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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 張淑媛(Sui-Yuan Chang) | |
| dc.contributor.author | Yi-Ting Chen | en |
| dc.contributor.author | 陳怡婷 | zh_TW |
| dc.date.accessioned | 2021-06-08T03:29:57Z | - |
| dc.date.copyright | 2019-08-27 | |
| dc.date.issued | 2019 | |
| dc.date.submitted | 2019-08-15 | |
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Emiliani, S., et al., Integrase mutants defective for interaction with LEDGF/p75 are impaired in chromosome tethering and HIV-1 replication. J Biol Chem, 2005. 280(27): p. 25517-23. 70. Bhatia, A.K., et al., Characterization of replication defects induced by mutations in the basic domain and C-terminus of HIV-1 matrix. Virology, 2007. 369(1): p. 47-54. 71. Ludwig, C., A. Leiherer, and R. Wagner, Importance of protease cleavage sites within and flanking human immunodeficiency virus type 1 transframe protein p6* for spatiotemporal regulation of protease activation. J Virol, 2008. 82(9): p. 4573-84. 72. Le Rouzic, E. and S. Benichou, The Vpr protein from HIV-1: distinct roles along the viral life cycle. Retrovirology, 2005. 2: p. 11. 73. Sharma, S., et al., PTAP motif duplication in the p6 Gag protein confers a replication advantage on HIV-1 subtype C. J Biol Chem, 2018. 293(30): p. 11687-11708. 74. Martins, A.N., et al., Accumulation of P(T/S)AP late domain duplications in HIV type 1 subtypes B, C, and F derived from individuals failing ARV therapy and ARV drug-naive patients. AIDS Res Hum Retroviruses, 2011. 27(6): p. 687-92. 75. Peters, S., et al., Resistance to nucleoside analog reverse transcriptase inhibitors mediated by human immunodeficiency virus type 1 p6 protein. J Virol, 2001. 75(20): p. 9644-53. 76. Holguin, A., A. Alvarez, and V. Soriano, Differences in the length of gag proteins among different HIV type 1 subtypes. AIDS Res Hum Retroviruses, 2005. 21(10): p. 886-93. 77. Cohen, M.S., et al., Acute HIV-1 Infection. N Engl J Med, 2011. 364(20): p. 1943-54. 78. Dam, E., et al., Gag mutations strongly contribute to HIV-1 resistance to protease inhibitors in highly drug-experienced patients besides compensating for fitness loss. PLoS Pathog, 2009. 5(3): p. e1000345. 79. Kozisek, M., et al., Mutations in HIV-1 gag and pol compensate for the loss of viral fitness caused by a highly mutated protease. Antimicrob Agents Chemother, 2012. 56(8): p. 4320-30. 80. Martins, A.N., et al., Elucidation of the Molecular Mechanism Driving Duplication of the HIV-1 PTAP Late Domain. J Virol, 2016. 90(2): p. 768-79. 81. HIV Drug Resistance Database - Stanford University. Available from: https://hivdb.stanford.edu/. 82. Zdanowicz, M.M., The pharmacology of HIV drug resistance. Am J Pharm Educ, 2006. 70(5): p. 100. 83. Aralaguppe, S.G., et al., Increased replication capacity following evolution of PYxE insertion in Gag-p6 is associated with enhanced virulence in HIV-1 subtype C from East Africa. J Med Virol, 2017. 89(1): p. 106-111. 84. de Silva, S., V. Planelles, and L. Wu, Differential effects of Vpr on single-cycle and spreading HIV-1 infections in CD4+ T-cells and dendritic cells. PLoS One, 2012. 7(5): p. e35385. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/21271 | - |
