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CN1352649A - 来自tt病毒序列的肽和结合tt病毒的单特异性抗体 - Google Patents

来自tt病毒序列的肽和结合tt病毒的单特异性抗体 Download PDF

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CN1352649A
CN1352649A CN00807153A CN00807153A CN1352649A CN 1352649 A CN1352649 A CN 1352649A CN 00807153 A CN00807153 A CN 00807153A CN 00807153 A CN00807153 A CN 00807153A CN 1352649 A CN1352649 A CN 1352649A
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M·萨尔伯格
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Abstract

描述了具有氨基酸序列SEQ ID No:1的肽,和可选地与一个或多个序列为SEQ ID No:13－11的肽混合的该肽。所有这些肽对应于TT病毒基因组序列区域。还公开了结合TT病毒的单特异性抗体。这些肽可偶联到载体和/或标记上,或固定到固相上。该肽或肽混合物,或单特异性抗体可用于药物或诊断试剂盒中。该肽或肽混合物还可用于免疫非人哺乳动物,以生产抗TT病毒的单特异性抗体。

Description

来自TT病毒序列的肽和结合TT病毒的单特异性抗体
本发明涉及来自TT病毒基因组序列的肽和结合TT病毒的单特异性抗体。本发明还涉及本发明的肽或抗体分别用于药物。含有本发明的肽作为诊断抗原的诊断试剂盒和含有本发明的抗体作为诊断抗原的诊断试剂盒也包括在本发明之中。本发明的肽可用来免疫非人哺乳动物，以产生针对TT病毒的单特异性抗体。背景
1997年从患有输血后非甲-庚型肝炎的日本患者血清中发现了一种新的人传染源，命名为TT病毒(TTV)[1]。在47％暴发型非甲-庚型肝炎患者和46％未知病因的慢性肝病患者中检出了TTV DNA[2]，表明TTV可能为一些自发性肝病的病因。TTV在全球范围内存在[3]，似乎在感染血液传播病毒的高危人群中更为普遍[2]，如血友病病人和吸毒者中。然而，肠胃传播似乎也是可能的[2]。
TTV为无包膜单链DNA病毒，基因组至少为3.7kb[4]。它具有广泛的序列变异，可分为不同基因型和亚型[4]。在文献[4]中已讨论了它与细小病毒科的关系。随后分析表明了TTV的嗜肝性[2]，在一些非甲-庚型输血后肝炎和TTV DNA病毒血症患者中，TTV DNA滴度与氨基转移酶水平相关[1]。
然而，不能进一步证实TTV感染和严重肝病的联系[3，5，6]。TTV感染的流行病学、免疫学和临床重要性仍不明确。而且，至今仍没有TTV感染的血清学检测，目前PCR是唯一的诊断工具。
能够诊断TTV对人的感染并开发基于免疫肽和/或抗TTV抗体的药物是人们所希望的。
发明描述
本发明基于对应于最近描述的TT病毒(TTV；[1])基因组序列不同区域的合成肽。合成了对应于两个开放读码框(ORFs；Genebank登记号AB008394)1和2的总共80个重叠肽。用8份TTV感染的人血清样品和8份无TTV感染的人样品对它们进行分析。可反应性人血清样品均与具有序列SEQ ID NO：1：TATTTTYAYPGTNRPPV的肽反应。反应性可精确地作图到序列SEQ ID NO：2：YAYPGTNRPPV，发现其中PV残基为结合人抗体最必需的。
这样，本发明针对具有氨基酸序列SEQ ID NO：1TATTTTYAYPGTNRPPV的多肽，其中N-末端氨基酸TATTTT中的一到所有六个可以去除。
在本发明的一个实施方案中，本发明的肽具有氨基酸序列SEQ ID NO：2
YAYPGTNRPPV。
本发明也针对包含肽SEQ ID NO：1(TATTTTYAYPGTNRPPV，其中N-末端氨基酸TATTTT中的一到所有六个可以去除)和至少一个在表4中列出的具有氨基酸序列SEQ ID NO：3-11的其它肽的肽混合物。
本发明的肽和/或肽混合物中至少一个肽可以偶联到载体和/或标记上。载体的实例为塑料表面，如微量滴定板和珠子等；有机分子如生物素；蛋白如牛血清白蛋白；肽接头或多肽。可使用的标记实例(主要用于诊断目的)为放射性同位素、酶和荧光标记等。
此外，本发明的肽和/或肽混合物中至少一个肽可以被固定到固相上，如玻璃或塑料表面，主要用于诊断目的或纯化抗体。
本发明也涉及将本发明的肽或肽混合物可选地与其它生物活性或非活性成分偶联或组合，用作药物，如预防TT病毒感染的疫苗。
此外，本发明针对结合TT病毒的单特异性抗体。
在本发明的一个实施方案中，单特异性抗体结合选自氨基酸序列SEQID NO：1-11的氨基酸序列。
此外，本发明涉及根据本发明的单特异性抗体可选地与其它生物活性或非活性成分偶联或组合，用作药物，如给已经感染了TTV的患者施用的药物。
本发明还针对含有根据本发明的肽或肽混合物作为诊断抗原的诊断试剂盒。该试剂盒可用于免疫学分析如EIA、RIA等，来检测生物学体液(如血液或血浆)中抗TTV抗体的存在。
本发明还针对含有根据本发明的一个或多个单特异性抗体作为诊断抗体的诊断试剂盒。该试剂盒可用于免疫学分析如EIA、RIA等，来检测生物学体液(如血液或血浆)中抗TTV抗体的存在。
该诊断试剂盒通常包含进行免疫学分析的其它成分。这些其它成分将取决于使用的实际分析方法，通常包括阳性和阴性标准血清样品和使用说明书。
此外，本发明针对根据本发明的肽在免疫非人哺乳动物以产生针对TT病毒的单特异性抗体中的用途。
通过参考以下实验描述和本发明的具体实施方案，本发明将被进一步阐明。这些实验描述和具体实施方案不认为是对权利要求书中定义的本
发明范围的限制。实验描述
血清样品
从含有健康血液供体、有或无肝病的儿童、静脉使用毒品(IVDU)的母亲和她们的小孩的血清库获得编号血清样品。
PCR扩增检测血清中的TTV DNA
从50μl患者血清中通过酚/氯仿纯化分离总DNA。所有患者DNA使用两套不同引物通过(半)巢式PCR进行分析。5μl患者DNA加入45μl含有1U taq聚合酶(Perkin-Elmer Applied Biosystems，Norwalk，CO)，10×PCR缓冲液，200μmol MgCl2，dNTPs(125μmol/核苷酸)和20pmol每种引物的反应混合物中。第一轮引物为5TTVout5(5’-ACA GAC AGA GGA GAAGGC AAC ATG-3’)和或者3TTVout(5’-CTG GCA TTT TAC CAT TTC CAA AGT T-3’)或者3TTXout(5’-TAC CAY TTA GCT CTC ATT CTW AT-3’)作为下游引物。DNA扩增如下：95℃4.5分钟；然后95℃30秒，50℃30秒，72℃1分钟，共33循环；最后72℃4分钟。使用5μl第一轮PCR产物在相同条件下进行第二轮PCR。第二轮内引物为5TTVin(5’GGC AAC ATG YTR TGG ATA GACTGG-3’)或5TTVXin(5’-ACA GGA GAC HMA AAC ATA SA-3’)作为上游引物和3TTVout。通过琼脂糖凝胶电泳(3％)确定大约分别为275bp和140bp的正确大小。两套引物均为阳性或一套引物可重复出现阳性的样品判定为TTV阳性。引物序列根据Genebank录入号AB008394。
肽合成
