Lys
645 650 655
Thr Arg Glu Leu
660
<210> 12
<211> 660
<212> PRT
<213> Hepatitis E virus
<400> 12
Met Arg Pro Arg Pro Ile Leu Leu Leu Leu Leu Met Phe Leu Pro Met
1 5 10 15
Leu Pro Ala Pro Pro Pro Gly Gln Pro Ser Gly Arg Arg Arg Gly Arg
20 25 30
Arg Ser Gly Gly Ser Gly Gly Gly Phe Trp Gly Asp Arg Val Asp Ser
35 40 45
Gln Pro Phe Ala Ile Pro Tyr Ile His Pro Thr Asn Pro Phe Ala Pro
50 55 60
Asp Val Thr Ala Ala Ala Gly Ala Gly Pro Arg Val Arg Gln Pro Ala
65 70 75 80
Arg Pro Leu Gly Ser Ala Trp Arg Asp Gln Ala Gln Arg Pro Ala Val
85 90 95
Ala Ser Arg Arg Arg Pro Thr Thr Ala Gly Ala Ala Pro Leu Thr Ala
100 105 110
Val Ala Pro Ala His Asp Thr Pro Pro Val Pro Asp Val Asp Ser Arg
115 120 125
Gly Ala Ile Leu Arg Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr
130 135 140
Ser Ser Val Ala Thr Gly Thr Asn Leu Val Leu Tyr Ala Ala Pro Leu
145 150 155 160
Ser Pro Leu Leu Pro Leu Gln Asp Gly Thr Asn Thr His Ile Met Ala
165 170 175
Thr Glu Ala Ser Asn Tyr Ala Gln Tyr Arg Val Ala Arg Ala Thr Ile
180 185 190
Arg Tyr Arg Pro Leu Val Pro Asn Ala Val Gly Gly Tyr Ala Ile Ser
195 200 205
Ile Ser Phe Trp Pro Gln Thr Thr Thr Thr Pro Thr Ser Val Asp Met
210 215 220
Asn Ser Ile Thr Ser Thr Asp Val Arg Ile Leu Val Gln Pro Gly Ile
225 230 235 240
Ala Ser Glu Leu Val Ile Pro Ser Glu Arg Leu His Tyr Arg Asn Gln
245 250 255
Gly Trp Arg Ser Val Glu Thr Ser Gly Val Ala Glu Glu Glu Ala Thr
260 265 270
Ser Gly Leu Val Met Leu Cys Ile His Gly Ser Leu Val Asn Ser Tyr
275 280 285
Thr Asn Thr Pro Tyr Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu
290 295 300
Glu Leu Glu Phe Arg Asn Leu Thr Pro Gly Asn Thr Asn Thr Arg Val
305 310 315 320
Ser Arg Tyr Ser Ser Thr Ala Arg His Arg Leu Arg Arg Gly Ala Asp
325 330 335
Gly Thr Ala Glu Leu Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp
340 345 350
Leu Tyr Phe Thr Ser Thr Asn Gly Val Gly Glu Ile Gly Arg Gly Ile
355 360 365
Ala Leu Thr Leu Phe Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro
370 375 380
Thr Glu Leu Ile Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro
385 390 395 400
Val Val Ser Ala Asn Gly Glu Pro Thr Val Lys Leu Tyr Thr Ser Val
405 410 415
Glu Asn Ala Gln Gln Asp Lys Gly Ile Ala Ile Pro His Asp Ile Asp
420 425 430
Leu Gly Glu Ser Arg Val Val Ile Gln Asp Tyr Asp Asn Gln His Glu
435 440 445
Gln Asp Arg Pro Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val
450 455 460
Leu Arg Ala Asn Asp Val Leu Trp Leu Ser Leu Thr Ala Ala Glu Tyr
465 470 475 480
Asp Gln Ser Thr Tyr Gly Ser Ser Thr Gly Pro Val Tyr Val Ser Asp
485 490 495
Ser Val Thr Leu Val Asn Val Ala Thr Gly Ala Gln Ala Val Ala Arg
500 505 510
Ser Leu Asp Trp Thr Lys Val Thr Leu Asp Gly Arg Pro Leu Ser Thr
515 520 525
Ile Gln Gln Tyr Ser Lys Thr Phe Phe Val Leu Pro Leu Arg Gly Lys
530 535 540
Leu Ser Phe Trp Glu Ala Gly Thr Thr Lys Ala Gly Tyr Pro Tyr Asn
545 550 555 560
Tyr Asn Thr Thr Ala Ser Asp Gln Leu Leu Val Glu Asn Ala Ala Gly
565 570 575
His Arg Val Ala Ile Ser Thr Tyr Thr Thr Ser Leu Gly Ala Gly Pro
580 585 590
Val Ser Ile Ser Ala Val Ala Val Leu Ala Pro His Ser Ala Leu Ala
595 600 605
Leu Leu Glu Asp Thr Leu Asp Tyr Pro Ala Arg Ala His Thr Phe Asp
610 615 620
Asp Phe Cys Pro Glu Cys Arg Pro Leu Gly Leu Gln Gly Cys Ala Phe
625 630 635 640
Gln Ser Thr Val Ala Glu Leu Gln Arg Leu Lys Met Lys Val Gly Lys
645 650 655
Thr Arg Glu Leu
660
<210> 13
<211> 660
<212> PRT
<213> Hepatitis E virus
<400> 13
Met Arg Pro Arg Ala Val Leu Leu Leu Leu Phe Val Leu Leu Pro Met
1 5 10 15
Leu Pro Ala Pro Pro Ala Gly Gln Pro Ser Gly Arg Arg Arg Gly Arg
20 25 30
Arg Asn Gly Gly Ala Gly Gly Gly Phe Trp Gly Asp Arg Val Asp Ser
35 40 45
Gln Pro Phe Ala Leu Pro Tyr Ile His Pro Thr Asn Pro Phe Ala Ala
50 55 60
Asp Val Val Ser Gln Pro Gly Ala Gly Ala Arg Pro Arg Gln Pro Pro
65 70 75 80
Arg Pro Leu Gly Ser Ala Trp Arg Asp Gln Ser Gln Arg Pro Ser Thr
85 90 95
Ala Pro Arg Arg Arg Ser Ala Pro Ala Gly Ala Ala Pro Leu Thr Ala
100 105 110
Val Ser Pro Ala Pro Asp Thr Ala Pro Val Pro Asp Val Asp Ser Arg
115 120 125
Gly Ala Ile Leu Arg Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr
130 135 140
Ser Ser Val Ala Ala Gly Thr Asn Leu Val Leu Tyr Ala Ala Pro Leu
145 150 155 160
Asn Pro Leu Leu Pro Leu Gln Asp Gly Thr Asn Thr His Ile Met Ala
165 170 175
Thr Glu Ala Ser Asn Tyr Ala Gln Tyr Arg Val Val Arg Ala Thr Ile
180 185 190
Arg Tyr Arg Pro Leu Val Pro Asn Ala Val Gly Gly Tyr Ala Ile Ser
195 200 205
Ile Ser Phe Trp Pro Gln Thr Thr Thr Thr Pro Thr Ser Val Asp Met
210 215 220
Asn Ser Ile Thr Ser Thr Asp Val Arg Ile Leu Val Gln Pro Gly Ile
225 230 235 240
Ala Ser Glu Leu Val Ile Pro Ser Glu Arg Leu His Tyr Arg Asn Gln
245 250 255
Gly Trp Arg Ser Val Glu Thr Thr Gly Val Ala Glu Glu Glu Ala Thr
260 265 270
Ser Gly Leu Val Met Leu Cys Ile His Gly Ser Pro Val Asn Ser Tyr
275 280 285
Thr Asn Thr Pro Tyr Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu
290 295 300
Glu Leu Glu Phe Arg Asn Leu Thr Pro Gly Asn Thr Asn Thr Arg Val
305 310 315 320
Ser Arg Tyr Thr Ser Thr Ala Arg His Arg Leu Arg Arg Gly Ala Asp
325 330 335
Gly Thr Ala Glu Leu Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp
340 345 350
Leu His Phe Thr Gly Thr Asn Gly Val Gly Glu Val Gly Arg Gly Ile
355 360 365
Ala Leu Thr Leu Phe Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro
370 375 380
Thr Glu Leu Ile Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro
385 390 395 400
Val Val Ser Ala Asn Gly Glu Pro Thr Val Lys Leu Tyr Thr Ser Val
405 410 415
Glu Asn Ala Gln Gln Asp Lys Gly Ile Thr Ile Pro His Asp Ile Asp
420 425 430
Leu Gly Asp Ser Arg Val Val Ile Gln Asp Tyr Asp Asn Gln His Glu
435 440 445
Gln Asp Arg Pro Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val
450 455 460
Leu Arg Ala Asn Asp Val Leu Trp Leu Ser Leu Thr Ala Ala Glu Tyr
465 470 475 480
Asp Gln Thr Thr Tyr Gly Ser Ser Thr Asn Pro Met Tyr Val Ser Asp
485 490 495
Thr Val Thr Leu Val Asn Val Ala Thr Gly Ala Gln Ala Val Ala Arg
500 505 510
Ser Leu Asp Trp Ser Lys Val Thr Leu Asp Gly Arg Pro Leu Thr Thr
515 520 525
Ile Gln Gln Tyr Ser Lys Thr Phe Tyr Val Leu Pro Leu Arg Gly Lys
530 535 540
Leu Ser Phe Trp Glu Ala Gly Thr Thr Lys Ala Gly Tyr Pro Tyr Asn
545 550 555 560
Tyr Asn Thr Thr Ala Ser Asp Gln Ile Leu Ile Glu Asn Ala Ala Gly
565 570 575
His Arg Val Ala Ile Ser Thr Tyr Thr Thr Ser Leu Gly Ala Gly Pro
580 585 590
Thr Ser Ile Ser Ala Val Gly Val Leu Ala Pro His Ser Ala Leu Ala
595 600 605
Val Leu Glu Asp Thr Val Asp Tyr Pro Ala Arg Ala His Thr Phe Asp
610 615 620
Asp Phe Cys Pro Glu Cys Arg Thr Leu Gly Leu Gln Gly Cys Ala Phe
625 630 635 640
Gln Ser Thr Ile Ala Glu Leu Gln Arg Leu Lys Met Lys Val Gly Lys
645 650 655
Thr Arg Glu Ser
660
<210> 14
<211> 660
<212> PRT
<213> Hepatitis E virus
<400> 14
Met Arg Pro Arg Pro Ile Leu Leu Leu Leu Leu Met Phe Leu Pro Met
1 5 10 15
Leu Pro Ala Pro Pro Pro Gly Gln Pro Ser Gly Arg Arg Arg Gly Arg
20 25 30
Arg Ser Gly Gly Ser Gly Gly Gly Phe Trp Gly Asp Arg Val Asp Ser
35 40 45
Gln Pro Phe Ala Ile Pro Tyr Ile His Pro Thr Asn Pro Phe Ala Pro
50 55 60
Asp Val Thr Ala Ala Ala Gly Ala Gly Pro Arg Val Arg Gln Pro Ala
65 70 75 80
Arg Pro Leu Gly Ser Ala Trp Arg Asp Gln Ala Gln Arg Pro Ala Val
85 90 95
Ala Ser Arg Arg Arg Pro Thr Thr Ala Gly Ala Ala Pro Leu Thr Ala
100 105 110
Val Ala Pro Ala His Asp Thr Pro Pro Val Pro Asp Val Asp Ser Arg
115 120 125
Ala Ala Ile Leu Arg Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr
130 135 140
Ser Ser Val Ala Thr Gly Thr Asn Leu Val Leu Tyr Ala Ala Pro Leu
145 150 155 160
Ser Pro Leu Leu Pro Leu Gln Asp Gly Thr Asn Thr His Ile Met Ala
165 170 175
Thr Glu Ala Ser Asn Tyr Ala Gln Tyr Arg Val Val Arg Ala Thr Ile
180 185 190
Arg Tyr Arg Pro Leu Val Pro Asn Ala Val Gly Gly Tyr Ala Ile Ser
195 200 205
Ile Ser Phe Trp Pro Gln Thr Thr Thr Thr Pro Thr Ser Val Asp Met
210 215 220
Asn Ser Ile Thr Ser Thr Asp Val Arg Ile Leu Val Gln Pro Gly Ile
225 230 235 240
Ala Ser Glu Leu Val Ile Pro Ser Glu Arg Leu His Tyr Arg Asn Gln
245 250 255
Gly Trp Arg Ser Val Glu Thr Ser Gly Val Ala Glu Glu Glu Ala Thr
260 265 270
Ser Gly Leu Val Met Leu Cys Ile His Gly Ser Pro Val Asn Ser Tyr
275 280 285
Thr Asn Thr Pro Tyr Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu
290 295 300
Glu Leu Glu Phe Arg Asn Leu Thr Pro Gly Asn Thr Asn Thr Arg Val
305 310 315 320
Ser Arg Tyr Ser Ser Thr Ala Arg His Arg Leu Arg Arg Gly Ala Asp
325 330 335
Gly Thr Ala Glu Leu Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp
340 345 350
Leu Tyr Phe Thr Ser Thr Asn Gly Val Gly Glu Ile Gly Arg Gly Ile
355 360 365
Ala Leu Thr Leu Phe Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro
370 375 380
Thr Glu Leu Ile Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro
385 390 395 400
Val Val Ser Ala His Gly Glu Pro Thr Val Lys Leu Tyr Thr Ser Val
405 410 415
Glu Asn Ala Gln Gln Asp Lys Gly Ile Ala Ile Pro His Asp Ile Asp
420 425 430
Leu Gly Glu Ser Arg Val Val Ile Gln Asp Tyr Asp Asn Gln His Glu
435 440 445
