臺灣博碩士論文加值系統

D型肝炎病毒(HDV)，因其核酸及所產生之D型肝炎抗原(HDAg)之變異，可區分為不同基因型，但是不同基因型HDAg之胺基酸變異所扮演的重要性並不清楚。先前對HDV之研究多集中於第一基因型，顯示許多HDAg有趣的性質。小型D型肝炎抗原(HDAg-S)可刺激HDV的複製，但是大型D型肝炎抗原(HDAg-L)卻會抑制HDV的複製，而HDAg-L只比HDAg-S在蛋白質的C-端多了19個胺基酸，卻可以和B型肝炎病毒的表面蛋白(HBsAg)作用而促進HDV病毒顆粒的包裹。HDAg在基因型上的差異遍布整個蛋白質，主要位於兩個區域。一個是位於蛋白質N-端第3至40個胺基酸負責HDAg間交互作用的區域，稱為coiled-coil domain，其差異有百分之45至50。另一個差異更大的區域是位於HDAg-L之C-端第196至214個胺基酸，為HDAg-L的裝配訊號，其差異大於百分之74。
在此研究中，我們用不同的方法來檢測HDAg在第一及第二基因型間之不同。首先，利用分別合成具有第一及第二基因型HDAg-L蛋白質C-端19個胺基酸之peptide作為抗原，製備具有基因型專一性的抗體。這兩個抗體已被証實可對於肝切片用免疫組織學的方式區分HDV的基因型，可應用於臨床及流行病學的研究。第二，利用cDNA轉染的系統將不同的HDAg表現於人類肝癌細胞株(HuH-7)中，再利用不同的專一性抗體作免疫沈澱分析，發現不同基因型之HDAgs間可交互作用，沒有基因型間的限制。第三，在同時表現HBsAg時，測量HDAg-L在病毒顆粒包裝的效率，發現不同的基因型及分離株間皆有差異，但整體而言，第二基因型HDAg-L在病毒顆粒包裝的效率上較第一基因型為差，並且影響病毒顆粒包裝的主要因素是位於HDAg-L的C端19個胺基酸。第四，在D型病毒可進行複製的模式下，比較第一及第二基因型肝炎病毒，發現兩者RNA的複製效率是相當的，但是經過複製過程後才會產生的HDAg-L，其量卻不同，並進一步造成病毒顆粒包裝效率的差異。利用RT-PCR方式分析不同基因型HDV之antigenomic RNA，發現第一基因型HDV之RNA editing效率較第二基因型HDV為好，是造成HDAg-L量不同的原因。
總而言之，在本論文的第一部分製備了具基因型專一性的抗體，並証實其在HDV的流行病學、臨床及分子生物學的研究是相當有價值的。在其他部分，觀察到第一基因型及第二基因型HDV在功能上的差異，可部分解釋在臨床上為何感染第二基因型HDV之病患，其預後通常較感染第一基因型HDV者為好。

Different hepatitis D virus (HDV) genotypes vary in both nucleotide and the encoded hepatitis delta antigen (HDAg) sequences. The significance of these variations is unclear. Previous HDV studies focusing on the most common genotype I have revealed interesting properties of HDAg. The small form HDAg (HDAg-S) activates HDV replication while the large form (HDAg-L) with a C-terminal 19-amino acid extension plays a key role in the assembly of HDV particle by interacting with the helper hepatitis B virus surface antigen (HBsAg). These genotypic differences of HDAg-L scatter along the entire sequences, but two major regions could be identified. One located at the N-terminal residues 3-40 has a 45-50% amino acid difference and overlaps with the coiled-coil domain critical for the HDAg oligomerization. The second located at the C-terminus (residues 196-214) has an amino acid sequence divergence up to 74%.
In this study, we have used several different approaches to examine the differences of HDAg between genotypes I and II. (1) Peptides covering the carboxyl-terminal 19 amino acids of HDAg-L were used as immunogens to generate genotype-specific antibodies. These antibodies were proven to be useful in immunohistochemical differentiation of HDV genotypes in liver biopsies. (2) In a cDNA transfection system, two antigens were co-expressed in HuH-7 cells and followed by specific antibody precipitation. HDAgs of different origins were found to interact with each other without genotypic discrimination. (3) The assembling efficiency of virus particle by HDAg-L (in the presence of HBsAg) varied among isolates and genotypes. The genotype II HDAg-L tended to assemble viral particles less efficiently. (4) A comparative analysis of HDV replication between genotypes I and II revealed that the HDV RNA replications of these two genotypes are similar, but vary in HDAg-L production. An RT-PCR based assay demonstrated that genotype I antigenomic HDV RNA was more efficienctly edited than genotype II.
In summary, the specific antibodies produced in the first part are valuable in epidemiological, clinical and molecular study of HDV. The functional differences between genotypes I and II HDV may explain, at least in part, why genotype II HDV infection is less frequently associated with poor clinical outcomes.