通过多肽合成仪使用标准Fmoc化学方法[7](Syro，Synter，德国)制备对应于TTV的ORF1和ORF2(表1；Genebank录入号AB008394)的重叠肽(18个氨基酸长，8个氨基酸重叠)。
检测血清中的人抗体
EIAs主要按照以前的操作流程[8]。用含有10μg/ml合成肽的0.05M碳酸钠缓冲液(pH9.6)包被微量滴定板(Nunc，丹麦)48小时。用含有1％牛血清白蛋白、2％山羊血清和0.05％Tween 20(稀释缓冲液)的磷酸缓冲盐水室温封闭2小时后，用稀释缓冲液1∶100稀释的人血清孵育微量滴定板。用结合碱性磷酸酶的抗人IgG抗体(Sigma Chemicals，St.Louis，MO)来指示结合的人IgG，通过加入二硝基苯二胺(Sigma)显色，测定405nm处的光密度。
免疫和诱生TTV特异性抗体
用在完全弗氏佐剂中1∶1乳化的100μg肽35(SEQ ID NO：1)通过腹膜内免疫多组Balb/c。四周后用不完全弗氏佐剂中的100μg剂量进行加强。每星期采集静脉血样品，共6星期，并检测对TTV肽35(SEQ ID NO：1)的反应性。
结果
表2和3给出了对覆盖ORF1和ORF2的97个肽的人反应性。发现ORF1中的反应性肽是肽10(SEQ ID NO：3)、18(SEQ ID NO：4)、29(SEQ ID NO：5)、35(SEQ ID NO：1)、42(SEQ ID NO：6)、44(SEQ ID NO：7)、50(SEQ IDNO：8)、51(SEQ ID NO：9)和69(SEQ ID NO：10)(表2)。两份被检测的人血清与来源于ORF2的肽19(SEQ ID NO：11)有反应。所有反应性肽列于表4。最常检测到的肽为具有序列TATTTTYAYPGTNRPPV(SEQ ID NO：1)的肽35。对肽35的反应性依赖于血清样品的稀释度(表5)。微量滴定板上人血清对该肽的反应性可被溶液中相同肽的加入所抑制，但不被非相关肽所抑制(未显示数据)。这表明该反应性对具有序列TATTTTYAYPGTNRPPV(SEQ ID NO：1)的肽35是特异的。
通过使用缺失和替换肽类似物进一步表征肽TATTTTYAYPGTNRPPV的反应性。分析表明识别区域含有序列YAYPGTNRPPV(SEQ ID NO：2)(表6)。使用丙氨酸替换类似物发现Pro-Val序列为人抗体结合最为必需的序列(表6)。
表1.用于合成80个重叠肽的TTV ORFs1和2的完整氨基酸序列(Genebank录入号AB008394)。ORF1MAYGWWRRRRRRWRRWRRRPWRRRWRTRRRRPARRRGRRRNVRRRRRGGRWRRRYRRWKRKGRRRKKAKIIIRQWQPNYRRRCNIVGYIPVLICGENTVSRNYATHSDDTNYPGPFGGGMTTDKFTLRILYDEYKRFMNYWTASNEDLDLCRYLGVNLYFFRHPDVDFIIKINTMPPFLDTELTAPSIHPGMLALDKRARWIPSLKSRPGKKHYIKIRVGAPRMFTDKWYPQTDLCDMVLLTVYATAADMQYPFGSPLTDSVVVNFQVLQSMYDKTISLLPDEKSQREILLNKIASYIPFYNTTQTLAQLKPFIDAGNVTSGATATTWASYINTTKFTTATTTTYAYPGTNRPPVTMLTCNDSWYRGTVYNTQIQQLPIKAAKLYLEATKTLLGNTFTNEDYTLEYHGGLYSSIWLSPGRSYFETTGAYTDIKYNPFTDRGEGNMLWIDWLSKKNMNYDKVQSKCLISDLPLWAAAYGYVEFCAKSTGDQNIHMNARLLIRSPFTDPQLLVHTDPTKGFVPYSLNFGNGKMPGGSSNVPIRMRAKWYPTLFHQQEVLEALAQSGPFAYHSDIKKVSLGMKYRFKWTWGGNPVRQQVVRNPCKETHSSGNRVPRSLQIVDPKYNSPELTFHTWDFRRGLFGPKAIQRMQQQPTTTDIFSAGRKRPRRDTEVYHSSQEGEQKESLLFPPVKLLRRVPPWEDSQQEESGSQSSEEETQTVSQQLKQQLQQQRILGVKLRLLFNQVQKIQQNQDINPTLLPRGGDLASLFQIAPORF2MAEFSTPVRSGEATEGDLRVPRAGAEGEFTHRSQGAIRARDWPGYGQGSEKSMFIGRHYRKKRALSLCAVRTTKKACKLLIVMWTPPRNDQHYLNWQWYSSILSSHAAMCGCPDAVAHFNHLASVLRAPQNPPPPGPQRNLPLRRLPALPAAPEAPGDRAPWPMAGGAEGEDGGAGGDADHGGAAGGPEDADLLDAVAAAE
表2.在EIA中分析对与TT病毒完整开放读码框1(ORF1)对应的重叠合成肽的人抗体反应性。给出数值为405nm处的光密度。OD值大于0.500判定为阳性，并用粗体标出。
  TTVORF1肽 通过PCR确定为TTVDNA阴性的样品 通过PCR确定为TTV DNA阳性的样品
   1    2    3    4    5    6    7    11    9    18    36    48    98    110    155    157
  1    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00
  2    0.08    0.08    0.07    0.11    0.07    0.09    0.08    0.14    0.07    0.06    0.08    0.10    0.05    0.08    0.07    0.08
  3    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00
  4    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00
  5    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00
  6    0.08    0.08    0.07    0.10    0.07    0.09    0.07    0.11    0.08    0.06    0.08    0.09    0.05    0.07    0.08    0.07
  7    0.07    0.07    0.08    0.10    0.07    0.08    0.08    0.10    0.07    0.064    0.07    0.09    0.05    0.07    0.08    0.08
  8    0.07    0.06    0.07    0.08    0.07    0.09    0.07    0.10    0.07    0.07    0.08    0.10    0.05    0.07    0.09    0.09
  9    0.07    0.08    0.08    0.09    0.08    0.10    0.07    0.10    0.08    0.06    0.07    0.10    0.05    0.08    0.10    0.11
  10    0.09    0.10    0.11    0.11    0.11    0.13    1.09    0.12    0.09    0.07    0.07    0.11    0.06    0.09    0.12    0.12