Gln Asp Arg Pro Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val
450 455 460
Leu Arg Ala Asn Asp Val Leu Trp Leu Ser Leu Thr Ala Ala Glu Tyr
465 470 475 480
Asp Gln Ser Thr Tyr Gly Ser Ser Thr Ala Pro Val Tyr Val Ser Asp
485 490 495
Ser Val Thr Leu Val Asn Val Ala Thr Gly Ala Gln Ala Val Ala Arg
500 505 510
Ser Leu Asp Trp Thr Lys Val Thr Leu Asp Gly Arg Pro Leu Ser Thr
515 520 525
Ile Gln Gln Tyr Pro Lys Thr Phe Phe Val Leu Pro Leu Arg Gly Lys
530 535 540
Leu Ser Phe Trp Glu Ala Gly Thr Thr Lys Ala Gly Tyr Pro Tyr Asn
545 550 555 560
Tyr Asn Thr Thr Ala Ser Asp Gln Leu Leu Val Glu Asn Ala Ala Gly
565 570 575
His Arg Val Ala Ile Ser Thr Tyr Thr Thr Ser Leu Gly Ala Gly Pro
580 585 590
Val Ser Ile Ser Ala Val Ala Val Leu Ala Pro His Ser Ala Leu Ala
595 600 605
Leu Leu Glu Asp Thr Leu Asp Tyr Pro Ala Cys Ala His Thr Phe Asp
610 615 620
Asp Phe Cys Pro Glu Cys Arg Pro Leu Gly Leu Gln Gly Cys Ala Phe
625 630 635 640
Gln Ser Thr Val Ala Glu Leu Gln Arg Leu Lys Met Lys Val Gly Lys
645 650 655
Thr Arg Glu Leu
660
<210> 15
<211> 660
<212> PRT
<213> Hepatitis E virus
<400> 15
Met Gly Pro Arg Pro Ile Leu Leu Leu Phe Leu Met Phe Leu Pro Met
1 5 10 15
Leu Leu Ala Pro Pro Pro Gly Gln Pro Ser Gly Arg Arg Arg Gly Arg
20 25 30
Arg Ser Gly Gly Ser Gly Gly Gly Phe Trp Gly Asp Arg Val Asp Ser
35 40 45
Gln Pro Phe Ala Ile Pro Tyr Ile His Pro Thr Asn Pro Phe Ala Pro
50 55 60
Asn Val Thr Ala Ala Ala Gly Ala Gly Pro Arg Val Arg Gln Pro Val
65 70 75 80
Arg Pro Leu Gly Ser Ala Trp Arg Asp Gln Ala Gln Arg Pro Ala Ala
85 90 95
Ala Ser Arg Arg Arg Pro Thr Thr Ala Gly Ala Ala Pro Leu Thr Ala
100 105 110
Val Ala Pro Ala His Asp Thr Pro Pro Val Pro Asp Val Asp Ser Arg
115 120 125
Gly Ala Ile Leu Arg Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr
130 135 140
Ser Ser Val Ala Thr Gly Thr Asn Leu Val Leu Tyr Ala Ala Pro Leu
145 150 155 160
Ser Pro Leu Leu Pro Leu Gln Asp Gly Thr Asn Thr His Ile Met Ala
165 170 175
Thr Glu Ala Ser Asn Tyr Ala Gln Tyr Arg Val Ala Arg Ala Thr Ile
180 185 190
Arg Tyr Arg Pro Leu Val Pro Asn Ala Val Gly Gly Tyr Ala Ile Ser
195 200 205
Ile Ser Phe Trp Pro Gln Thr Thr Pro Thr Pro Thr Ser Val Asp Met
210 215 220
Asn Ser Ile Thr Ser Thr Asp Val Arg Ile Leu Val Gln Pro Gly Ile
225 230 235 240
Ala Ser Glu Leu Val Ile Pro Ser Glu Arg Leu His Tyr Arg Asn Gln
245 250 255
Gly Trp Arg Ser Val Glu Thr Ser Gly Val Ala Glu Glu Glu Ala Thr
260 265 270
Ser Gly Leu Val Met Leu Cys Ile His Gly Ser Pro Val Asn Ser Tyr
275 280 285
Thr Asn Thr Pro Tyr Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu
290 295 300
Glu Leu Glu Phe Arg Asn Leu Thr Pro Gly Asn Thr Asn Thr Arg Val
305 310 315 320
Ser Arg Tyr Ser Ser Thr Ala Arg His Arg Leu Arg Arg Gly Ala Asp
325 330 335
Gly Thr Ala Glu Leu Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp
340 345 350
Leu Tyr Phe Thr Ser Thr Asn Gly Val Gly Glu Ile Gly Arg Gly Ile
355 360 365
Ala Leu Thr Leu Phe Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro
370 375 380
Thr Glu Leu Ile Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro
385 390 395 400
Val Val Ser Ala Asn Gly Glu Pro Thr Val Lys Leu Tyr Thr Ser Val
405 410 415
Glu Asn Ala Gln Gln Asp Lys Gly Ile Ala Ile Pro Asn Asp Ile Asp
420 425 430
Leu Gly Glu Ser Arg Val Val Ile Gln Asp Tyr Asp Asn Gln His Glu
435 440 445
Gln Asp Arg Pro Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val
450 455 460
Leu Arg Ala Asn Asp Val Leu Trp Leu Ser Leu Thr Ala Ala Glu Tyr
465 470 475 480
Asp Gln Ser Thr Tyr Gly Ser Ser Thr Gly Pro Val Tyr Val Ser Asp
485 490 495
Ser Val Thr Leu Val Asn Val Ala Thr Gly Ala Gln Ala Val Ala Arg
500 505 510
Ser Leu Asp Trp Thr Lys Val Thr Leu Asp Gly Arg Pro Leu Ser Thr
515 520 525
Ile Gln Gln Tyr Ser Lys Ile Phe Phe Val Leu Pro Leu Arg Gly Lys
530 535 540
Leu Ser Phe Trp Glu Ala Gly Thr Thr Arg Pro Gly Tyr Pro Tyr Asn
545 550 555 560
Tyr Asn Thr Thr Ala Ser Asp Gln Leu Leu Val Glu Asn Ala Ala Gly
565 570 575
His Arg Val Ala Ile Ser Thr Tyr Thr Thr Ser Leu Gly Ala Gly Pro
580 585 590
Val Ser Ile Ser Ala Val Ala Val Leu Gly Pro His Ser Ala Leu Ala
595 600 605
Leu Leu Glu Asp Thr Leu Asp Tyr Pro Ala Arg Ala His Thr Phe Asp
610 615 620
Asp Phe Cys Pro Glu Cys Arg Pro Leu Gly Leu Gln Gly Cys Ala Phe
625 630 635 640
Gln Ser Thr Val Ala Glu Leu Gln Arg Leu Lys Met Lys Val Gly Lys
645 650 655
Thr Arg Glu Leu
660
<210> 16
<211> 660
<212> PRT
<213> Hepatitis E virus
<400> 16
Met Arg Pro Arg Ala Val Leu Leu Leu Leu Phe Val Leu Leu Pro Met
1 5 10 15
Leu Pro Ala Pro Pro Ala Gly Gln Pro Ser Gly Arg Arg Arg Gly Arg
20 25 30
Arg Ser Gly Gly Ala Gly Gly Gly Phe Trp Gly Asp Arg Val Asp Ser
35 40 45
Gln Pro Phe Ala Leu Pro Tyr Ile His Pro Thr Asn Pro Phe Ala Ala
50 55 60
Asp Val Val Ser Gln Pro Gly Ala Gly Thr Arg Pro Arg Gln Pro Pro
65 70 75 80
Arg Pro Leu Gly Ser Ala Trp Arg Asp Gln Ser Gln Arg Pro Ser Ala
85 90 95
Ala Pro Arg Arg Arg Ser Ala Pro Ala Gly Ala Ala Pro Leu Thr Ala
100 105 110
Val Ser Pro Ala Pro Asp Thr Ala Pro Val Pro Asp Val Asp Ser Arg
115 120 125
Gly Ala Ile Leu Arg Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr
130 135 140
Ser Ser Val Ala Ser Gly Thr Asn Leu Val Leu Tyr Ala Ala Pro Leu
145 150 155 160
Asn Pro Leu Leu Pro Leu Gln Asp Gly Thr Asn Thr His Ile Met Ala
165 170 175
Thr Glu Ala Ser Asn Tyr Ala Gln Tyr Arg Val Val Arg Ala Thr Ile
180 185 190
Arg Tyr Arg Pro Leu Val Pro Asn Ala Val Gly Gly Tyr Ala Ile Ser
195 200 205
Ile Ser Phe Trp Pro Gln Thr Thr Thr Thr Pro Thr Ser Val Asp Met
210 215 220
Asn Ser Ile Thr Ser Thr Asp Val Arg Ile Leu Val Gln Pro Gly Ile
225 230 235 240
Ala Ser Glu Leu Val Ile Pro Ser Glu Arg Leu His Tyr Arg Asn Gln
245 250 255
Gly Trp Arg Ser Val Glu Thr Thr Gly Val Ala Glu Glu Glu Ala Thr
260 265 270
Ser Gly Leu Val Met Leu Cys Ile His Gly Ser Pro Val Asn Ser Tyr
275 280 285
Thr Asn Thr Pro Tyr Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu
290 295 300
Glu Leu Glu Phe Arg Asn Leu Thr Pro Gly Asn Thr Asn Thr Arg Val
305 310 315 320
Ser Arg Tyr Thr Ser Thr Ala Arg His Arg Leu Arg Arg Gly Ala Asp
325 330 335
Gly Thr Ala Glu Leu Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp
340 345 350
Leu His Phe Ala Gly Thr Asn Gly Val Gly Glu Val Gly Arg Gly Ile
355 360 365
Ala Leu Thr Leu Phe Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro
370 375 380
Thr Glu Leu Ile Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro
385 390 395 400
Val Val Ser Ala Asn Gly Glu Pro Thr Val Lys Leu Tyr Thr Ser Val
405 410 415
Glu Asn Ala Gln Gln Asp Lys Gly Ile Thr Ile Pro His Asp Ile Asp
420 425 430
Leu Gly Asp Ser Arg Val Val Ile Gln Asp Tyr Asp Asn Gln His Glu
435 440 445
Gln Asp Arg Pro Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val
450 455 460
Leu Arg Ala Asn Asp Val Leu Trp Leu Ser Leu Thr Ala Ala Glu Tyr
465 470 475 480
Asp Gln Thr Thr Tyr Gly Ser Ser Thr Asn Pro Met Tyr Val Ser Asp
485 490 495
Thr Val Thr Leu Val Asn Val Ala Thr Gly Ala Gln Ala Val Ala Arg
500 505 510
Ser Leu Asp Trp Ser Lys Val Thr Leu Asp Gly Arg Pro Leu Thr Thr
515 520 525
Ile Gln Gln Tyr Ser Lys Thr Phe Tyr Val Leu Pro Leu Arg Gly Lys
530 535 540
Leu Ser Phe Trp Glu Ala Gly Thr Thr Lys Ala Gly Tyr Pro Tyr Asn
545 550 555 560
Tyr Asn Thr Thr Ala Ser Asp Gln Ile Leu Ile Glu Asn Ala Ala Gly
565 570 575
His Arg Val Ala Ile Ser Thr Tyr Thr Thr Ser Leu Gly Ala Gly Pro
580 585 590
Thr Ser Ile Ser Ala Val Gly Val Leu Ala Pro His Ser Ala Leu Ala
595 600 605
Val Leu Glu Asp Thr Ile Asp Tyr Pro Ala Arg Ala His Thr Phe Asp
610 615 620
Asp Phe Cys Pro Glu Cys Arg Thr Leu Gly Leu Gln Gly Cys Ala Phe
625 630 635 640
Gln Ser Thr Ile Ala Glu Leu Gln Arg Leu Lys Met Lys Val Gly Lys
645 650 655
Thr Arg Glu Ser
660
<210> 17
<211> 660
<212> PRT
<213> Hepatitis E virus
<400> 17
Met Arg Pro Arg Pro Ile Leu Leu Leu Leu Leu Met Phe Leu Pro Met
1 5 10 15
Leu Pro Ala Pro Pro Pro Gly Gln Pro Ser Gly Arg Arg Arg Gly Arg
20 25 30
Arg Ser Gly Gly Ser Gly Gly Gly Phe Trp Gly Asp Arg Val Asp Ser
35 40 45
Gln Pro Phe Ala Ile Pro Tyr Ile His Pro Thr Asn Pro Phe Ala Pro
50 55 60
Asp Val Thr Ala Ala Ala Gly Ala Gly Pro Arg Val Arg Gln Pro Ala
65 70 75 80
Arg Pro Leu Gly Ser Ala Trp Arg Asp Gln Ala Gln Arg Pro Ala Ala
85 90 95
Ala Ser Arg Arg Arg Pro Thr Thr Ala Gly Ala Ala Pro Leu Thr Ala
100 105 110
Val Ala Pro Ala His Asp Thr Pro Pro Val Pro Asp Val Asp Ser Arg
115 120 125
Gly Ala Ile Leu Arg Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr
130 135 140
Ser Ser Val Ala Thr Gly Thr Asn Leu Val Leu Tyr Ala Ala Pro Leu
145 150 155 160
Ser Pro Leu Leu Pro Leu Gln Asp Gly Thr Asn Thr His Ile Met Ala
165 170 175
Thr Glu Ala Ser Asn Tyr Ala Gln Tyr Arg Val Ala Arg Ala Thr Ile
180 185 190
Arg Tyr Arg Pro Leu Val Pro Asn Ala Val Gly Gly Tyr Ala Ile Ser
195 200 205
Ile Ser Phe Trp Pro Gln Thr Thr Thr Thr Pro Thr Ser Val Asp Met
210 215 220
Asn Ser Ile Thr Ser Thr Asp Val Arg Ile Leu Val Gln Pro Gly Ile
225 230 235 240
Ala Ser Glu Leu Val Ile Pro Ser Glu Arg Leu His Tyr Arg Asn Gln
245 250 255
Gly Trp Arg Ser Val Glu Thr Ser Gly Val Ala Glu Glu Glu Ala Thr