| dc.description.abstract | 第一型人類免疫缺乏病毒（HIV-1）的組裝與釋出由其結構蛋白Gag所主導。Gag之組成由N端依序為基質蛋白（Matrix, p17）、衣殼蛋白（Capsid, p24）、核蛋白殼（Nucleocapsid, p7）以及C端的p6蛋白。病毒之出芽需藉由p6蛋白的late domain召集細胞內之內吞體分選轉運複合體(Endosomal-sorting complex required for transport, ESCRT)來進行。p6蛋白亦於病毒組裝時結合Vpr蛋白，並將其帶入病毒顆粒內，以利進一步的病毒複製。p6蛋白基因的變異性相對高，在實驗室過去所收集的HIV-1臨床病毒樣本中，可於p6區域發現許多胺基酸的插入（Insertion）變異。這些變異是否會如先前本實驗室發現在p6有七個胺基酸刪除（30-36）的重組型CRF07_BC，會造成病毒釋出效率及生長較差的現象目前仍不清楚。
本研究針對2013年至2018年共2086個來自臨床之HIV-1 p6蛋白基因樣本之胺基酸序列進行分析，並統計最常見之插入胺基酸模式。統計結果發現最常見的插入位置為鄰近late domain的P11，其中佔最多數的插入胺基酸序列為APP （304/586, 51.9%）與EPSAPP（63/586, 10.8%）。首先以演化樹分析確認感染此兩種病毒病人並非由單一來源傳播，接著進一步分析發現感染此兩種病毒之病人族群基礎點的血漿病毒量較高。為了進一步了解這些胺基酸插入對於病毒複製的影響，我們建構重組病毒株，並分析其表型。帶有APP與EPSAPP插入的病毒分別命名為Ins3與Ins6。實驗結果顯示Ins6病毒生長能力較原生型（WT）佳；而病毒蛋白表現部分，透過分析結構蛋白Gag的切割，所得之切割效率（processing efficiency）與相對釋放係數（relative releasing factor）皆與WT沒有差異，也確認病毒蛋白酶表現量亦無差異。最後發現Ins6病毒顆粒的Vpr含量較高，可能藉此促進病毒複製功能。最後也進行藥物感受性分析，結果顯示帶有插入胺基酸之病毒對LPV、EFV、FTC和DTG等藥物的感受性較差。 | zh_TW |
| dc.description.abstract | The assembly of human immunodeficiency virus type 1(HIV-1) virus is driven by the Gag precursor Pr55Gag, which is composed of matrix (MA), capsid (CA), nucleocapsid (NC), and p6Gag protein. Virus budding is facilitated by p6Gag protein through recruiting endosomal sorting complex required for transport (ESCRT) machinery of host cells. The p6Gag protein can also help to recruit the accessory protein Vpr into virus particles. The genetic sequence of p6Gag is quite polymorphic, and amino acid-insertions in p6Gag have been observed in our clinical samples. However, whether these polymorphisms could contribute to phenotypic changes similar to our previously reported 7-amino acid deletion in p6Gag of CRF07_BC remains unclear.
The study aimed to analyze the amino acid insertion patterns of p6Gag among 2086 clinical HIV-1 samples collected from 2013 to 2018, and further investigate whether there are phenotypic changes due to the genetic variations. We found the most common insertion site are located at P11, which is located beside one of the late domains, and the most frequent observed insertion patterns are 3-amino acid insertion APP (304/586, 51.9%) and 6-amino acid insertion EPSAPP (63/586, 10.8%). Phylogenetic analysis was conducted to exclude the potential spreading of a single source virus for the observed insertion patterns. Those patients who infected with APP-insertion or EPSAPP-insertion virus tend to have higher baseline plasma viral load. To further characterize the phenotypes of viruses with APP-insertion or EPSAPP-insertion, recombinant virus clones were constructed and the respective clones were named as Ins3 and Ins6, respectively. The Ins3 and Ins6 viruses demonstrated greater growth capacity than wild type. However, Gag processing analysis showed no significant difference of relative releasing factor as well as processing efficiency between these two mutant viruses and WT; expression levels of protease was also similar. Interestingly, we found Ins6 virus incorporated more Vpr than WT, which might contribute to the increased replication capacity. Finally, the drug susceptibility of these mutatnt viruses was determined and viruses with insertion showed reduced susceptibility to LPV, EFV, FTC and DTG. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T03:29:57Z (GMT). No. of bitstreams: 1 ntu-108-R06424006-1.pdf: 2953380 bytes, checksum: a82e12a4af1374ae1053a0b1f13ec861 (MD5) Previous issue date: 2019 | en |