  11    0.09    0.10    0.10    0.10    0.09    0.11    0.09    0.12    0.09    0.07    0.08    0.10    0.07    0.08    0.12    0.13
  12    0.09    0.09    0.10    0.10    0.08    0.11    0.09    0.12    0.10    0.08    0.08    0.11    0.06    0.08    0.13    0.13
  13    0.09    0.08    0.08    0.09    0.08    0.09    0.09    0.10    0.09    0.07    0.08    0.10    0.07    0.08    0.11    0.11
  14    0.09    0.10    0.11    0.11    0.08    0.12    0.09    0.12    0.08    0.07    0.07    0.09    0.05    0.07    0.14    0.14
  15    0.08    0.09    0.11    0.10    0.09    0.13    0.09    0.13    0.09    0.06    0.07    0.13    0.05    0.08    0.15    0.16
  16    0.08    0.09    0.08    0.10    0.08    0.14    0.09    0.11    0.08    0.07    0.07    0.09    0.04    0.06    0.12    0.12
  17    0.08    0.10    0.09    0.11    0.09    0.13    0.09    0.13    0.08    0.08    0.08    0.11    0.04    0.09    0.12    0.13
  18    0.09    0.09    0.15    0.29    0.07    0.13    0.62    0.28    0.08    0.07    0.13    0.12    0.04    0.08    0.19    0.18
  19    0.08    0.09    0.10    0.10    0.09    0.16    0.12    0.13    0.08    0.07    0.07    0.14    0.04    0.08    0.15    0.14
  20    0.07    0.06    0.06    0.07    0.06    0.08    0.08    0.11    0.08    0.07    0.07    0.09    0.04    0.06    0.09    0.10
  21    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00
    22     0.07     0.07  0.07     0.08  0.08     0.09     0.09     0.11     0.08     0.07     0.08     0.10     0.04     0.07     0.11     0.11
    23     0.09     0.09  0.11     0.11  0.08     0.16     0.09     0.12     0.08     0.07     0.07     0.10     0.05     0.07     0.14     0.14
    24     0.07     0.09  0.12     0.12  0.08     0.12     0.08     0.11     0.08     0.07     0.07     0.10     0.05     0.10     0.13     0.15
    25     0.07     0.09  0.08     0.08  0.06     0.11     0.07     0.12     0.07     0.06     0.06     0.06     0.06     0.07     0.11     0.12
    26     0.07     0.09  0.07     0.08  0.08     0.10     0.07     0.10     0.07     0.07     0.06     0.05     0.07     0.08     0.09     0.11
    27     0.07     0.08  0.07     0.08  0.06     0.11     0.07     0.08     0.06     0.06     0.06     0.06     0.08     0.06     0.09     0.10
    28     0.07     0.08  0.08     0.08  0.07     0.50     0.07     0.10     0.07     0.06     0.06     0.06     0.07     0.06     0.09     0.10
    29     0.42     0.36  0.45     0.53  0.22     0.95     0.29     0.14     0.21     0.11     0.09     0.10     0.09     0.25     0.59     0.62
    30     0.07     0.07  0.06     0.07  0.06     0.09     0.07     0.09     0.07     0.07     0.07     0.07     0.08     0.08     0.09     0.12
    31     0.05     0.09  0.09     0.08  0.06     0.09     0.07     0.08     0.06     0.06     0.06     0.06     0.06     0.06     0.09     0.09
    32     0.06     0.08  0.06     0.25  0.06     0.09     0.06     0.07     0.06     0.05     0.06     0.05     0.07     0.06     0.09     0.09
    33     0.07     0.08  0.06     0.07  0.06     0.08     0.06     0.07     0.06     0.05     0.06     0.05     0.07     0.06     0.08     0.09
    34     0.07     0.07  0.05     0.06  0.06     0.06     0.06     0.07     0.06     0.09     0.06     0.15     0.06     0.06     0.08     0.08