260 265 270
Ser Gly Leu Val Met Leu Cys Ile His Gly Ser Pro Val Asn Ser Tyr
275 280 285
Thr Asn Thr Pro Tyr Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu
290 295 300
Glu Leu Glu Phe Arg Asn Leu Thr Pro Gly Asn Thr Asn Thr Arg Val
305 310 315 320
Ser Arg Tyr Ser Ser Thr Ala Arg His Arg Leu Arg Arg Gly Ala Asp
325 330 335
Gly Thr Ala Glu Leu Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp
340 345 350
Leu Tyr Phe Thr Ser Thr Asn Gly Val Gly Glu Ile Gly Arg Gly Ile
355 360 365
Ala Leu Thr Leu Phe Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro
370 375 380
Thr Glu Leu Ile Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro
385 390 395 400
Val Val Ser Ala Asn Gly Glu Pro Thr Val Lys Leu Tyr Thr Ser Val
405 410 415
Glu Asn Ala Gln Gln Asp Lys Gly Ile Ala Ile Pro His Asp Ile Asp
420 425 430
Leu Gly Glu Ser Arg Val Val Ile Gln Asp Tyr Asp Asn Gln His Glu
435 440 445
Gln Asp Arg Pro Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val
450 455 460
Leu Arg Ala Asn Asp Val Leu Trp Leu Ser Leu Thr Ala Ala Glu Tyr
465 470 475 480
Asp Gln Ser Thr Tyr Gly Ser Ser Thr Gly Pro Val Tyr Val Ser Asp
485 490 495
Ser Val Thr Leu Val Asn Val Ala Thr Gly Ala Gln Ala Val Ala Arg
500 505 510
Ser Leu Asp Trp Thr Lys Val Thr Leu Asp Gly Arg Pro Leu Ser Thr
515 520 525
Ile Gln Gln Tyr Ser Lys Thr Phe Phe Val Leu Pro Leu Arg Gly Lys
530 535 540
Leu Ser Phe Trp Glu Ala Gly Thr Thr Lys Ala Gly Tyr Pro Tyr Asn
545 550 555 560
Tyr Asn Thr Thr Ala Ser Asp Gln Leu Leu Val Glu Asn Ala Ala Gly
565 570 575
His Arg Val Ala Ile Ser Thr Tyr Thr Thr Ser Leu Gly Ala Gly Pro
580 585 590
Val Ser Ile Ser Ala Val Ala Val Leu Ala Pro His Ser Val Leu Ala
595 600 605
Leu Leu Glu Asp Thr Met Asp Tyr Pro Ala Arg Ala His Thr Phe Asp
610 615 620
Asp Phe Cys Pro Glu Cys Arg Pro Leu Gly Leu Gln Gly Cys Ala Phe
625 630 635 640
Gln Ser Thr Val Ala Glu Leu Gln Arg Leu Lys Met Lys Val Gly Lys
645 650 655
Thr Arg Glu Leu
660
<210> 18
<211> 660
<212> PRT
<213> Hepatitis E virus
<220>
<221> misc_feature
<222> (481)..(481)
<223> Xaa can be any naturally occurring amino acid
<400> 18
Met Arg Pro Arg Ala Val Leu Leu Leu Phe Leu Met Phe Leu Pro Met
1 5 10 15
Leu Pro Ala Pro Pro Ala Gly Gln Pro Ser Gly Arg Arg Arg Gly Arg
20 25 30
Arg Ser Gly Gly Ala Gly Gly Gly Phe Trp Ser Asp Arg Val Asp Ser
35 40 45
Gln Pro Phe Ala Leu Pro Tyr Ile His Pro Thr Asn Pro Phe Ala Ala
50 55 60
Asp Val Val Ser Gln Pro Gly Ala Gly Thr Arg Pro Arg Gln Pro Pro
65 70 75 80
Arg Pro Leu Gly Ser Ala Trp Arg Asp Gln Ser Lys Arg Pro Ser Val
85 90 95
Ala Pro Arg Arg Arg Ser Thr Pro Ala Gly Ala Ala Pro Leu Thr Ala
100 105 110
Ile Ser Pro Ala Pro Asp Thr Ala Pro Val Pro Asp Val Asp Ser Arg
115 120 125
Gly Ala Ile Leu Arg Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr
130 135 140
Ser Ser Val Ala Ser Gly Thr Asn Leu Val Leu Tyr Ala Ala Pro Leu
145 150 155 160
Asn Pro Leu Leu Pro Leu Gln Asp Gly Thr Asn Thr His Ile Met Ala
165 170 175
Thr Glu Ala Ser Asn Tyr Ala Gln Tyr Arg Val Val Arg Ala Thr Ile
180 185 190
Arg Tyr Arg Pro Leu Val Pro Asn Ala Val Gly Gly Tyr Ala Ile Ser
195 200 205
Ile Ser Phe Trp Pro Gln Thr Thr Thr Thr Pro Thr Ser Val Asp Met
210 215 220
Asn Ser Ile Thr Ser Thr Asp Val Arg Ile Leu Val Gln Pro Gly Ile
225 230 235 240
Ala Ser Glu Leu Val Ile Pro Ser Glu Arg Leu His Tyr Arg Asn Gln
245 250 255
Gly Trp Arg Ser Val Glu Thr Thr Gly Val Ala Glu Glu Glu Ala Thr
260 265 270
Ser Gly Leu Val Met Leu Cys Ile His Gly Ser Pro Val Asn Ser Tyr
275 280 285
Thr Asn Thr Pro Tyr Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu
290 295 300
Glu Leu Glu Phe Arg Asn Leu Thr Pro Gly Asn Thr Asn Thr Arg Val
305 310 315 320
Ser Arg Tyr Thr Ser Thr Ala Arg His Arg Leu Arg Arg Gly Ala Asp
325 330 335
Gly Thr Ala Glu Leu Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp
340 345 350
Leu His Phe Thr Gly Thr Asn Gly Val Gly Glu Val Gly Arg Gly Ile
355 360 365
Ala Leu Thr Leu Phe Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro
370 375 380
Thr Glu Leu Ile Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro
385 390 395 400
Val Val Ser Ala Asn Gly Glu Pro Thr Val Lys Leu Tyr Thr Ser Val
405 410 415
Glu Asn Ala Gln Gln Asp Lys Gly Ile Thr Ile Pro His Asp Ile Asp
420 425 430
Leu Gly Asp Ser Arg Val Val Ile Gln Asp Tyr Asp Asn Gln His Glu
435 440 445
Gln Asp Arg Pro Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val
450 455 460
Leu Arg Ala Asn Asp Val Leu Trp Leu Ser Leu Thr Ala Ala Glu Tyr
465 470 475 480
Xaa Gln Thr Thr Tyr Gly Ser Ser Thr Asn Pro Met Tyr Val Ser Asp
485 490 495
Thr Val Thr Leu Val Asn Val Ala Thr Gly Ala Gln Ala Val Ala Arg
500 505 510
Ser Leu Asp Trp Ser Lys Val Thr Leu Asp Gly Arg Pro Leu Thr Thr
515 520 525
Ile Gln Gln Tyr Ser Lys Lys Phe Tyr Val Leu Pro Leu Arg Gly Lys
530 535 540
Leu Ser Phe Trp Glu Ala Gly Thr Thr Lys Ala Gly Tyr Pro Tyr Asn
545 550 555 560
Tyr Asn Thr Thr Ala Ser Asp Gln Ile Leu Ile Glu Asn Ala Ala Gly
565 570 575
His Arg Val Ala Ile Ser Thr Tyr Thr Thr Ser Leu Gly Ala Gly Pro
580 585 590
Thr Ser Ile Ser Ala Val Gly Val Leu Ala Pro His Ser Ala Leu Ala
595 600 605
Val Leu Glu Asp Thr Val Asp Tyr Pro Ala Arg Ala His Thr Phe Asp
610 615 620
Asp Phe Cys Pro Glu Cys Arg Thr Leu Gly Leu Gln Gly Cys Ala Phe
625 630 635 640
Gln Ser Thr Ile Ala Glu Leu Gln Arg Leu Lys Met Lys Val Gly Lys
645 650 655
Thr Arg Glu Ser
660
<210> 19
<211> 660
<212> PRT
<213> Hepatitis E virus
<400> 19
Met Arg Pro Arg Ala Val Leu Leu Leu Phe Phe Val Leu Leu Pro Met
1 5 10 15
Leu Pro Ala Pro Pro Ala Gly Gln Pro Ser Gly Arg Arg Arg Gly Arg
20 25 30
Arg Ser Gly Gly Thr Gly Gly Gly Phe Trp Gly Asp Arg Val Asp Ser
35 40 45
Gln Pro Phe Ala Leu Pro Tyr Ile His Pro Thr Asn Pro Phe Ala Ser
50 55 60
Asp Ile Pro Thr Ala Thr Gly Ala Gly Ala Arg Pro Arg Gln Pro Ala
65 70 75 80
Arg Pro Leu Gly Ser Ala Trp Arg Asp Gln Ser Gln Arg Pro Ala Ala
85 90 95
Pro Ala Arg Arg Arg Ser Ala Pro Ala Gly Ala Ser Pro Leu Thr Ala
100 105 110
Val Ala Pro Ala Pro Asp Thr Ala Pro Val Pro Asp Val Asp Ser Arg
115 120 125
Gly Ala Ile Leu Arg Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr
130 135 140
Ser Thr Ile Ala Thr Gly Thr Asn Leu Val Leu Tyr Ala Ala Pro Leu
145 150 155 160
Ser Pro Leu Leu Pro Leu Gln Asp Gly Thr Asn Thr His Ile Ile Ala
165 170 175
Thr Glu Ala Ser Asn Tyr Ala Gln Tyr Arg Val Val Arg Ala Thr Ile
180 185 190
Arg Tyr Arg Pro Leu Val Pro Asn Ala Val Gly Gly Tyr Ala Ile Ser
195 200 205
Ile Ser Phe Trp Pro Gln Thr Thr Thr Thr Pro Thr Ser Val Asp Met
210 215 220
Asn Ser Ile Thr Ser Thr Asp Val Arg Ile Leu Val Gln Pro Gly Ile
225 230 235 240
Ala Ser Glu Leu Val Ile Pro Ser Glu Arg Leu His Tyr Arg Asn Gln
245 250 255
Gly Trp Arg Ser Val Glu Thr Ser Gly Val Ala Glu Glu Glu Ala Thr
260 265 270
Ser Gly Leu Val Met Leu Cys Ile His Gly Ser Pro Val Asn Ser Tyr
275 280 285
Thr Asn Thr Pro Tyr Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu
290 295 300
Glu Leu Glu Phe Arg Asn Leu Thr Pro Gly Asn Thr Asn Thr Arg Val
305 310 315 320
Ser Arg Tyr Ser Ser Ser Ala Arg His Lys Leu Cys Arg Gly Pro Asp
325 330 335
Gly Thr Ala Glu Leu Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp
340 345 350
Leu His Phe Thr Gly Thr Asn Gly Val Gly Glu Val Gly Arg Gly Ile
355 360 365
Ala Leu Thr Leu Leu Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro
370 375 380
Thr Glu Leu Ile Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro
385 390 395 400
Val Val Ser Ala Asn Gly Glu Pro Thr Val Lys Leu Tyr Thr Ser Val
405 410 415
Glu Asn Ala Gln Gln Asp Lys Gly Ile Ala Ile Pro His Asp Ile Asp
420 425 430
Leu Gly Glu Ser Arg Val Val Ile Gln Asp Tyr Asp Asn Gln His Glu
435 440 445
Gln Asp Arg Pro Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val
450 455 460
Leu Arg Ala Asn Asp Val Leu Trp Leu Ser Leu Thr Ala Ala Glu Tyr
465 470 475 480
Asp Gln Thr Thr Tyr Gly Ser Ser Thr Asn Pro Met Tyr Val Ser Asp
485 490 495
Thr Val Thr Phe Val Asn Val Ala Thr Gly Thr Gln Gly Val Ser Arg
500 505 510
Ser Leu Asp Trp Ser Lys Val Thr Leu Asp Gly Arg Pro Leu Thr Thr
515 520 525
Ile Gln Gln Tyr Ser Lys Thr Phe Phe Val Leu Pro Leu Arg Gly Lys
530 535 540
Leu Ser Phe Trp Glu Ala Gly Thr Thr Lys Ala Gly Tyr Pro Tyr Asn
545 550 555 560
Tyr Asn Thr Thr Ala Ser Asp Gln Ile Leu Ile Glu Asn Ala Pro Gly
565 570 575
His Arg Val Cys Ile Ser Thr Tyr Thr Thr Asn Leu Gly Ser Gly Pro
580 585 590
Val Ser Ile Ser Ala Val Gly Val Leu Ala Pro His Ser Ala Leu Ala
595 600 605
Ala Leu Glu Asp Thr Val Asp Tyr Pro Ala Arg Ala His Thr Phe Asp
610 615 620
Asp Phe Cys Pro Glu Cys Arg Ala Leu Gly Leu Gln Gly Cys Ala Phe
625 630 635 640
Gln Ser Thr Val Ala Glu Leu Gln Arg Leu Lys Met Lys Val Gly Lys
645 650 655
Thr Gln Glu Tyr
660
<210> 20
<211> 660
<212> PRT
<213> Hepatitis E virus
<400> 20
Met Arg Pro Arg Pro Ile Leu Leu Leu Leu Leu Met Phe Leu Pro Met
1 5 10 15
Leu Pro Ala Pro Pro Pro Gly Gln Pro Ser Gly Arg Arg Arg Gly Arg
20 25 30
Arg Ser Gly Gly Ser Gly Gly Gly Phe Trp Gly Asp Arg Val Asp Ser