| dc.description.tableofcontents | 致謝 I
中文摘要 II 英文摘要 III 目錄 V 圖目錄 IX 表目錄 X 附錄 XI 第一章 緒論 1 1.1 人類免疫缺陷病毒（HIV-1）與後天免疫缺乏症候群（AIDS） 1 1.1.1 HIV-1傳染途徑與致病機制簡介 1 1.1.2 流行現況 1 1.1.3 HIV-1病毒基因及構造簡介 2 1.2 HIV-1病毒之組裝（Assembly）及出芽（Budding） 2 1.2.1 病毒組裝（Assembly）與出芽（Budding）簡介 2 1.2.2 病毒組裝（Assembly）與Gag前驅蛋白（Pr55） 4 1.2.3 病毒出芽（Budding）與內吞體分選轉運複合體（ESCRT） 5 1.3 HIV-1 p6蛋白 6 1.3.1 p6蛋白與病毒出芽（Budding） 6 1.3.2 p6蛋白之結構 8 1.3.3 p6蛋白之功能 9 1.3.4 p6蛋白之基因多型性 10 1.4 HIV-1之基因多型性 11 1.4.1 HIV-1之基因多型性成因 11 1.4.2 HIV-1基因多型性對病毒表型（Phenotype）之影響 12 1.5 研究動機 13 第二章 實驗材料與方法 14 2.1 實驗材料 14 2.1.1 細胞 14 2.1.2 商業試劑套組 14 2.1.3 抗體 15 2.2 實驗方法 15 2.2.1 定位突變實驗（Site-directed mutagenesis） 15 2.2.2 轉型作用（Transformation） 16 2.2.3 小量細菌質體萃取（Mini plasmid extraction） 16 2.2.4 大量細菌質體萃取（Maxi plasmid extraction） 17 2.2.5 限制酶切割（Restriction enzyme digestion） 17 2.2.6 製備結晶紫（crystal violet）洋菜膠與電泳 18 2.2.7 洋菜膠萃取DNA片段（DNA gel purification） 18 2.2.8 T4 DNA連接酶反應（T4 DNA ligase ligation） 19 2.2.9 293T 細胞株培養 19 2.2.10 轉染作用（Transfection） 19 2.2.11 蔗糖梯度超高速離心（Sucrose gradient ultracentrifugation） 20 2.2.12 蛋白質電泳（SDS-polyacrylamide gel electrophoresis, SDS-PAGE） 20 2.2.13 西方墨點法（Western blot） 21 2.2.14 周邊血液單核細胞分離培養（PBMC purification） 22 2.2.15 p24酵素結合免疫吸附分析（p24 enzyme-linked immunosorbent assay, ELISA） 22 2.2.16 周邊血液單核細胞感染實驗（PBMC infection） 23 2.2.17 病毒RNA萃取（RNA extraction） 23 2.2.18 單步驟即時定量聚合酶連鎖反應（One-step real-time PCR） 24 2.2.19 RNA反轉錄反應（Reverse Transcription） 24 2.2.20 HIV-1 B亞型病毒Gag基因巢式聚合酶連鎖反應（Nested PCR） 24 2.2.21 統計方法與分析軟體 25 第三章 實驗結果 26 3.1 臨床檢體HIV-1 p6序列分析 26 3.1.1 2013-2018臨床檢體基本資料 26 3.1.2 2013-2018臨床HIV-1 p6蛋白序列插入位置與胺基酸序列分析 26 3.2 帶有p6 Ins 3與Ins 6 HIV-1之病人 28 3.2.1 感染p6 Ins 3與Ins 6 HIV-1病人基本資料 28 3.2.2 帶有p6 Ins 3與Ins 6 HIV-1序列演化樹分析 28 3.3 帶有p6 Ins 3與Ins 6之HXB2質體建構 29 3.4 帶有p6 Ins 3與Ins 6之病毒於人類周邊血單核細胞之生長能力 30 3.5 造成p6 Ins 6之病毒生長能力差異原因探討 30 3.5.1 Gag前驅蛋白切割與病毒釋出 31 3.5.2 病毒蛋白酶（Protease）表現量 31 3.5.3 病毒Vpr蛋白表現量 32 3.5.4 p6Gag蛋白結構預測 33 3.6 帶有p6 Ins 3與Ins 6之病毒對藥物感受性 33 第四章 實驗討論 35 第五章 參考文獻 63 | |
| dc.language.iso | zh-TW | |
| dc.title | 第一型人類免疫缺乏病毒於p6蛋白PTAP具插入胺基酸之功能探討 | zh_TW |
| dc.title | Functional characterization of HIV-1 with insertions near the p6 PTAP motif | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 107-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 高全良(Chuan-Liang Kao),林靜宜(Ching-Yi Lin) | |
| dc.subject.keyword | p6蛋白,PTAP motif 重複,Vpr, | zh_TW |
| dc.subject.keyword | p6 protein,PTAP motif duplication,Vpr, | en |
| dc.relation.page | 71 | |
| dc.identifier.doi | 10.6342/NTU201903664 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2019-08-15 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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| ntu-108-1.pdf 未授權公開取用 | 2.88 MB | Adobe PDF |
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