    35     0.18     0.17  0.27     1.40  0.25     0.64     2.10     0.64     0.10     0.10     1.22     1.11     0.05     0.47     0.95     0.86
    36     0.07     0.07  0.06     0.07  0.06     0.11     0.07     0.08     0.09     0.06     0.06     0.07     0.07     0.07     0.08     0.08
    37     0.10     0.11  0.11     0.12  0.09     0.14     0.12     0.14     0.09     0.08     0.08     0.20     0.10     0.08     0.14     0.14
    38     0.07     0.08  0.08     0.09  0.08     0.11     0.09     0.11     0.08     0.07     0.07     0.07     0.09     0.08     0.19     0.11
    39     0.08     0.09  0.07     0.09  0.07     0.37     0.09     0.10     0.08     0.09     0.09     0.08     0.09     0.09     0.11     0.13
    40     0.09     0.16  0.24     0.12  0.11     0.16     0.09     0.12     0.09     0.09     0.08     0.08     0.10     0.09     0.15     0.16
    41     0.08     0.12  0.10     0.11  0.10     0.20     0.09     0.15     0.09     0.07     0.09     0.08     0.11     0.09     0.15     0.16
    42     0.08     0.11  0.09     0.10  0.17     0.23     0.11     0.19     0.27     0.12     0.10     0.09     0.16     0.42     0.35     1.24
    43     0.09     0.21  0.11     0.11  0.10     0.41     0.10     0.14     0.08     0.08     0.08     0.08     0.12     0.11     0.20     0.25
    44     0.09     0.11  0.11     0.12  0.98     0.15     0.10     0.14     0.09     0.09     0.08     0.08     0.12     0.13     0.17     1.25
    45     0.08     0.06  0.06     0.12  0.10     0.17     0.10     0.14     0.09     0.08     0.06     0.09     0.11     0.09     0.16     0.17
    46     0.08     0.08  0.07     0.09  0.08     0.22     0.10     0.12     0.08     0.07     0.07     0.07     0.09     0.08     0.19     0.26
    47     0.07     0.09  0.08     0.09  0.09     0.13     0.09     0.12     0.07     0.07     0.07     0.07     0.10     0.09     0.15     0.19
    48     0.08     0.11  0.10     0.12  0.10     0.16     0.11     0.13     0.08     0.09     0.08     0.08     0.12     0.09     0.15     0.15
    49     0.09     0.11  0.10     0.11  0.10     0.15     0.15     0.15     0.08     0.08     0.07     0.08     0.10     0.11     0.26     0.25
    50     0.07     0.09  0.08     0.09  0.08     0.86     0.29     0.18     0.08     0.07     0.07     0.07     0.10     0.20     0.63     0.46
    51     0.06     0.09   0.08     0.10   0.12     0.24     0.13     0.13     0.07     0.07     0.08     0.08     0.11     0.09     0.24     0.78
    52     0.10     0.13   0.11     0.11   0.10     0.20     0.11     0.13     0.10     0.09     0.08     0.08     0.14     0.11     0.21     0.38
    53     0.12     0.12   0.09     0.10   0.08     0.16     0.09     0.11     0.09     0.10     0.08     0.07     0.09     0.10     0.16     0.15
    54     0.00     0.00   0.00     0.00   0.00     0.00     0.00     0.00     0.00     0.00     0.00     0.00     0.00     0.00     0.00     0.00
    55     0.10     0.10   0.07     0.08   0.07     0.14     0.09     0.08     0.35     0.08     0.07     0.07     0.08     0.09     0.14     0.12
    56     0.10     0.16   0.11     0.11   0.09     0.18     0.09     0.11     0.10     0.09     0.09     0.09     0.10     0.10     0.18     0.15
    57     0.14     0.12   0.10     0.12   0.09     0.17     0.11     0.12     0.11     0.08     0.09     0.09     0.10     0.12     0.19     0.43