35 40 45
Gln Pro Phe Ala Ile Pro His Ile His Pro Thr Asn Pro Phe Ala Pro
50 55 60
Asp Val Thr Ala Ala Ala Gly Ala Gly Pro Arg Val Arg Gln Pro Ala
65 70 75 80
Arg Pro Leu Gly Ser Ala Trp Arg Asp Gln Ala Gln Arg Pro Ala Ala
85 90 95
Thr Ser Arg Arg Arg Pro Thr Thr Ala Gly Ala Ala Pro Leu Thr Ala
100 105 110
Val Ala Pro Ala His Asp Thr Pro Pro Val Pro Asp Val Asp Ser Arg
115 120 125
Gly Ala Ile Leu Arg Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr
130 135 140
Ser Pro Val Ala Thr Gly Thr Asn Leu Val Leu Tyr Ala Ala Pro Leu
145 150 155 160
Ser Pro Leu Leu Pro Leu Gln Asp Gly Thr Asn Thr His Ile Met Ala
165 170 175
Thr Glu Ala Ser Asn Tyr Ala Gln Tyr Arg Val Ala Arg Ala Thr Ile
180 185 190
Arg Tyr Arg Pro Leu Val Pro Asn Ala Val Gly Gly Tyr Ala Ile Ser
195 200 205
Ile Ser Phe Trp Pro Gln Thr Thr Thr Thr Pro Thr Ser Val Asp Met
210 215 220
Asn Ser Ile Thr Ser Thr Asp Val Arg Ile Leu Val Gln Pro Gly Ile
225 230 235 240
Ala Ser Glu Leu Val Ile Pro Ser Glu Arg Leu His Tyr Arg Asn Gln
245 250 255
Gly Trp Arg Ser Val Glu Thr Ser Gly Val Ala Glu Glu Glu Ala Thr
260 265 270
Ser Gly Leu Val Met Leu Cys Ile His Gly Leu Pro Val Asn Ser Tyr
275 280 285
Thr Asn Thr Pro Tyr Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu
290 295 300
Glu Phe Glu Phe Arg Asn Leu Thr Pro Gly Asn Thr Asn Thr Arg Val
305 310 315 320
Ser Arg Tyr Ser Ser Thr Ala Arg His Arg Leu Arg Arg Gly Ala Asp
325 330 335
Gly Thr Ala Glu Leu Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp
340 345 350
Leu Tyr Phe Thr Ser Thr Asn Gly Val Gly Glu Ile Gly Arg Gly Ile
355 360 365
Ala Leu Thr Leu Phe Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro
370 375 380
Thr Glu Leu Ile Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro
385 390 395 400
Val Val Ser Ala Asn Gly Glu Pro Thr Val Lys Leu Tyr Thr Ser Val
405 410 415
Glu Asn Ala Gln Gln Asp Lys Gly Ile Ala Ile Pro His Asp Ile Asp
420 425 430
Leu Gly Glu Ser Arg Val Val Ile Gln Asp Tyr Asp Asn Gln His Glu
435 440 445
Gln Asp Arg Pro Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val
450 455 460
Leu Arg Ala Asn Asp Val Leu Trp Leu Ser Leu Thr Ala Ala Glu Tyr
465 470 475 480
Asp Gln Ser Thr Tyr Gly Ser Ser Thr Gly Pro Val Tyr Val Ser Asp
485 490 495
Ser Val Thr Leu Val Asn Val Ala Thr Gly Ala Gln Ala Val Ala Arg
500 505 510
Ser Leu Asp Trp Thr Lys Val Thr Leu Asp Gly Arg Pro Leu Ser Thr
515 520 525
Ile Gln Gln Tyr Ser Lys Thr Phe Phe Val Leu Pro Leu Arg Gly Lys
530 535 540
Leu Ser Phe Trp Glu Ala Gly Thr Thr Lys Ala Gly Tyr Pro Tyr Asn
545 550 555 560
Tyr Asn Thr Thr Ala Ser Asp Gln Leu Leu Ile Glu Asn Ala Ala Gly
565 570 575
His Arg Val Ala Ile Ser Thr Tyr Thr Thr Ser Leu Gly Ala Gly Pro
580 585 590
Val Ala Ile Ser Ala Val Ala Val Leu Ala Pro His Ser Ala Leu Ala
595 600 605
Leu Leu Glu Asp Thr Met Asp Tyr Pro Ala Arg Ala His Thr Phe Asp
610 615 620
Asp Phe Cys Pro Glu Cys Arg Pro Leu Gly Leu Gln Gly Cys Ala Phe
625 630 635 640
Gln Ser Thr Val Ala Glu Leu Gln Arg Leu Lys Met Lys Val Gly Lys
645 650 655
Thr Arg Glu Leu
660
<210> 21
<211> 660
<212> PRT
<213> Hepatitis E virus
<400> 21
Met Arg Pro Arg Ala Val Leu Leu Leu Phe Phe Val Leu Leu Pro Met
1 5 10 15
Leu Pro Ala Pro Pro Ala Gly Gln Pro Ser Gly Arg Arg Arg Gly Arg
20 25 30
Arg Ser Gly Gly Ala Gly Gly Gly Phe Trp Gly Asp Arg Val Asp Ser
35 40 45
Gln Pro Phe Ala Leu Pro Tyr Ile His Pro Thr Asn Pro Phe Ala Ala
50 55 60
Asp Val Ala Ser Gln Ser Gly Ala Gly Ala Arg Pro Arg Gln Pro Pro
65 70 75 80
Arg Pro Leu Gly Ser Ala Trp Arg Asp Gln Ser Gln Arg Pro Pro Ala
85 90 95
Val Pro Arg Arg Arg Ser Ala Pro Ala Gly Ala Ala Pro Leu Thr Ala
100 105 110
Ile Ser Pro Ala Pro Asp Thr Ala Pro Val Pro Asp Val Asp Ser Arg
115 120 125
Gly Ala Ile Leu Arg Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr
130 135 140
Ser Ser Val Ala Ser Gly Thr Asn Leu Val Leu Tyr Ala Ala Pro Leu
145 150 155 160
Asn Pro Leu Leu Pro Leu Gln Asp Gly Thr Asn Thr His Ile Met Ala
165 170 175
Thr Glu Ala Ser Asn Tyr Ala Gln Tyr Arg Val Val Arg Ala Thr Ile
180 185 190
Arg Tyr Arg Pro Leu Val Pro Asn Ala Val Gly Gly Tyr Ala Ile Ser
195 200 205
Ile Ser Phe Trp Pro Gln Thr Thr Thr Thr Pro Thr Ser Val Asp Met
210 215 220
Asn Ser Ile Thr Ser Thr Asp Val Arg Ile Leu Val Gln Pro Gly Ile
225 230 235 240
Ala Ser Glu Leu Val Ile Pro Ser Glu Arg Leu His Tyr Arg Asn Gln
245 250 255
Gly Trp Arg Ser Val Glu Thr Thr Gly Val Ala Glu Glu Glu Ala Thr
260 265 270
Ser Gly Leu Val Met Leu Cys Ile His Gly Ser Pro Val Asn Ser Tyr
275 280 285
Thr Asn Thr Pro Tyr Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu
290 295 300
Glu Leu Glu Phe Arg Asn Leu Thr Pro Gly Asn Thr Asn Thr Arg Val
305 310 315 320
Ser Arg Tyr Thr Ser Thr Ala Arg His Arg Leu Arg Arg Gly Ala Asp
325 330 335
Gly Thr Ala Glu Leu Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp
340 345 350
Leu His Phe Thr Gly Thr Asn Gly Val Gly Glu Val Gly Arg Gly Ile
355 360 365
Ala Leu Thr Leu Phe Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro
370 375 380
Thr Glu Leu Ile Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro
385 390 395 400
Val Ala Ser Ala Asn Gly Glu Pro Thr Val Lys Leu Tyr Thr Ser Val
405 410 415
Glu Asn Ala Gln Gln Asp Lys Gly Ile Thr Ile Pro His Asp Ile Asp
420 425 430
Leu Gly Asp Ser Arg Val Val Ile Gln Asp Tyr Asp Asn Gln His Glu
435 440 445
Gln Asp Arg Pro Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val
450 455 460
Leu Arg Ala Asn Asp Val Leu Trp Leu Ser Leu Thr Val Ala Glu Tyr
465 470 475 480
Asp Gln Thr Thr Tyr Gly Ser Ser Thr Asn Pro Met Tyr Val Ser Asp
485 490 495
Thr Ala Thr Phe Val Asn Val Ala Thr Gly Ala Gln Ala Val Ala Arg
500 505 510
Ser Leu Asp Trp Ser Lys Val Thr Leu Asp Gly Arg Pro Leu Thr Thr
515 520 525
Ile Gln Gln Tyr Ser Lys Thr Phe Tyr Val Leu Pro Leu Arg Gly Lys
530 535 540
Leu Ser Phe Trp Glu Ala Gly Thr Thr Lys Ala Gly Tyr Pro Tyr Asn
545 550 555 560
Tyr Asn Thr Ala Ala Ser Asp Gln Ile Leu Ile Glu Asn Ala Ala Gly
565 570 575
His Arg Val Ala Ile Ser Thr Tyr Thr Thr Ser Leu Gly Ala Ser Pro
580 585 590
Thr Ser Ile Ser Ala Val Gly Val Leu Ala Pro His Ser Ala Leu Ala
595 600 605
Val Leu Glu Asp Thr Val Asp Tyr Pro Ala Arg Ala His Thr Phe Asp
610 615 620
Asp Phe Cys Pro Glu Cys Arg Thr Leu Gly Leu Gln Gly Cys Ala Phe
625 630 635 640
Gln Ser Thr Ile Ala Glu Leu Gln Arg Leu Lys Met Lys Val Gly Lys
645 650 655
Thr Arg Glu Ser
660
<210> 22
<211> 660
<212> PRT
<213> Hepatitis E virus
<400> 22
Met Arg Pro Arg Ala Val Leu Leu Leu Leu Phe Val Leu Leu Pro Met
1 5 10 15
Leu Pro Ala Pro Pro Ala Gly Gln Pro Ser Gly Arg Arg Arg Gly Arg
20 25 30
Arg Ser Gly Gly Ala Gly Gly Gly Phe Trp Gly Asp Arg Val Asp Ser
35 40 45
Gln Pro Phe Ala Leu Pro Tyr Ile His Pro Thr Asn Pro Phe Ala Ala
50 55 60
Asp Val Val Ser Gln Pro Gly Ala Gly Thr Arg Pro Arg Gln Pro Pro
65 70 75 80
Arg Pro Leu Gly Ser Ala Trp Arg Asp Gln Ser Gln Arg Pro Ser Ala
85 90 95
Ala Pro Arg Arg Arg Pro Ala Pro Ala Gly Ala Thr Pro Leu Thr Ala
100 105 110
Val Ser Pro Ala Pro Asp Ala Ala Pro Val Pro Asp Val Asp Ser Arg
115 120 125
Gly Ala Ile Leu Arg Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr
130 135 140
Ser Ser Val Ala Ser Gly Thr Asn Leu Val Leu Tyr Ala Ala Pro Leu
145 150 155 160
Asn Pro Leu Leu Pro Leu Gln Asp Gly Thr Asn Thr His Ile Met Ala
165 170 175
Thr Glu Ala Ser Asn Tyr Ala Gln Tyr Arg Val Val Arg Ala Thr Ile
180 185 190
Arg Tyr Arg Pro Leu Val Pro Asn Ala Val Gly Gly Tyr Ala Val Ser
195 200 205
Ile Ser Phe Trp Pro Gln Thr Thr Thr Thr Pro Thr Ser Val Asp Met
210 215 220
Asn Ser Ile Thr Ser Thr Asp Val Arg Ile Leu Val Gln Pro Gly Val
225 230 235 240
Ala Ser Glu Leu Val Ile Pro Ser Glu Arg Leu His Tyr Arg Asn Gln
245 250 255
Gly Trp Arg Ser Val Glu Thr Thr Gly Val Ala Glu Glu Glu Ala Thr
260 265 270
Ser Gly Leu Val Met Leu Cys Ile His Gly Ser Pro Val Asn Ser Tyr
275 280 285
Thr Asn Thr Pro Tyr Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu
290 295 300
Glu Leu Glu Phe Arg Asn Leu Thr Pro Gly Asn Thr Asn Thr Arg Val
305 310 315 320
Ser Arg Tyr Thr Ser Thr Ala Arg His Arg Leu Arg Arg Gly Ala Asp
325 330 335
Gly Thr Ala Glu Leu Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp
340 345 350
Leu His Phe Thr Gly Thr Asn Gly Val Gly Glu Val Gly Arg Gly Ile
355 360 365
Ala Leu Thr Leu Phe Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro
370 375 380
Thr Glu Leu Ile Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro
385 390 395 400
Val Val Ser Ala Asn Gly Glu Pro Thr Val Lys Leu Tyr Thr Ser Val
405 410 415
Glu Asn Ala Gln Gln Asp Lys Gly Ile Thr Ile Pro His Asp Ile Asp
420 425 430
Leu Gly Asp Ser Arg Val Val Ile Gln Asp Tyr Asp Asn Gln His Glu
435 440 445
Gln Asp Arg Pro Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val
450 455 460
Leu Arg Ala Asn Asp Val Leu Trp Leu Ser Leu Thr Ala Ala Glu Tyr
465 470 475 480
Asp Gln Thr Thr Tyr Gly Ser Ser Thr Asn Pro Met Tyr Val Ser Asp
485 490 495
Thr Val Thr Leu Val Asn Val Ala Thr Gly Ala Gln Ala Val Ala Arg
500 505 510