封面
目次
縮寫
中文摘要
英文摘要(Abstract)
緒言
壹、Ｄ型肝炎病毒之背景介紹
一、ＨＤＶ病毒顆粒的組成
二、ＨＤＶ基因體的特性
1.基因體的結構及複製
2.RNA polymerase II的角色
3.RNA editing
三、D型肝炎病毒抗原(HDAg)的結構及功能
1.Coil-coiled結構
2.核集訊號(NLS)
3.RNA結合區域
4.HDAg與RNA polymerase II結合區域
5.HDAgs於ＨＤＶ複製的重要性
6.其他結構及功能
7.HDAgs於HDV複製的重要性
四、病毒顆粒的包裝
五、ＨＤＶ的變異及臨床表徵
貳、研究動機與重點
材料與方法
壹、實驗材料
一、菌株
二、細菌培養液與培養基
三、細胞株
四、細胞培養液
五、引子(Primer)
六、質體
1.HDAg的表現質體
2.構築chimeric HDAg
3.構築進行HDV基因組複製的質體
4.表現Ｂ型肝炎病毒表面抗原於真核細胞之質體
七、抗體
八、勝任細包之製備溶液
九、質體抽取溶液
十、ＳＤＡ－ＰＡＧE配製溶液
十一、西戶墨點法(Western blotting)
十二、細胞轉染(Transfection)試液及緩衝液
十三、Epitope mapping所需試液
貳、實驗方法
一、接合反應
二、勝任細胞之製備與大腸桿菌之轉型
三、質體之抽取
四、雙股ＤＮＡ模板的變性與核酸定序
五、聚合酵素連鎖反應(PCR)
六、免疫源的製備
七、多源抗體之製備
八、細胞轉染
九、SDS聚丙烯醯氨凝膠電泳(SDS-PAGE)
十、西方點墨法(Western blotting)
十一、免疫沈澱法(Immunoprecipitation)
十二、間接免疫螢光法(Indirect immunofluorescence staining)
十三、肝臟切片染色
十四、抗原決定位的mapping
十五、HDV病毒顆粒的純化
十六、細胞內RNA的抽取
十七、病毒顆粒RNA的抽取
十八、北方墨點法(Northern blotting)
十九、32p-DNA探針的製備
二十、雜交反應(Hybridization)
二十一、RNA editing分析
第一章、免疫組織化學法區分不同基因型之Ｄ型肝炎病毒
壹、前言
貳、結果
一、抗體的專一性
二、評估抗體之交互反應
三、HDAg-L在細胞內的表現和位置
參、討論
第二章、第一、二基因型HDAgs間的交互作用
壹、前言
貳、結果
一、HDAg-L和HDAg-S間複合物的形成
二、不同基因型間HDAg-L複合物之形成
三、不同基因型間HDAg-S複合物之形成
四、HDAg-S與HDAg-L共同包裝於病毒顆粒無基因型限制
參、討論
第三章、第一、二基因型HDV之病毒包裝與RNA editing效率
壹、前言
貳、結果
一、第一、二基因型HDV之病毒包裝的效率不同
二、決定基因型間病毒顆粒包裝效率差異之HDAg-L區域
三、HDAg-L、HDAg-S和HBsAg共同組成的病毒顆粒於基因型的差別
四、HDV進行複製的模式下觀察基因型間的不同
五、第一、二基因型HDV於RNA editing的差異
參、討論
綜合討論
參考文獻
圖表
圖一、第一、二基因型HDAg-L的胺基酸序列比對
圖二、經由西方點墨法顯示抗T1C和T2C抗體在HDV基因型的專一性
圖三、利用M13 phage表現peptides分析抗體的抗原決定位
圖四、抗T1C和抗T2C抗體於免疫螢光法分析HDAg-L的專一性
圖五、利用抗T1C和抗T2C抗體對肝臟切片作免疫組織化學染色
圖六、第一、二基因型間HDAg-L與HDAg-S的相互作用
圖七、不同基因型間HDAg-L的相互作用
圖八、不同基因型間HDAg-S的相互作用
圖九、HDAg-L與不同基因型HDAg-S的類病毒顆粒包裝
圖十、不同基因型之HDAg-L在包裝類病毒顆粒效率的差異
圖十一、Chimeric HDAg-L共同組合VLPs不影響基因型間的差異
圖十二、HDAg-S與HDAg-L共同組合VLPs不影響基因型間的差異
圖十三、第一、二基因型HDV於HuH-7細胞之複製與產生HDAgs的情形
圖十四、第一、二基因型HDV於HuH-7細胞複製時產生VLPs的差異
圖十五、第一、二基因型HDV於細包複製時的RNA editing效率
附錄
附錄圖一、D型肝炎病毒顆粒模型
附錄圖二、HDV基因體之雙滾圈複製
附錄圖三、HDV基因體之editing過程
附圖四、HDAg的功能性結構示意圖
附錄五、不同基因型HDV的地理性分佈
附錄圖六、不同基因型HDAg-L的胺基酸序列心對
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