    58     0.07     0.06   0.06     0.07   0.06     0.07     0.07     0.08     0.07     0.06     0.08     0.08     0.04     0.06     0.08     0.09
    59     0.06     0.05   0.05     0.06   0.06     0.06     0.06     0.08     0.06     0.05     0.05     0.06     0.04     0.05     0.07     0.08
    60     0.00     0.00   0.00     0.00   0.00     0.00     0.00     0.00     0.00     0.00     0.00     0.00     0.00     0.00     0.00     0.00
    61     0.07     0.06   0.06     0.08   0.06     0.10     0.07     0.10     0.08     0.05     0.06     0.08     0.04     0.07     0.12     0.12
    62     0.07     0.07   0.06     0.09   0.07     0.08     0.07     0.09     0.08     0.05     0.07     0.11     0.05     0.07     0.11     0.14
    63     0.11     0.16   0.12     0.13   0.11     0.16     0.11     0.05     0.08     0.08     0.08     0.08     0.11     0.09     0.15     0.15
    64     0.09     0.08   0.08     0.09   0.07     0.10     0.08     0.09     0.08     0.08     0.08     0.07     0.08     0.08     0.11     0.12
    65     0.00     0.00   0.00     0.00   0.00     0.00     0.00     0.00     0.00     0.00     0.00     0.00     0.00     0.00     0.00     0.00
    66     0.10     0.12   0.10     0.10   0.10     0.14     0.12     0.16     0.10     0.09     0.09     0.09     0.11     0.10     0.13     0.15
    67     0.10     0.11   0.09     0.12   0.10     0.15     0.12     0.15     0.10     0.09     0.09     0.09     0.10     0.10     0.21     0.24
    68     0.11     0.14   0.16     0.16   0.13     0.23     0.13     0.19     0.10     0.10     0.09     0.10     0.12     0.12     0.20     0.21
    69     0.10     0.15   0.16     0.14   0.12     0.51     0.11     0.13     0.09     0.08     0.08     0.09     0.10     0.11     0.15     0.21
    70     0.09     0.11   0.11     0.11   0.09     0.19     0.12     0.12     0.08     0.08     0.08     0.09     0.10     0.11     0.18     0.20
    71     0.10     0.13   0.14     0.14   0.11     0.20     0.11     0.17     0.10     0.08     0.10     0.09     0.13     0.14     0.21     0.20
    72     0.10     0.15   0.12     0.13   0.10     0.19     0.12     0.16     0.08     0.08     0.09     0.09     0.11     0.11     0.18     0.19
    73     0.08     0.09   0.09     0.10   0.09     0.12     0.10     0.13     0.09     0.08     0.07     0.08     0.11     0.09     0.13     0.14
    74     0.08     0.09   0.07     0.08   0.08     0.10     0.09     0.11     0.09     0.08     0.07     0.08     0.08     0.08     0.09     0.11
    75     0.11     0.12   0.12     0.11   0.10     0.17     0.44     0.15     0.10     0.10     0.10     0.09     0.11     0.10     0.15     0.16
    76     0.10     0.13   0.15     0.14   0.11     0.28     0.13     0.14     0.11     0.09     0.08     0.09     0.12     0.26     0.01     0.22
    77     0.14     0.14   0.15     0.12   0.09     0.18     0.12     0.13     0.18     0.07     0.07     0.08     0.08     0.09     0.11     0.14
表3.在EIA中分析对与TT病毒完整开放读码框2(ORF2)对应的重叠合成肽的人抗体反应性。给出数值为405nm处的光密度。OD值大于0.500判定为阳性，并用粗体标出。
   TTVORF2肽 通过PCR确定为TTV DNA阴性的样品 通过PCR确定为TTV DNA阳性的样品
  1   2   3   4   5   6   7   11   9   18   36   48   98   110   155   157
    1   0.09   0.10   0.13   0.11   0.10   0.16   0.09   0.12   0.08   0.08   0.09   0.08   0.08   0.08   0.14   0.14