Ser Leu Asp Trp Ser Lys Val Thr Leu Asp Gly Arg Pro Leu Thr Thr
515 520 525
Ile Gln Gln Tyr Ser Lys Thr Phe Tyr Val Leu Pro Leu Arg Gly Lys
530 535 540
Leu Ser Phe Trp Glu Ala Gly Thr Thr Lys Ala Gly Tyr Pro Tyr Asn
545 550 555 560
Tyr Asn Thr Thr Ala Ser Asp Gln Ile Leu Ile Glu Asn Ala Ser Gly
565 570 575
His Arg Val Ala Ile Ser Thr Tyr Thr Thr Ser Leu Gly Ala Gly Pro
580 585 590
Thr Ser Ile Ser Ala Val Gly Val Leu Ala Pro His Ser Ala Leu Ala
595 600 605
Val Leu Glu Asp Thr Ile Asp Tyr Pro Ala Arg Ala His Thr Phe Asp
610 615 620
Asp Phe Cys Pro Glu Cys Arg Ala Leu Gly Phe Gln Gly Cys Ala Phe
625 630 635 640
Gln Ser Thr Ile Ala Glu Leu Gln Arg Leu Lys Met Lys Val Gly Lys
645 650 655
Thr Arg Glu Ser
660
<210> 23
<211> 660
<212> PRT
<213> Hepatitis E virus
<400> 23
Met Cys Pro Arg Ala Val Leu Leu Leu Leu Phe Val Leu Leu Pro Met
1 5 10 15
Leu Pro Ala Pro Pro Ala Gly Gln Pro Ser Gly Arg Arg Arg Gly Arg
20 25 30
Arg Ser Gly Gly Ala Gly Gly Gly Phe Trp Gly Asp Arg Val Asp Ser
35 40 45
Gln Pro Phe Ala Leu Pro Tyr Ile His Pro Thr Asn Pro Phe Ala Ala
50 55 60
Asp Val Phe Ser Gln Ser Gly Ala Gly Ala Arg Pro Arg Gln Pro Pro
65 70 75 80
Arg Pro Leu Gly Ser Ala Trp Arg Asp Gln Ser Gln Arg Pro Ser Ala
85 90 95
Ala Pro Arg Arg Arg Ser Thr Pro Ala Gly Ala Ala Pro Leu Thr Ala
100 105 110
Thr Ser Pro Ala Pro Asp Thr Ala Pro Val Pro Asp Val Asp Ser Arg
115 120 125
Gly Ala Ile Leu Arg Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr
130 135 140
Ser Ser Val Ala Ser Gly Thr Asn Leu Val Leu Tyr Ala Ala Pro Leu
145 150 155 160
Asn Pro Leu Leu Pro Leu Gln Asp Gly Thr Asn Thr His Ile Met Ala
165 170 175
Thr Glu Ala Ser Asn Tyr Ala Gln Tyr Arg Val Val Arg Ala Thr Ile
180 185 190
Arg Tyr Arg Pro Leu Val Pro Asn Ala Val Gly Gly Tyr Ala Ile Ser
195 200 205
Ile Ser Phe Trp Pro Gln Thr Thr Thr Thr Pro Thr Ser Val Asp Met
210 215 220
Asn Ser Ile Thr Ser Thr Asp Val Arg Ile Leu Val Gln Pro Gly Ile
225 230 235 240
Ala Ser Glu Leu Val Ile Pro Ser Glu Arg Leu His Tyr Arg Asn Gln
245 250 255
Gly Trp Arg Ser Val Glu Thr Thr Gly Val Ala Glu Glu Glu Ala Thr
260 265 270
Ser Gly Leu Val Met Leu Cys Ile His Gly Ser Pro Val Asn Ser Tyr
275 280 285
Thr Asn Thr Pro Tyr Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu
290 295 300
Glu Leu Glu Phe Arg Asn Leu Thr Pro Gly Asn Thr Asn Thr Arg Val
305 310 315 320
Ser Arg Tyr Thr Ser Thr Ala Arg His Arg Leu Arg Arg Gly Ala Asp
325 330 335
Gly Thr Ala Glu Leu Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp
340 345 350
Leu His Phe Thr Gly Thr Asn Gly Val Gly Glu Val Gly Arg Gly Ile
355 360 365
Ala Leu Thr Leu Phe Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro
370 375 380
Thr Glu Leu Ile Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro
385 390 395 400
Val Val Ser Ala Asn Gly Glu Pro Thr Val Lys Leu Tyr Thr Ser Val
405 410 415
Glu Asn Ala Gln Gln Asp Lys Gly Ile Thr Ile Pro His Asp Ile Asp
420 425 430
Leu Gly Asp Ser Arg Val Val Ile Gln Asp Tyr Asp Asn Gln His Glu
435 440 445
Gln Asp Arg Pro Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val
450 455 460
Leu Arg Ala Asn Asp Val Leu Trp Leu Ser Leu Thr Ala Ala Glu Tyr
465 470 475 480
Asp Gln Thr Thr Tyr Gly Ser Ser Thr Asn Pro Met Tyr Val Ser Asp
485 490 495
Thr Val Thr Phe Val Asn Val Ala Thr Gly Ala Gln Ala Val Ala Arg
500 505 510
Ser Leu Asp Trp Ser Lys Val Thr Leu Asp Gly Arg Pro Leu Thr Thr
515 520 525
Ile Gln Gln Tyr Ser Lys Thr Phe Tyr Val Leu Pro Leu Arg Gly Lys
530 535 540
Leu Ser Phe Trp Glu Ala Gly Thr Thr Lys Ala Gly Tyr Pro Tyr Asn
545 550 555 560
Tyr Asn Thr Thr Ala Ser Asp Gln Ile Leu Ile Glu Asn Ala Ala Gly
565 570 575
His Arg Val Ala Ile Ser Thr Tyr Thr Thr Ser Leu Gly Ala Gly Pro
580 585 590
Thr Ser Ile Ser Ala Val Gly Val Leu Ala Pro His Ser Ala Leu Ala
595 600 605
Val Leu Glu Asp Thr Val Asp Tyr Pro Ala Arg Ala His Thr Phe Asp
610 615 620
Asp Phe Cys Pro Glu Cys Arg Ala Leu Gly Leu Gln Gly Cys Ala Phe
625 630 635 640
Gln Ser Thr Val Ala Glu Leu Gln Arg Leu Lys Met Lys Val Gly Lys
645 650 655
Thr Arg Glu Ser
660
<210> 24
<211> 659
<212> PRT
<213> Hepatitis E virus
<400> 24
Met Arg Pro Arg Pro Leu Leu Leu Leu Phe Leu Leu Phe Leu Pro Met
1 5 10 15
Leu Pro Ala Pro Pro Thr Gly Gln Pro Ser Gly Arg Arg Arg Gly Arg
20 25 30
Arg Ser Gly Gly Thr Gly Gly Gly Phe Trp Gly Asp Arg Val Asp Ser
35 40 45
Gln Pro Phe Ala Ile Pro Tyr Ile His Pro Thr Asn Pro Phe Ala Pro
50 55 60
Asp Val Ala Ala Ala Ser Gly Ser Gly Pro Arg Leu Arg Gln Pro Ala
65 70 75 80
Arg Pro Leu Gly Ser Thr Trp Arg Asp Gln Ala Gln Arg Pro Ser Ala
85 90 95
Ala Ser Arg Arg Arg Pro Ala Thr Ala Gly Ala Ala Ala Leu Thr Ala
100 105 110
Val Ala Pro Ala His Asp Thr Ser Pro Val Pro Asp Val Asp Ser Arg
115 120 125
Gly Ala Ile Leu Arg Arg Gln Tyr Asn Leu Ser Thr Ser Pro Leu Thr
130 135 140
Ser Ser Val Ala Ser Gly Thr Asn Leu Val Leu Tyr Ala Ala Pro Leu
145 150 155 160
Asn Pro Pro Leu Pro Leu Gln Asp Gly Thr Asn Thr His Ile Met Ala
165 170 175
Thr Glu Ala Ser Asn Tyr Ala Gln Tyr Arg Val Ala Arg Ala Thr Ile
180 185 190
Arg Tyr Arg Pro Leu Val Pro Asn Ala Val Gly Gly Tyr Ala Ile Ser
195 200 205
Ile Ser Phe Trp Pro Gln Thr Thr Thr Thr Pro Thr Ser Val Asp Met
210 215 220
Asn Ser Ile Thr Ser Thr Asp Val Arg Ile Leu Val Gln Pro Gly Ile
225 230 235 240
Ala Ser Glu Leu Val Ile Pro Ser Glu Arg Leu His Tyr Arg Asn Gln
245 250 255
Gly Trp Arg Ser Val Glu Thr Ser Gly Val Ala Glu Glu Glu Ala Thr
260 265 270
Ser Gly Leu Val Met Leu Cys Ile His Gly Ser Pro Val Asn Ser Tyr
275 280 285
Thr Asn Thr Pro Tyr Thr Gly Ala Leu Gly Leu Leu Asp Phe Ala Leu
290 295 300
Glu Leu Glu Phe Arg Asn Leu Thr Thr Cys Asn Thr Asn Thr Arg Val
305 310 315 320
Ser Arg Tyr Ser Ser Thr Ala Arg His Ser Ala Arg Gly Ala Asp Gly
325 330 335
Thr Ala Glu Leu Thr Thr Thr Ala Ala Thr Arg Phe Met Lys Asp Leu
340 345 350
His Phe Thr Gly Leu Asn Gly Val Gly Glu Val Gly Arg Gly Ile Ala
355 360 365
Leu Thr Leu Leu Asn Leu Ala Asp Thr Leu Leu Gly Gly Leu Pro Thr
370 375 380
Glu Leu Ile Ser Ser Ala Gly Gly Gln Leu Phe Tyr Ser Arg Pro Val
385 390 395 400
Val Ser Ala Asn Gly Glu Pro Thr Val Lys Leu Tyr Thr Ser Val Glu
405 410 415
Asn Ala Gln Gln Asp Lys Gly Val Ala Ile Pro His Asp Ile Asp Leu
420 425 430
Gly Asp Ser Arg Val Val Ile Gln Asp Tyr Asp Asn Gln His Glu Gln
435 440 445
Asp Arg Pro Thr Pro Ser Pro Ala Pro Ser Arg Pro Phe Ser Val Leu
450 455 460
Arg Ala Asn Asp Val Leu Trp Leu Ser Leu Thr Ala Ala Glu Tyr Asp
465 470 475 480
Gln Ser Thr Tyr Gly Ser Ser Thr Gly Pro Val Tyr Ile Ser Asp Ser
485 490 495
Val Thr Leu Val Asn Val Ala Thr Gly Ala Gln Ala Val Ala Arg Ser
500 505 510
Leu Asp Trp Ser Lys Val Thr Leu Asp Gly Arg Pro Leu Pro Thr Val
515 520 525
Glu Gln Tyr Ser Lys Thr Phe Phe Val Leu Pro Leu Arg Gly Lys Leu
530 535 540
Ser Phe Trp Glu Ala Gly Thr Thr Lys Ala Gly Tyr Pro Tyr Asn Tyr
545 550 555 560
Asn Thr Thr Ala Ser Asp Gln Ile Leu Ile Glu Asn Ala Ala Gly His
565 570 575
Arg Val Ala Ile Ser Thr Tyr Thr Thr Arg Leu Gly Ala Gly Pro Val
580 585 590
Ala Ile Ser Ala Ala Ala Val Leu Ala Pro Arg Ser Ala Leu Ala Leu
595 600 605
Leu Glu Asp Thr Phe Asp Tyr Pro Gly Arg Ala His Thr Phe Asp Asp
610 615 620
Phe Cys Pro Glu Cys Arg Ala Leu Gly Leu Gln Gly Cys Ala Phe Gln
625 630 635 640
Ser Thr Val Ala Glu Leu Gln Arg Leu Lys Val Lys Val Gly Lys Thr
645 650 655
Arg Glu Leu
<210> 25
<211> 12
<212> PRT
<213> artificial sequence
<220>
<223> HEV peptide
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> X repr閟ente P, T, S ou A
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> X repr閟ente L ou F
<400> 25
Cys Pro Glu Cys Arg Xaa Leu Gly Xaa Gln Gly Cys
1 5 10
<210> 26
<211> 267
<212> PRT
<213> Hepatitis E virus
<400> 26
Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala Asn Gly Glu Pro Thr
1 5 10 15
Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile
20 25 30
Ala Ile Pro His Asp Ile Asp Leu Gly Glu Ser Arg Val Val Ile Gln
35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
50 55 60
Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
65 70 75 80
Ser Leu Thr Ala Ala Glu Tyr Asp Gln Ser Thr Tyr Gly Ser Ser Thr
85 90 95
Gly Pro Val Tyr Val Ser Asp Ser Val Thr Leu Val Asn Val Ala Thr
100 105 110
Gly Ala Gln Ala Val Ala Arg Ser Leu Asp Trp Thr Lys Val Thr Leu
115 120 125
Asp Gly Arg Pro Leu Ser Thr Thr Gln Gln Tyr Ser Lys Thr Phe Phe
130 135 140
Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
145 150 155 160
Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Leu
165 170 175
Leu Val Glu Asn Ala Ala Gly His Arg Val Ala Ile Ser Thr Tyr Thr
180 185 190
Thr Ser Leu Gly Ala Gly Pro Val Ser Ile Ser Ala Val Ala Val Leu
195 200 205
Ala Pro His Ser Ala Leu Ala Leu Leu Glu Asp Thr Met Asp Tyr Pro
210 215 220
Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu Cys Arg Pro Leu
225 230 235 240
Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Val Ala Glu Leu Gln Arg
245 250 255
Leu Lys Met Lys Val Gly Lys Thr Arg Glu Leu
260 265
<210> 27
<211> 267
<212> PRT
<213> artificial sequence
<220>
<223> HEV Peptide mut?