    2   0.10   0.11   0.11   0.10   0.08   0.12   0.09   0.14   0.08   0.08   0.08   0.08   0.08   0.09   0.14   0.13
    3   0.08   0.10   0.11   0.10   0.08   0.29   0.28   0.14   0.10   0.08   0.13   0.08   0.11   0.10   0.14   0.04
    4   0.09   0.09   0.08   0.08   0.07   0.09   0.07   0.09   0.08   0.07   0.07   0.07   0.07   0.07   0.10   0.10
    5   0.08   0.08   0.08   0.08   0.07   0.10   0.08   0.10   0.07   0.07   0.07   0.07   0.07   0.08   0.12   0.13
    6   0.07   0.10   0.08   0.10   0.07   0.10   0.07   0.10   0.08   0.28   0.09   0.08   0.10   0.09   0.09   0.11
    7   0.11   0.10   0.11   0.14   0.91   0.13   0.10   0.11   0.08   0.09   0.10   0.11   0.10   0.09   0.10   0.13
    8   0.09   0.10   0.11   0.13   0.10   0.12   0.10   0.14   0.09   0.08   0.10   0.11   0.10   0.10   0.11   0.12
    9   0.08   0.09   0.09   0.09   0.09   0.10   0.09   0.11   0.09   0.08   0.08   0.09   0.09   0.09   0.13   0.14
    10   0.09   0.11   0.10   0.09   0.08   0.11   0.08   0.10   0.09   0.09   0.07   0.08   0.08   0.08   0.11   0.13
    11   0.10   0.10   0.11   0.08   0.09   0.09   0.09   0.11   0.10   0.12   0.09   0.07   0.09   0.09   0.14   0.14
    12   0.12   0.09   0.09   0.08   0.09   0.09   0.08   0.07    0.13   0.09   0.08   0.10   0.14   0.12   0.16   0.14
    13   0.07   0.09   0.09   0.08   0.08   0.10   0.09   0.11   0.07   0.08   0.07   0.08   0.09   0.08   0.12   0.12
    14   0.08   0.07   0.08   0.07   0.07   0.08   0.08   0.10   0.07   0.07   0.07   0.07   0.07   0.07   0.10   0.10
    15   0.08   0.08   0.08   0.07   0.07   0.09   0.07   0.10   0.08   0.07   0.07   0.07   0.08   0.08   0.10   0.12
    16   0.08   0.09   0.09   0.07   0.07   0.09   0.08   0.09   0.08   0.08   0.08   0.07   0.08   0.08   0.12   0.11
    17   0.00   0.00   0.00   0.00   0.00   0.00   0.00   0.00   0.00   0.00   0.00   0.00   0.00   0.00   0.00   0.00
    18   0.00   0.00   0.00   0.00   0.00   0.00   0.00   0.00   0.00   0.00   0.00   0.00   0.00   0.00   0.00   0.00
    19   0.09   0.12   0.17   0.12   0.08   0.51   0.57   0.15   0.08   0.07   0.33   0.07   0.08   0.08   0.14   0.14
    20   0.09   0.10   0.09   0.08   0.07   0.10   0.07   0.09   0.10   0.10   0.08   0.08   0.08   0.10   0.14   0.16
表4.与人血清样品反应的TTV肽序列.ORF1肽编号    肽序列10        VLICGENTVSRNYATHS    SEQ ID NO：318        KINTMPPFLDTELTAPS    SEQ ID NO：429        PDEKSQREILLNKIASY    SEQ ID NO：535        TATTTTYAYPGTNRPPV    SEQ ID NO：142        GLYSSIWLSPGRSYFET    SEQ ID NO：644        YTDIKYNPFTDRGEGNM    SEQ ID NO：750        DQNIHMNARLLIRSPFT    SEQ ID NO：851        LIRSPFTDPQLLVHTDP    SEQ ID NO：969        QKESLLFPPVKLLRRVP    SEQ ID NO：10ORF2肽编号   肽序列19       EDGGAGGDADHGGAAGGP   SEQ ID NO：11
表5.分析系列稀释的三份人血清样品与TTV肽TATTTTYAYPGTNRPPV(SEQ ID NO：1)的反应性。给出值为405nm处OD和标准差(SD)。
 血清样品稀释度  人血清样品
 P4  SD  P6  SD  P7  SD
 1∶100  1.285  0.072  0.687  0.082  1.782  0.054
 1∶200  0.758  0.056  0.375  0.003  1.23  0.02
 1∶400  0.411  0.021  0.19  0.007  0.79  0.018
 1∶800  0.234  0.008  0.104  0.003  0.45  0.002
 1∶1600  0.131  0.005  0.067  0.001  0.246  0.013
 1∶3200  0.076  0.003  0.049  0.131  0.006
 1∶6400  0.058  0.001  0.043  0.087
 1∶12800  0.046  0.041  0.061
表6.分析三份人血清样品对TTV肽TATTTTYAYPGTNRPPV(SEQ ID NO：1)的缺失和丙氨酸替换类似物的反应性。给出值为405nm处OD。阳性反应(即大于50％初始肽反应性)以粗体标出。
 缺失或替代类似物  人血清样品P4            P7           P36
 TATTTTYAYPGTNRPPV  0.839  1.845  0.825
 TATTTTYAYPGTNRPP  0.096  0.144  0.086
 TATTTTYAYPGTNRP  0.100  0.099  0.078
 TATTTTYAYPGTNR  0.092  0.103  0.078
 TATTTTYAYPGTN  0.186  0.888  0.083
 TATTTTYAYPGT  0.095  0.087  0.072
 TATTTTYAYPG  0.095  0.085  0.074
 TATTTTYAYP  0.095  0.096  0.082
 TATTTTYAY  0.098  0.089  0.083
 TATTTTYA  0.115  0.089  0.090
 TATTTTY  0.142  0.105  0.076
 TATTTT  0.108  0.093  0.082
 TATTT  0.101  0.091  0.078
 TATT  0.099  0.105  0.076
                ATTTTYAYPGTNRPPV  1.042  1.960  0.923
                 TTTTYAYPGTNRPPV  0.805  1.587  0.776
                  TTTYAYPGTNRPPV  0.697  1.488  0.810
                   TTYAYPGTNRPPV  0.748  1.659  0.722
                    TYAYPGTNRPPV  0.707  1.508  0.712
                     YAYPGTNRPPV  0.647  1.546  0.677
                      AYPGTNRPPV  0.662  1.488  0.669
                       YPGTNRPPV  0.300  1.091  0.406
                        PGTNRPPV  0.166  0.430  0.123
                         GTNRPPV  0.300  0.887  0.210
                          TNRPPV  0.110  0.146  0.056
                           NRPPV  0.135  0.242  0.076
AATTTTYAYPGTNRPPV  1.045  1.852  0.915
TGTTTTYAYPGTNRPPV  0.855  1.829  0.806
TAATTTYAYPGTNRPPV  0.897  1.675  0.764
TATATTYAYPGTNRPPV  0.971  1.722  0.824
TATTATYAYPGTNRPPV  1.076  1.867  0.955
TATTTAYAYPGTNRPPV  1.011  1.833  1.027
TATTTTAAYPGTNRPPV  0.898  1.619  0.901
TATTTTYGYPGTNRPPV  0.836  1.769  0.850
TATTTTYAAPGTNRPPV  0.899  1.697  0.903
TATTTTYAYAGTNRPPV  0.886  1.738  0.903
TATTTTYAYPATNRPPV  0.895  1.503  0.734
TATTTTYAYPGANRPPV  0.891  1.594  0.714
TATTTTYAYPGTARPPV  1.226  1.723  0.696
TATTTTYAYPGTNAPPV  0.761  1.558  0.708
TATTTTYAYPGTNRAPV  0.720  1.551  0.812
TATTTTYAYPGTNRPAV  0.090  0.092  0.100
TATTTTYAYPGTNRPPA  0.108  0.105  0.095
参考文献
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2.Okamoto H，Akahane Y，Ukita M，Fukuda M，Tsuda F，MiyakawaY，Mayumi M.粪便排出一种与输血后非甲-庚型肝炎相关的非包膜DNA病毒(TTV)(Fecal excreton of a nonenveloped DNA virus(TTV)associatedwith posttransfusion non-A-G hepatitis)，医学病毒学杂志(J MedVirol)1998；56：128-32
3.Cossart Y.TTV，一种常见病毒，但是致病？(TTV a commonvirus，but pathogenic？)，[评论]。Lancet 1998；352：164
4.Okamoto H，Kato N，Iizuka H，Tsuda F，Miyakawa Y，Mayumi M.血浆或外周血单核细胞中与输血后非甲-庚型肝炎相关的非包膜DNA病毒(TT病毒)的独特基因型(Distinct genotypes of a nonenveloped DNA virusassociated with posttransfusion non-A-G hepatitis(TT virus)inplasma and peripheral blood mononuclear cells)[In process Citation].医学病毒学杂志1999；57：252-8
5.Naoumov NV，Petrova EP，Thomas MG，Williams R.肝病患者中存在一种新描述的人类DNA病毒(TTV)(Presence of a newly describedhuman DNA virus (TTV) in patients with liver disease[seecomments])，Lancet 1998；352：195-7
6.Viazov S，Ross RS，Varenholz C，Lange R，Holtmann M，NielC，Roggendorf M.TTV感染和严重肝病的相关性缺乏证据(Lack of evidencefor an association between TTV infection and severe liver disease[Inprocess Citation])。临床病毒学杂志(J Clin Virol)1998；11：183-7
7.Sllberg M，Ruden U，Magnius LO，Norrby E，Wahren B.使用9-芴基甲氧基羰基(Fmoc)保护的氨基酸的快速“茶包”肽合成法应用于病毒蛋白的抗原性作图(Rapid‘tea-bag’peptide synthesis using 9-fluorenylmethoxycarbonyl(Fmoc)protected amino acids applied forantigenic maping of viral proteins)。免疫学通讯(ImmunologyLetters)1991；30：59-68