<400> 27
Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala Asn Gly Glu Pro Thr
1 5 10 15
Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile
20 25 30
Ala Ile Pro His Asp Ile Asp Leu Gly Glu Ser Arg Val Val Ile Gln
35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
50 55 60
Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
65 70 75 80
Ser Leu Thr Ala Ala Glu Tyr Asp Gln Ser Thr Tyr Gly Ser Ser Thr
85 90 95
Gly Pro Val Tyr Val Ser Asp Ser Val Thr Leu Val Asn Val Ala Thr
100 105 110
Gly Ala Gln Ala Val Ala Arg Ser Leu Asp Trp Thr Lys Val Thr Leu
115 120 125
Asp Gly Arg Pro Leu Ser Thr Thr Gln Gln Tyr Ser Lys Thr Phe Phe
130 135 140
Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
145 150 155 160
Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Leu
165 170 175
Leu Val Glu Asn Ala Ala Gly His Arg Val Ala Ile Ser Thr Tyr Thr
180 185 190
Thr Ser Leu Gly Ala Gly Pro Val Ser Ile Ser Ala Val Ala Val Leu
195 200 205
Ala Pro His Ser Ala Leu Ala Leu Leu Glu Asp Thr Met Asp Tyr Pro
210 215 220
Ala Arg Ala His Thr Phe Asp Asp Phe Ser Pro Glu Ser Arg Pro Leu
225 230 235 240
Gly Leu Gln Gly Ser Ala Phe Gln Ser Thr Val Ala Glu Leu Gln Arg
245 250 255
Leu Lys Met Lys Val Gly Lys Thr Arg Glu Leu
260 265
<210> 28
<211> 267
<212> PRT
<213> artificial sequence
<220>
<223> Hepatitis E virus
<400> 28
Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala Asn Gly Glu Pro Thr
1 5 10 15
Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile
20 25 30
Ala Ile Pro His Asp Ile Asp Leu Gly Glu Ser Arg Val Val Ile Gln
35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
50 55 60
Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
65 70 75 80
Ser Leu Thr Ala Ala Glu Tyr Asp Gln Thr Thr Tyr Gly Ser Ser Thr
85 90 95
Asn Pro Met Tyr Val Ser Asp Thr Val Thr Phe Val Asn Val Ala Thr
100 105 110
Gly Ala Gln Gly Val Ser Arg Ser Leu Asp Trp Ser Lys Val Thr Leu
115 120 125
Asp Gly Arg Pro Leu Met Thr Ile Gln Gln Tyr Ser Lys Thr Phe Phe
130 135 140
Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
145 150 155 160
Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Ile
165 170 175
Leu Ile Glu Asn Ala Ala Gly His Arg Val Cys Ile Ser Thr Tyr Thr
180 185 190
Thr Asn Leu Gly Ser Gly Pro Val Ser Ile Ser Ala Val Gly Val Leu
195 200 205
Ala Pro His Ser Ala Leu Ala Ala Leu Glu Asp Thr Val Asp Tyr Pro
210 215 220
Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu Cys Arg Ala Leu
225 230 235 240
Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Val Ala Glu Leu Gln Arg
245 250 255
Leu Lys Met Lys Val Gly Lys Thr Arg Glu Tyr
260 265
<210> 29
<211> 267
<212> PRT
<213> artificial sequence
<220>
<223> Hepatitis E virus
<400> 29
Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala Asn Gly Glu Pro Thr
1 5 10 15
Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile
20 25 30
Ala Ile Pro His Asp Ile Asp Leu Gly Glu Ser Arg Val Val Ile Gln
35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
50 55 60
Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
65 70 75 80
Ser Leu Thr Ala Ala Glu Tyr Asp Gln Thr Thr Tyr Gly Ser Ser Thr
85 90 95
Asn Pro Met Tyr Val Ser Asp Thr Val Thr Phe Val Asn Val Ala Thr
100 105 110
Gly Ala Gln Gly Val Ser Arg Ser Leu Asp Trp Ser Lys Val Thr Leu
115 120 125
Asp Gly Arg Pro Leu Thr Thr Ile Gln Gln Tyr Ser Lys Thr Phe Phe
130 135 140
Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
145 150 155 160
Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Ile
165 170 175
Leu Ile Glu Asn Ala Ala Gly His Arg Val Cys Ile Ser Thr Tyr Thr
180 185 190
Thr Asn Leu Gly Ser Gly Pro Val Ser Ile Ser Ser Val Gly Val Leu
195 200 205
Ala Pro His Ser Ala Leu Ala Ala Leu Glu Asp Thr Val Asp Tyr Pro
210 215 220
Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu Cys Arg Thr Leu
225 230 235 240
Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Val Ala Glu Leu Gln Arg
245 250 255
Leu Lys Met Lys Val Gly Lys Thr Arg Glu Tyr
260 265
<210> 30
<211> 267
<212> PRT
<213> artificial sequence
<220>
<223> Hepatitis E virus
<400> 30
Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala Asn Gly Glu Pro Thr
1 5 10 15
Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile
20 25 30
Ala Ile Pro His Asp Ile Asp Leu Gly Glu Ser Arg Val Val Ile Gln
35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
50 55 60
Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
65 70 75 80
Ser Leu Thr Ala Ala Glu Tyr Asp Gln Thr Thr Tyr Gly Ser Ser Thr
85 90 95
Asn Pro Met Tyr Val Ser Asp Thr Val Thr Phe Val Asn Val Ala Thr
100 105 110
Gly Ala Gln Gly Val Ser Arg Ser Leu Asp Trp Ser Lys Val Thr Leu
115 120 125
Asp Gly Arg Pro Leu Thr Thr Ile Gln Gln Tyr Ser Lys Thr Phe Phe
130 135 140
Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
145 150 155 160
Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Ile
165 170 175
Leu Ile Glu Asn Ala Ala Gly His Arg Val Cys Ile Ser Thr Tyr Thr
180 185 190
Thr Asn Leu Gly Ser Gly Pro Val Ser Ile Ser Ser Val Gly Val Leu
195 200 205
Ala Pro His Ser Ala Leu Ala Ala Leu Glu Asp Thr Val Asp Tyr Pro
210 215 220
Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu Cys Arg Thr Leu
225 230 235 240
Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Val Ala Glu Leu Gln Arg
245 250 255
Leu Lys Met Lys Val Gly Lys Thr Arg Glu Tyr
260 265
<210> 31
<211> 267
<212> PRT
<213> artificial sequence
<220>
<223> Hepatitis E virus
<400> 31
Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala Asn Gly Glu Pro Thr
1 5 10 15
Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile
20 25 30
Ala Ile Pro His Asp Ile Asp Leu Gly Glu Ser Arg Val Val Ile Gln
35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
50 55 60
Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
65 70 75 80
Ser Leu Thr Ala Ala Glu Tyr Asp Gln Thr Thr Tyr Gly Ser Ser Thr
85 90 95
Asn Pro Met Tyr Val Ser Asp Thr Val Thr Phe Val Asn Val Ala Thr
100 105 110
Gly Ala Gln Gly Val Ser Arg Ser Leu Asp Trp Ser Lys Val Thr Leu
115 120 125
Asp Gly Arg Pro Leu Met Thr Ile Gln Gln Tyr Ser Lys Thr Phe Phe
130 135 140
Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
145 150 155 160
Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Ile
165 170 175
Leu Ile Glu Asn Ala Ala Gly His Arg Val Cys Ile Ser Thr Tyr Thr
180 185 190
Thr Asn Leu Gly Ser Gly Pro Val Ser Ile Ser Ala Val Gly Val Leu
195 200 205
Ala Pro His Ser Ala Leu Ala Ala Leu Glu Asp Thr Val Asp Tyr Pro
210 215 220
Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu Cys Arg Thr Leu
225 230 235 240
Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Val Ala Glu Leu Gln Arg
245 250 255
Leu Lys Met Lys Val Gly Lys Thr Arg Glu Tyr
260 265
<210> 32
<211> 267
<212> PRT
<213> artificial sequence
<220>
<223> Hepatitis E virus
<400> 32
Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala Asn Gly Glu Pro Thr
1 5 10 15
Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile
20 25 30
Ala Ile Pro His Asp Ile Asp Leu Gly Glu Ser Arg Val Val Ile Gln
35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
50 55 60
Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
65 70 75 80
Ser Leu Thr Ala Ala Glu Tyr Asp Gln Thr Thr Tyr Gly Ser Ser Thr
85 90 95
Asn Pro Met Tyr Val Ser Asp Thr Val Thr Phe Val Asn Val Ala Thr
100 105 110
Gly Ala Gln Gly Val Ser Arg Ser Leu Asp Trp Ser Lys Val Thr Leu
115 120 125
Asp Gly Arg Pro Leu Met Thr Ile Gln Gln Tyr Ser Lys Thr Phe Phe
130 135 140
Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
145 150 155 160
Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Ile
165 170 175
Leu Ile Glu Asn Ala Ala Gly His Arg Val Cys Ile Ser Thr Tyr Thr
180 185 190
Thr Asn Leu Gly Ser Gly Pro Val Ser Ile Ser Ala Val Gly Val Leu
195 200 205
Ala Pro His Ser Ala Leu Ala Ala Leu Glu Asp Thr Val Asp Tyr Pro
210 215 220
Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu Cys Arg Ala Leu
225 230 235 240
Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Val Ala Glu Leu Gln Arg
245 250 255
Leu Lys Met Lys Val Gly Lys Thr Arg Glu Tyr
260 265
<210> 33
<211> 267
<212> PRT
<213> artificial sequence
<220>
<223> Hepatitis E virus
<400> 33
Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala Asn Gly Glu Pro Thr
1 5 10 15
Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile
20 25 30
Ala Ile Pro His Asp Ile Asp Leu Gly Glu Ser Arg Val Val Ile Gln
35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
50 55 60
Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
65 70 75 80
Ser Leu Thr Ala Ala Glu Tyr Asp Gln Thr Thr Tyr Gly Ser Ser Thr
85 90 95
Asn Pro Met Tyr Val Ser Asp Thr Val Thr Phe Val Asn Val Ala Thr
100 105 110
Gly Ala Gln Gly Val Ser Arg Ser Leu Asp Trp Ser Lys Val Thr Leu
115 120 125
Asp Gly Arg Pro Leu Thr Thr Ile Gln Gln Tyr Ser Lys Thr Phe Tyr
130 135 140
Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
145 150 155 160
Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Ile
165 170 175
Leu Ile Glu Asn Ala Ala Gly His Arg Val Cys Ile Ser Thr Tyr Thr
180 185 190
Thr Asn Leu Gly Ser Gly Pro Val Ser Ile Ser Ala Val Gly Val Leu
195 200 205
Ala Pro His Ser Ala Leu Ala Val Leu Glu Asp Thr Val Asp Tyr Pro
210 215 220
Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu Cys Arg Ala Leu
225 230 235 240
Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Val Ala Glu Leu Gln Arg
245 250 255
Leu Lys Met Lys Val Gly Lys Thr Arg Glu Tyr
260 265
<210> 34
<211> 267
<212> PRT
<213> artificial sequence
<220>
<223> Hepatitis E virus
<400> 34
Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala Asn Gly Glu Pro Thr
1 5 10 15
Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile
20 25 30
Ala Ile Pro His Asp Ile Asp Leu Gly Glu Ser Arg Val Val Ile Gln
35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
50 55 60
Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
65 70 75 80
Ser Leu Thr Ala Ala Glu Tyr Asp Gln Thr Thr Tyr Gly Ser Ser Thr
85 90 95
Asn Pro Met Tyr Val Ser Asp Thr Val Thr Phe Val Asn Val Ala Thr
100 105 110
Gly Ala Gln Gly Val Ser Arg Ser Leu Asp Trp Ser Lys Val Thr Leu
115 120 125
Asp Gly Arg Pro Leu Thr Thr Ile Gln Gln Tyr Ser Lys Thr Phe Tyr
130 135 140
Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
145 150 155 160
Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Ile
165 170 175
Leu Ile Glu Asn Ala Ala Gly His Arg Val Cys Ile Ser Thr Tyr Thr
180 185 190
Thr Asn Leu Gly Ser Gly Pro Val Ser Ile Ser Ala Val Gly Val Leu
195 200 205
Ala Pro His Ser Ala Leu Ala Ile Leu Glu Asp Thr Ala Asp Tyr Pro
210 215 220
Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu Cys Arg Ser Leu
225 230 235 240
Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Val Ala Glu Leu Gln Arg
245 250 255
Leu Lys Met Lys Val Gly Lys Thr Arg Glu Tyr
260 265
<210> 35
<211> 267
<212> PRT
<213> artificial sequence
<220>
<223> Hepatitis E virus
<400> 35
Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala Asn Gly Glu Leu Thr
1 5 10 15
Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Val
20 25 30
Ala Ile Pro His Asp Ile Asp Leu Gly Glu Ser Arg Val Val Ile Gln
35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
50 55 60
Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
65 70 75 80
Ser Leu Thr Ala Ala Glu Tyr Asp Gln Thr Thr Tyr Gly Ser Ser Thr
85 90 95
Asn Pro Met Tyr Val Ser Asp Thr Val Thr Phe Val Asn Val Ala Thr
100 105 110
Gly Ala Gln Gly Val Ser Arg Ser Leu Asp Trp Ser Lys Val Thr Leu
115 120 125
Asp Gly Arg Pro Leu Thr Thr Ile Gln Gln Tyr Ser Lys Thr Phe Tyr
130 135 140
Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
145 150 155 160
Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Ile
165 170 175
Leu Ile Glu Asn Ala Ala Gly His Arg Val Cys Ile Ser Thr Tyr Thr
180 185 190
Thr Asn Leu Gly Ser Gly Pro Val Ser Val Ser Ala Val Gly Val Leu
195 200 205
Ala Pro His Ser Ala Leu Ala Ala Leu Glu Asp Thr Ala Asp Tyr Pro
210 215 220
Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu Cys Arg Ala Leu
225 230 235 240
Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Val Gly Glu Leu Gln Arg
245 250 255
Leu Lys Met Lys Val Gly Lys Thr Arg Glu Tyr
260 265
<210> 36
<211> 267
<212> PRT
<213> artificial sequence
<220>
<223> Hepatitis E virus
<400> 36
Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala Asn Gly Glu Pro Thr
1 5 10 15
Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile
20 25 30
Ala Ile Pro His Asp Ile Asp Leu Gly Glu Ser Arg Val Val Ile Gln
35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
50 55 60
Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
65 70 75 80
Ser Leu Thr Ala Ala Glu Tyr Asp Gln Thr Thr Tyr Gly Ser Ser Thr
85 90 95
Asn Pro Met Tyr Val Ser Asp Thr Val Thr Phe Val Asn Val Ala Thr
100 105 110
Gly Ala Gln Gly Val Ser Arg Ser Leu Asp Trp Ser Lys Val Thr Leu
115 120 125
Asp Gly Arg Pro Leu Thr Thr Ile Gln Gln Tyr Ser Lys Thr Phe Phe
130 135 140
Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
145 150 155 160
Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Ile
165 170 175
Leu Ile Glu Asn Ala Ala Gly His Arg Val Cys Ile Ser Thr Tyr Thr
180 185 190
Thr Asn Leu Gly Ser Gly Pro Val Ser Ile Ser Ala Val Gly Val Leu
195 200 205
Ala Pro His Ser Ala Leu Ala Ala Leu Glu Asp Thr Val Asp Tyr Pro
210 215 220
Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu Cys Arg Thr Leu
225 230 235 240
Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Val Ala Glu Leu Gln Arg
245 250 255
Leu Lys Met Lys Val Gly Lys Thr Arg Glu Tyr
260 265
<210> 37
<211> 264
<212> PRT
<213> artificial sequence
<220>
<223> Hepatitis E virus
<400> 37
Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala Asn Gly Glu Pro Thr
1 5 10 15
Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile
20 25 30
Ala Ile Pro His Asp Ile Asp Leu Gly Glu Ser Arg Val Gly Ile Gln
35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
50 55 60
Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
65 70 75 80
Ser Leu Thr Ala Ala Glu Tyr Asp Gln Thr Thr Tyr Gly Ser Ser Thr
85 90 95
Asn Pro Met Tyr Val Ser Asp Thr Val Thr Phe Val Asn Val Ala Thr
100 105 110
Gly Ala Gln Gly Val Ser Arg Ser Leu Asp Trp Ser Lys Val Thr Leu
115 120 125
Asp Gly Arg Ser Leu Thr Thr Ile Gln Gln Tyr Ser Lys Thr Phe Phe
130 135 140
Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
145 150 155 160
Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Ile
165 170 175
Leu Ile Glu Asn Ala Ala Gly His Arg Val Cys Ile Ser Thr Tyr Thr
180 185 190
Thr Asn Leu Gly Ser Gly Pro Val Ser Ile Ser Ala Val Gly Val Leu
195 200 205
Ala Pro His Ser Ala Leu Ala Val Leu Glu Asp Thr Val Asp Tyr Pro
210 215 220
Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu Cys Arg Ala Leu
225 230 235 240
Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Val Ala Glu Leu Gln Arg
245 250 255
Leu Lys Met Lys Val Gly Asn His
260
<210> 38
<211> 267
<212> PRT
<213> artificial sequence
<220>
<223> Hepatitis E virus
<400> 38
Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala Asn Gly Glu Pro Thr
1 5 10 15
Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile
20 25 30
Ala Ile Pro His Asp Ile Asp Leu Gly Glu Ser Arg Val Val Ile Gln
35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
50 55 60
Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
65 70 75 80
Ser Leu Thr Ala Ala Glu Tyr Asp Gln Ser Thr Tyr Gly Ser Ser Thr
85 90 95
Gly Pro Val Tyr Val Ser Asp Ser Val Thr Leu Val Asn Val Ala Thr
100 105 110
Gly Ala Gln Ala Val Ala Arg Ser Leu Asp Trp Thr Lys Val Thr Leu
115 120 125
Asp Gly Arg Pro Leu Ser Thr Ile Gln Gln Tyr Ser Lys Thr Phe Phe
130 135 140
Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
145 150 155 160
Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Leu
165 170 175
Leu Val Glu Asn Ala Ala Gly His Arg Val Ala Ile Ser Thr Tyr Thr
180 185 190
Thr Ser Leu Gly Ala Gly Pro Val Ser Ile Ser Ala Val Ala Val Leu
195 200 205
Ala Pro His Ser Ala Leu Ala Leu Leu Glu Asp Thr Leu Asp Tyr Pro
210 215 220
Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu Cys Arg Pro Leu
225 230 235 240
Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Val Ala Glu Leu Gln Arg
245 250 255
Leu Lys Met Lys Val Gly Lys Thr Arg Glu Leu
260 265
<210> 39
<211> 267
<212> PRT
<213> artificial sequence
<220>
<223> Hepatitis E virus
<400> 39
Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala Asn Gly Glu Pro Thr
1 5 10 15
Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile
20 25 30
Thr Ile Pro His Asp Ile Asp Leu Gly Asp Ser Arg Val Val Ile Gln
35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
50 55 60
Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
65 70 75 80
Ser Leu Thr Ala Ala Glu Tyr Asp Gln Thr Thr Tyr Gly Ser Ser Thr
85 90 95
Asn Pro Met Tyr Val Ser Asp Thr Val Thr Leu Val Asn Val Ala Thr
100 105 110
Gly Ala Gln Ala Val Ala Arg Ser Leu Asp Trp Ser Lys Val Thr Leu
115 120 125
Asp Gly Arg Pro Leu Thr Thr Ile Gln Gln Tyr Ser Lys Thr Phe Tyr
130 135 140
Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
145 150 155 160
Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Ile
165 170 175
Leu Ile Glu Asn Ala Ala Gly His Arg Val Ala Ile Ser Thr Tyr Thr
180 185 190
Thr Ser Leu Gly Ala Gly Pro Thr Ser Ile Ser Ala Val Gly Val Leu
195 200 205
Ala Pro His Ser Ala Leu Ala Val Leu Glu Asp Thr Val Asp Tyr Pro
210 215 220
Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu Cys Arg Thr Leu
225 230 235 240
Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Ile Ala Glu Leu Gln Arg
245 250 255
Leu Lys Met Lys Val Gly Lys Thr Arg Glu Ser
260 265
<210> 40
<211> 267
<212> PRT
<213> artificial sequence
<220>
<223> Hepatitis E virus
<400> 40
Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala His Gly Glu Pro Thr
1 5 10 15
Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile
20 25 30
Ala Ile Pro His Asp Ile Asp Leu Gly Glu Ser Arg Val Val Ile Gln
35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
50 55 60
Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
65 70 75 80
Ser Leu Thr Ala Ala Glu Tyr Asp Gln Ser Thr Tyr Gly Ser Ser Thr
85 90 95
Ala Pro Val Tyr Val Ser Asp Ser Val Thr Leu Val Asn Val Ala Thr
100 105 110
Gly Ala Gln Ala Val Ala Arg Ser Leu Asp Trp Thr Lys Val Thr Leu
115 120 125
Asp Gly Arg Pro Leu Ser Thr Ile Gln Gln Tyr Pro Lys Thr Phe Phe
130 135 140
Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
145 150 155 160
Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Leu
165 170 175
Leu Val Glu Asn Ala Ala Gly His Arg Val Ala Ile Ser Thr Tyr Thr
180 185 190
Thr Ser Leu Gly Ala Gly Pro Val Ser Ile Ser Ala Val Ala Val Leu
195 200 205
Ala Pro His Ser Ala Leu Ala Leu Leu Glu Asp Thr Leu Asp Tyr Pro
210 215 220
Ala Cys Ala His Thr Phe Asp Asp Phe Cys Pro Glu Cys Arg Pro Leu
225 230 235 240
Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Val Ala Glu Leu Gln Arg
245 250 255
Leu Lys Met Lys Val Gly Lys Thr Arg Glu Leu
260 265
<210> 41
<211> 267
<212> PRT
<213> artificial sequence
<220>
<223> Hepatitis E virus
<400> 41
Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala Asn Gly Glu Pro Thr
1 5 10 15
Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile
20 25 30
Ala Ile Pro Asn Asp Ile Asp Leu Gly Glu Ser Arg Val Val Ile Gln
35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
50 55 60
Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
65 70 75 80
Ser Leu Thr Ala Ala Glu Tyr Asp Gln Ser Thr Tyr Gly Ser Ser Thr
85 90 95
Gly Pro Val Tyr Val Ser Asp Ser Val Thr Leu Val Asn Val Ala Thr
100 105 110
Gly Ala Gln Ala Val Ala Arg Ser Leu Asp Trp Thr Lys Val Thr Leu
115 120 125
Asp Gly Arg Pro Leu Ser Thr Ile Gln Gln Tyr Ser Lys Ile Phe Phe
130 135 140
Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
145 150 155 160
Arg Pro Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Leu
165 170 175
Leu Val Glu Asn Ala Ala Gly His Arg Val Ala Ile Ser Thr Tyr Thr
180 185 190
Thr Ser Leu Gly Ala Gly Pro Val Ser Ile Ser Ala Val Ala Val Leu
195 200 205
Gly Pro His Ser Ala Leu Ala Leu Leu Glu Asp Thr Leu Asp Tyr Pro
210 215 220
Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu Cys Arg Pro Leu
225 230 235 240
Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Val Ala Glu Leu Gln Arg
245 250 255
Leu Lys Met Lys Val Gly Lys Thr Arg Glu Leu
260 265
<210> 42
<211> 267
<212> PRT
<213> artificial sequence
<220>
<223> Hepatitis E virus
<400> 42
Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala Asn Gly Glu Pro Thr
1 5 10 15
Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile
20 25 30
Thr Ile Pro His Asp Ile Asp Leu Gly Asp Ser Arg Val Val Ile Gln
35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
50 55 60
Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
65 70 75 80
Ser Leu Thr Ala Ala Glu Tyr Asp Gln Thr Thr Tyr Gly Ser Ser Thr
85 90 95
Asn Pro Met Tyr Val Ser Asp Thr Val Thr Leu Val Asn Val Ala Thr
100 105 110
Gly Ala Gln Ala Val Ala Arg Ser Leu Asp Trp Ser Lys Val Thr Leu
115 120 125
Asp Gly Arg Pro Leu Thr Thr Ile Gln Gln Tyr Ser Lys Thr Phe Tyr
130 135 140
Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
145 150 155 160
Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Ile
165 170 175
Leu Ile Glu Asn Ala Ala Gly His Arg Val Ala Ile Ser Thr Tyr Thr
180 185 190
Thr Ser Leu Gly Ala Gly Pro Thr Ser Ile Ser Ala Val Gly Val Leu
195 200 205
Ala Pro His Ser Ala Leu Ala Val Leu Glu Asp Thr Ile Asp Tyr Pro
210 215 220
Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu Cys Arg Thr Leu
225 230 235 240
Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Ile Ala Glu Leu Gln Arg
245 250 255
Leu Lys Met Lys Val Gly Lys Thr Arg Glu Ser
260 265
<210> 43
<211> 267
<212> PRT
<213> artificial sequence
<220>
<223> Hepatitis E virus
<400> 43
Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala Asn Gly Glu Pro Thr
1 5 10 15
Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile
20 25 30
Ala Ile Pro His Asp Ile Asp Leu Gly Glu Ser Arg Val Val Ile Gln
35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
50 55 60
Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
65 70 75 80
Ser Leu Thr Ala Ala Glu Tyr Asp Gln Ser Thr Tyr Gly Ser Ser Thr
85 90 95
Gly Pro Val Tyr Val Ser Asp Ser Val Thr Leu Val Asn Val Ala Thr
100 105 110
Gly Ala Gln Ala Val Ala Arg Ser Leu Asp Trp Thr Lys Val Thr Leu
115 120 125
Asp Gly Arg Pro Leu Ser Thr Ile Gln Gln Tyr Ser Lys Thr Phe Phe
130 135 140
Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
145 150 155 160
Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Leu
165 170 175
Leu Val Glu Asn Ala Ala Gly His Arg Val Ala Ile Ser Thr Tyr Thr
180 185 190
Thr Ser Leu Gly Ala Gly Pro Val Ser Ile Ser Ala Val Ala Val Leu
195 200 205
Ala Pro His Ser Val Leu Ala Leu Leu Glu Asp Thr Met Asp Tyr Pro
210 215 220
Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu Cys Arg Pro Leu
225 230 235 240
Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Val Ala Glu Leu Gln Arg
245 250 255
Leu Lys Met Lys Val Gly Lys Thr Arg Glu Leu
260 265
<210> 44
<211> 267
<212> PRT
<213> artificial sequence
<220>
<223> Hepatitis E virus
<220>
<221> misc_feature
<222> (88)..(88)
<223> Xaa can be any naturally occurring amino acid
<400> 44
Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala Asn Gly Glu Pro Thr
1 5 10 15
Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile
20 25 30
Thr Ile Pro His Asp Ile Asp Leu Gly Asp Ser Arg Val Val Ile Gln
35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
50 55 60
Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
65 70 75 80
Ser Leu Thr Ala Ala Glu Tyr Xaa Gln Thr Thr Tyr Gly Ser Ser Thr
85 90 95
Asn Pro Met Tyr Val Ser Asp Thr Val Thr Leu Val Asn Val Ala Thr
100 105 110
Gly Ala Gln Ala Val Ala Arg Ser Leu Asp Trp Ser Lys Val Thr Leu
115 120 125
Asp Gly Arg Pro Leu Thr Thr Ile Gln Gln Tyr Ser Lys Lys Phe Tyr
130 135 140
Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
145 150 155 160
Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Ile
165 170 175
Leu Ile Glu Asn Ala Ala Gly His Arg Val Ala Ile Ser Thr Tyr Thr
180 185 190
Thr Ser Leu Gly Ala Gly Pro Thr Ser Ile Ser Ala Val Gly Val Leu
195 200 205
Ala Pro His Ser Ala Leu Ala Val Leu Glu Asp Thr Val Asp Tyr Pro
210 215 220
Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu Cys Arg Thr Leu
225 230 235 240
Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Ile Ala Glu Leu Gln Arg
245 250 255
Leu Lys Met Lys Val Gly Lys Thr Arg Glu Ser
260 265
<210> 45
<211> 267
<212> PRT
<213> artificial sequence
<220>
<223> Hepatitis E virus
<400> 45
Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala Asn Gly Glu Pro Thr
1 5 10 15
Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile
20 25 30
Ala Ile Pro His Asp Ile Asp Leu Gly Glu Ser Arg Val Val Ile Gln
35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
50 55 60
Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
65 70 75 80
Ser Leu Thr Ala Ala Glu Tyr Asp Gln Thr Thr Tyr Gly Ser Ser Thr
85 90 95
Asn Pro Met Tyr Val Ser Asp Thr Val Thr Phe Val Asn Val Ala Thr
100 105 110
Gly Thr Gln Gly Val Ser Arg Ser Leu Asp Trp Ser Lys Val Thr Leu
115 120 125
Asp Gly Arg Pro Leu Thr Thr Ile Gln Gln Tyr Ser Lys Thr Phe Phe
130 135 140
Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
145 150 155 160
Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Ile
165 170 175
Leu Ile Glu Asn Ala Pro Gly His Arg Val Cys Ile Ser Thr Tyr Thr
180 185 190
Thr Asn Leu Gly Ser Gly Pro Val Ser Ile Ser Ala Val Gly Val Leu
195 200 205
Ala Pro His Ser Ala Leu Ala Ala Leu Glu Asp Thr Val Asp Tyr Pro
210 215 220
Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu Cys Arg Ala Leu
225 230 235 240
Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Val Ala Glu Leu Gln Arg
245 250 255
Leu Lys Met Lys Val Gly Lys Thr Gln Glu Tyr
260 265
<210> 46
<211> 267
<212> PRT
<213> artificial sequence
<220>
<223> Hepatitis E virus
<400> 46
Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala Asn Gly Glu Pro Thr
1 5 10 15
Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile
20 25 30
Ala Ile Pro His Asp Ile Asp Leu Gly Glu Ser Arg Val Val Ile Gln
35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
50 55 60
Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
65 70 75 80
Ser Leu Thr Ala Ala Glu Tyr Asp Gln Ser Thr Tyr Gly Ser Ser Thr
85 90 95
Gly Pro Val Tyr Val Ser Asp Ser Val Thr Leu Val Asn Val Ala Thr
100 105 110
Gly Ala Gln Ala Val Ala Arg Ser Leu Asp Trp Thr Lys Val Thr Leu
115 120 125
Asp Gly Arg Pro Leu Ser Thr Ile Gln Gln Tyr Ser Lys Thr Phe Phe
130 135 140
Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
145 150 155 160
Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Leu
165 170 175
Leu Ile Glu Asn Ala Ala Gly His Arg Val Ala Ile Ser Thr Tyr Thr
180 185 190
Thr Ser Leu Gly Ala Gly Pro Val Ala Ile Ser Ala Val Ala Val Leu
195 200 205
Ala Pro His Ser Ala Leu Ala Leu Leu Glu Asp Thr Met Asp Tyr Pro
210 215 220
Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu Cys Arg Pro Leu
225 230 235 240
Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Val Ala Glu Leu Gln Arg
245 250 255
Leu Lys Met Lys Val Gly Lys Thr Arg Glu Leu
260 265
<210> 47
<211> 267
<212> PRT
<213> artificial sequence
<220>
<223> Hepatitis E virus
<400> 47
Gln Leu Phe Tyr Ser Arg Pro Val Ala Ser Ala Asn Gly Glu Pro Thr
1 5 10 15
Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile
20 25 30
Thr Ile Pro His Asp Ile Asp Leu Gly Asp Ser Arg Val Val Ile Gln
35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
50 55 60
Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
65 70 75 80
Ser Leu Thr Val Ala Glu Tyr Asp Gln Thr Thr Tyr Gly Ser Ser Thr
85 90 95
Asn Pro Met Tyr Val Ser Asp Thr Ala Thr Phe Val Asn Val Ala Thr
100 105 110
Gly Ala Gln Ala Val Ala Arg Ser Leu Asp Trp Ser Lys Val Thr Leu
115 120 125
Asp Gly Arg Pro Leu Thr Thr Ile Gln Gln Tyr Ser Lys Thr Phe Tyr
130 135 140
Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
145 150 155 160
Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Ala Ala Ser Asp Gln Ile
165 170 175
Leu Ile Glu Asn Ala Ala Gly His Arg Val Ala Ile Ser Thr Tyr Thr
180 185 190
Thr Ser Leu Gly Ala Ser Pro Thr Ser Ile Ser Ala Val Gly Val Leu
195 200 205
Ala Pro His Ser Ala Leu Ala Val Leu Glu Asp Thr Val Asp Tyr Pro
210 215 220
Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu Cys Arg Thr Leu
225 230 235 240
Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Ile Ala Glu Leu Gln Arg
245 250 255
Leu Lys Met Lys Val Gly Lys Thr Arg Glu Ser
260 265
<210> 48
<211> 267
<212> PRT
<213> artificial sequence
<220>
<223> Hepatitis E virus
<400> 48
Gln Leu Phe Tyr Ser Arg Pro Val Val Ser Ala Asn Gly Glu Pro Thr
1 5 10 15
Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile
20 25 30
Thr Ile Pro His Asp Ile Asp Leu Gly Asp Ser Arg Val Val Ile Gln
35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
50 55 60
Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
65 70 75 80
Ser Leu Thr Ala Ala Glu Tyr Asp Gln Thr Thr Tyr Gly Ser Ser Thr
85 90 95
Asn Pro Met Tyr Val Ser Asp Thr Val Thr Leu Val Asn Val Ala Thr
100 105 110
Gly Ala Gln Ala Val Ala Arg Ser Leu Asp Trp Ser Lys Val Thr Leu
115 120 125
Asp Gly Arg Pro Leu Thr Thr Ile Gln Gln Tyr Ser Lys Thr Phe Tyr
130 135 140
Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
145 150 155 160
Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Ile
165 170 175
Leu Ile Glu Asn Ala Ser Gly His Arg Val Ala Ile Ser Thr Tyr Thr
180 185 190
Thr Ser Leu Gly Ala Gly Pro Thr Ser Ile Ser Ala Val Gly Val Leu
195 200 205
Ala Pro His Ser Ala Leu Ala Val Leu Glu Asp Thr Ile Asp Tyr Pro
210 215 220
Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu Cys Arg Ala Leu
225 230 235 240
Gly Phe Gln Gly Cys Ala Phe Gln Ser Thr Ile Ala Glu Leu Gln Arg
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<210> 49
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Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Ile
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35 40 45
Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
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Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
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Ser Leu Thr Ala Ala Glu Tyr Asp Gln Thr Thr Tyr Gly Ser Ser Thr
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Asn Pro Met Tyr Val Ser Asp Thr Val Thr Phe Val Asn Val Ala Thr
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Gly Ala Gln Ala Val Ala Arg Ser Leu Asp Trp Ser Lys Val Thr Leu
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Asp Gly Arg Pro Leu Thr Thr Ile Gln Gln Tyr Ser Lys Thr Phe Tyr
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Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
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Thr Ser Leu Gly Ala Gly Pro Thr Ser Ile Ser Ala Val Gly Val Leu
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Ala Pro His Ser Ala Leu Ala Val Leu Glu Asp Thr Val Asp Tyr Pro
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Ala Arg Ala His Thr Phe Asp Asp Phe Cys Pro Glu Cys Arg Ala Leu
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Gly Leu Gln Gly Cys Ala Phe Gln Ser Thr Val Ala Glu Leu Gln Arg
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Val Lys Leu Tyr Thr Ser Val Glu Asn Ala Gln Gln Asp Lys Gly Val
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Asp Tyr Asp Asn Gln His Glu Gln Asp Arg Pro Thr Pro Ser Pro Ala
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Pro Ser Arg Pro Phe Ser Val Leu Arg Ala Asn Asp Val Leu Trp Leu
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Ser Leu Thr Ala Ala Glu Tyr Asp Gln Ser Thr Tyr Gly Ser Ser Thr
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Asp Gly Arg Pro Leu Pro Thr Val Glu Gln Tyr Ser Lys Thr Phe Phe
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Val Leu Pro Leu Arg Gly Lys Leu Ser Phe Trp Glu Ala Gly Thr Thr
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Lys Ala Gly Tyr Pro Tyr Asn Tyr Asn Thr Thr Ala Ser Asp Gln Ile
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Ala Pro Arg Ser Ala Leu Ala Leu Leu Glu Asp Thr Phe Asp Tyr Pro
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Claims (17)
1.戊型肝炎病毒的p-ORF2蛋白的多肽,其至少包含相对于660个氨基酸的p-ORF2蛋白编号的氨基酸序列394-660,其中位置627、630和638的三个半胱氨酸已被突变,或者对于不同长度的p-ORF2蛋白,其至少包含对应于660个氨基酸的p-ORF2蛋白的氨基酸394-660的氨基酸序列,其中位于对应于660个氨基酸的p-ORF2蛋白的位置627、630和638的三个位置的三个半胱氨酸已被突变。
2.权利要求1的多肽,其特征在于所述突变通过用除了脯氨酸、侧链带电荷的氨基酸以及侧链包含芳香族苯环的氨基酸以外的任何氨基酸置换所述三个半胱氨酸来进行。
3.权利要求1或2的多肽,其特征在于所述突变通过用选自丙氨酸、甘氨酸、苏氨酸、缬氨酸和丝氨酸的氨基酸置换所述三个半胱氨酸来进行。
4.权利要求1至3中任一项的多肽,其特征在于所述突变包含用相同的氨基酸取代所述半胱氨酸。
5.权利要求4的多肽,其特征在于所述突变通过用丝氨酸取代所述三个半胱氨酸来进行。
6.前述权利要求中任一项的多肽,其特征在于它由相对于660个氨基酸的p-ORF2蛋白编号的氨基酸序列394-660的多肽组成,其中位置627、630和638的三个半胱氨酸已被突变,或者对于不同长度的p-ORF2蛋白,其由对应于660个氨基酸的p-ORF2蛋白的氨基酸394-660的氨基酸序列的多肽组成,其中位于对应于660个氨基酸的p-ORF2蛋白的位置627、630和638的三个位置的三个半胱氨酸已被突变。
7.前述权利要求中任一项的多肽,其特征在于其还包含一个或多个不属于所述p-ORF2蛋白的氨基酸,或者特征在于其被标记。
8.一种分离的核酸,其包含编码权利要求1至7中任一项所定义的多肽的核苷酸序列或与所述编码序列互补的序列。
9.一种表达载体,其包含权利要求8所定义的核酸序列。
10.一种宿主细胞,其包含编码权利要求1至7中任一项所定义的多肽的核苷酸序列,或与所述编码序列互补的序列,或权利要求9所定义的表达载体。
11.一种通过免疫测定测定来自可能含有针对戊型肝炎病毒p-ORF2蛋白抗体应答的抗体的对象的生物样品中所述抗体应答的存在的方法,所述方法包括以下步骤:
-使所述生物样品与权利要求1至7中任一项所定义的多肽接触,
-如果所述抗体存在,使用能够发出可检测信号的标签检测由所述多肽和所述抗体之间的结合发出的信号,
-比较如此获得的信号与预先测定的两个群体对照的参考信号S,一个群体已经发展出所述抗体,而另一群体未发展出所述抗体,
-低于所述参考信号S的信号表示样品不含所述抗体,
-高于所述参考信号S的信号表示样品含有所述抗体。
12.一种通过免疫测定测定来自可能含有针对戊型肝炎病毒的p-ORF2蛋白的抗体的对象的生物样品中所述抗体的效价的方法,所述方法包括以下步骤:
-使所述生物样品与权利要求1至7中任一项所定义的多肽接触,
-如果所述抗体存在,使用能够发出可检测信号的标签检测由所述多肽和所述抗体之间的结合发出的信号,
-将检测到的信号转换成抗体效价。
13.权利要求11和12中任一项的方法,其特征在于所寻求的所述抗体是IgM或IgG。
14.权利要求11至13中任一项的方法的用途,用于协助体外诊断,用于体外诊断可能被感染的对象中的戊型肝炎病毒感染,用于治疗性监测感染了戊型肝炎病毒的对象或者用于在人群或特定地理区域中进行抗HEV抗体的血清阳性率的流行病学研究。
15.权利要求11或12的方法的用途,用于测定对象是否需要针对戊型肝炎病毒接种疫苗或重新接种疫苗,其中所寻求的所述抗体是IgG。
16.一种用于通过免疫测定测定可能已经产生针对戊型肝炎病毒的p-ORF2蛋白的抗体的对象中抗体应答的存在或这些抗体效价的试剂盒,其包含权利要求1至7中任一项的多肽。
17.权利要求16的试剂盒,其还包含至少一种阳性对照样品,所述阳性对照样品是含有给定效价的针对戊型肝炎病毒的p-ORF2蛋白的抗体的样品。
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PCT/FR2016/053127 WO2017093649A1 (fr) | 2015-11-30 | 2016-11-29 | Polypeptides mutés de hev et leur utilisation pour le dosage d'anticorps anti-hev |
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CN109593122A (zh) * | 2019-01-10 | 2019-04-09 | 西北农林科技大学 | 抗猪戊型肝炎病毒orf2蛋白单克隆抗体及其制备与应用 |
CN109765372A (zh) * | 2019-01-29 | 2019-05-17 | 中国医学科学院输血研究所 | 一种戊肝IgM抗体的检测方法及试剂盒 |
CN109765373A (zh) * | 2019-01-29 | 2019-05-17 | 中国医学科学院输血研究所 | 一种戊肝IgA抗体的检测方法及试剂盒 |
CN109765374A (zh) * | 2019-01-29 | 2019-05-17 | 中国医学科学院输血研究所 | 一种戊肝IgG抗体的检测方法及试剂盒 |
CN116003534A (zh) * | 2022-04-19 | 2023-04-25 | 徐州医科大学 | 一种正戊肝病毒属a泛基因型orf3蛋白及其应用 |
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KR20180083941A (ko) | 2018-07-23 |
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