8.Zhang ZX，Chen M，Hultgren C，Birkett A，Milich DR，Sallberg M.病毒基因型和宿主主要组织相容性复合物显著影响针对丙型肝炎病毒NS4a的免疫应答(Immune responses to the hepatitis C virus NS4a areprofoundly influenced by the combination of the viral genotype andthe host major histocompatibility complex)。普通病毒学杂志(J.Gen.Virol.)1997；78：2735-2746序列表<110>Tripep AB<120>来自TT病毒序列的肽和结合TT病毒的单特异性抗体<130>192975901<140><141><160>11<170>PatentIn Ver.2.1<210>1<211>17<212>PRT<213>TT病毒<400>1Thr Ala Thr Thr Thr Thr Tyr Ala Tyr Pro Gly Thr Asn Arg Pro pro1              5                   10                  15Val<210>2<211>11<212>PRT<213>TT病毒<400>2Tyr Ala Tyr Pro Gly Thr Asn Arg Pro Pro Val1               5              10<210>3<211>17<212>PRT<213>TT病毒<400>3Val Leu Ile Cys Gly Glu Asn Thr Val Ser Arg Asn Tyr Ala Thr His1               5                  10                  15Ser<210>4<211>17<212>PRT<213>TT病毒<400>4Lys Ile Asn Thr Met Pro Pro Phe Leu Asp Thr Glu Leu Thr Ala Pro1               5                  10                  15Ser<210>5<211>17<212>PRT<213>TT病毒<400>5Pro Asp Glu Lys Ser Gln Arg Glu Ile Leu Leu Asn Lys Ile Ala Ser1               5                  10                  15Tyr<210>6<211>17<212>PRT<213>TT病毒<400>6Gly Leu Tyr Ser Ser Ile Trp Leu Ser Pro Gly Arg Ser Tyr Phe Glu1               5                  10                  15Thr<210>7<211>17<212>PRT<213>TT病毒<400>7Tyr Thr Asp Ile Lys Tyr Asn Pro Phe Thr Asp Arg Gly Glu Gly Asn1               5                  10                  15Met<210>8<211>17<212>PRT<213>TT病毒<400>8Asp Gln Asn Ile His Met Asn Ala Arg Leu Leu Ile Arg Ser Pro Phe1               5                  10                  15Thr<210>9<211>17<212>PRT<213>TT病毒<400>9Leu Ile Arg Ser Pro Phe Thr Asp Pro Gln Leu Leu Val His Thr Asp1               5                  10                  15Pro<210>10<211>17<212>PRT<213>TT病毒<400>10Gln Lys Glu Ser Leu Leu Phe Pro Pro Val Lys Leu Leu Arg Arg Val1               5                  10                  15Pro<210>11<211>18<212>PRT<213>TT病毒<400>11Glu Asp Gly Gly Ala Gly Gly Asp Ala Asp His Gly Gly Ala Ala Gly1               5                  10                  15Gly Pro

Claims (12)

1.具有氨基酸序列SEQ ID NO：1Thr Ala Thr Thr Thr Thr Tyr Ala Tyr Pro Gly Thr Asn Arg Pro ProVal的肽，其中N-端氨基酸Thr Ala Thr Thr Thr Thr中的一到六个可以去除。
2.根据权利要求1的肽，其具有氨基酸序列SEQ ID NO：2Tyr Ala Tyr Pro Gly Thr Asn Arg Pro Pro Val。
3.肽混合物，其包含根据权利要求1的肽和至少一个以下肽：SEQ ID NO：3Val Leu Ile Cys Gly Glu Asn Thr Val Ser Arg Asn Tyr Ala Thr HisSer，SEQ ID NO：4Lys Ile Asn Thr Met Pro Pro Phe Leu Asp Thr Glu Leu Thr Ala ProSer，SEQ ID NO：5Pro Asp Glu Lys Ser Gln Arg Glu Ile Leu Leu Asn Lys Ile Ala SerTyr，SEQ ID NO：6Gly Leu Tyr Ser Ser Ile Trp Leu Ser Pro Gly Arg Ser Tyr Phe GluThr，SEQ ID NO：7Tyr Thr Asp Ile Lys Tyr Asn Pro Phe Thr Asp Arg Gly Glu Gly AsnMet，SEQ ID NO：8Asp Gln Asn Ile His Met Asn Ala Arg Leu Leu Ile Arg Ser Pro PheThr，SEQ ID NO：9Leu Ile Arg Ser Pro Phe Thr Asp Pro Gln Leu Leu Val His Thr AspPro，SEQ ID NO：10Gln Lys Glu Ser Leu Leu Phe Pro Pro Val Lys Leu Leu Arg Arg ValPro，和SEQ ID NO：11Glu Asp Gly Gly Ala Gly Gly Asp Ala Asp His Gly Gly Ala Ala GlyGly Pro。
4.根据权利要求1或2的肽，或根据权利要求3的肽混合物，其中至少一个肽被偶联到载体和/或标记上。
5.根据权利要求1或2的肽，或根据权利要求3的肽混合物，其中至少一个肽被固定到固相上。
6.根据前述权利要求之任何一项的肽或肽混合物，用于药物。
7.结合TT病毒的单特异性抗体。
8.根据权利要求7的单特异性抗体，其结合选自氨基酸序列SEQ IDNO：1-11的氨基酸序列。
9.根据权利要求7或8的用于药物的单特异性抗体。
10.包含根据权利要求1-5之任一项的肽或肽混合物作为诊断抗原的诊断试剂盒。
11.包含一个或多个根据权利要求7或8的单特异性抗体作为诊断抗体的诊断试剂盒。
12.根据权利要求1-4之任一项的肽或肽混合物在免疫非人哺乳动物产生抗TT病毒的单特异性抗体中的用途。
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