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研究生：	蔡偉蓁 Tsai, Wei-chen
論文名稱：	以培養細胞評估直接抗Ｃ型肝炎病毒藥物治療對載脂蛋白之變化 Cultivated cell-based evaluation of apolipoproteins changes with the treatment of direct-acting antiviral agents against hepatitis C virus
指導教授：	楊孔嘉 Young, Kung-Chia
學位類別：	碩士 Master
系所名稱：	醫學院 - 醫學檢驗生物技術學系 Department of Medical Laboratory Science and Biotechnology
論文出版年：	2016
畢業學年度：	104
語文別：	英文
論文頁數：	85
中文關鍵詞：	直接抗病毒藥物、細胞培養評估、載脂蛋白
外文關鍵詞：	direct-acting antiviral agents, cultivated cell-based evaluation, apolipoprotein
相關次數：	點閱：142 下載：2
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Ｃ型肝炎病毒目前已知造成全球超過180萬人慢性感染，此外它本身是一種對脂肪有偏好的病毒，在整個病毒的生命週期中與宿主的脂肪代謝有著很重要的關聯。Ｃ型肝炎病毒不只會造成肝臟方面的疾病，還有低脂血症與低膽固醇血症。自從2013年，一種高效率的直接抗病毒藥物sofosbuvir與加入peg-IFN(PEG)/Ribavirin(RBV) 的治療方式被啟用，在文獻中指出此種治療方式與原本單純使用PEG/RBV 的治療方式在被第一基因型的Ｃ型肝炎慢性感染病人身上可以得到良好的治療效果，其SVR大於90 百分比。在之前已經有研究，直接抗病毒藥物在治療Ｃ型肝炎病毒的病人體內的脂肪與脂蛋白研究。儘管研究顯示直接抗病毒藥物可以反轉脂肪與脂蛋白在病人體內惡化的情形，但是載脂蛋白在直接抗病毒藥物的研究卻仍然是未知的，尤其載脂蛋白對於脂蛋白代謝和病毒本身的複製與包過這方面扮演的即為重要的角色。本篇目的在於使用細胞培養方式，研究直接抗病毒藥物在治療病毒感染的過程中載脂蛋白的變化。為了去研究藥物濃度與加入時間對於抗病毒藥物在載脂蛋白上變化的影響，細胞使用五種方式去加入藥物，分別是：感染前，感染中，感染後（零小時、兩小時、四小時）。實驗結果顯示，直接抗病毒藥物本身卻是會抑制病毒蛋白的表現，而在量化的結果也發現不同的病毒蛋白其穩定性也不相同。此外，結果也表示，在四種藥物 sofosbuvir, daclatasvir、ledpasvir與MK-5172 可以回復Huh7.5-SEAP細胞內與分泌出細胞外的載脂蛋白Ａ-1 (apoA-1)與載脂蛋白B-100 (apoB-100)，而這個結果也表示載脂蛋白的變化可能反映了在直接抗病毒藥物治療後，慢性Ｃ型肝炎感染的病然體內的脂肪與脂蛋白的變化。

Hepatitis C virus (HCV), chronically infects over 180-million individuals worldwide, is a lipid-preferring virus for its lifecycle being closely connected with the host lipid metabolism. Chronic HCV infection causes not only liver disease, but exhibits dyslipidemia and low circulating cholesterol. Since 2013, a high-efficacy DAA, sofosbuvir, plus peg-IFN(PEG)/Ribavirin(RBV) was compared to PEG/RBV in genotype-1 HCV patients reached over 90% SVR. Previously, the DAAs-mediated changes of the lipids and lipoproteins in HCV-infected patients had been studied. However, its results indicated the DAAs might reverse the deteriorated changes of the lipids and lipoproteins in HCV-infected patients, the details of apolipoproteins, which play essential roles in lipoprotein metabolism and HCV replication/assembly still remained unclear. We aimed to evaluate apolipoproteins in DAAs-treated Huh7.5-based cell line, which infected by HCVcc. To determinate the dosage-kinetic effects of DAAs on major apolipoproteins by examining their expression levels, the cells were treated with DAAs in pre-, co-, and post-infections (P.I.= 0hr, 2hr, 4hr). The DAAs inhibition in HCV activity was analyzed of HCV viral proteins expression, showing distinct stability of HCV viral proteins with treatment. Furthermore, the results showed that the sofosbuvir, daclatasvir, and ledpasvir had ability of restoring intracellular and secreted apolipoprotein A-1 (apoA-1) and apolipoprotein B-100 (apoB-100) in Huh-7.5 cell lines. The results of evaluation of apolipoproteins may reflect the reversible changes of lipid and lipoprotein profiles in chronic hepatitis C patients receiving DAAs treatment.

Chinese abstract I
Abstract II 
Acknowledgement III 
Index IV 
Tables and Figures Index VIII 
Abbreviations IX 
Reagents and Instruments XI 
Chapter 1: Introduction 1
Hepatitis C virus (HCV) 2
1 Hepatitis C virus 2 
2 HCV life cycle- attachment and entry 2 
3 HCV life cycle- translation and replication 3 
4 HCV life cycle- assembly and release 4 
5 HCV causes the diseases, which is not only occur in liver 4 
Lipoprotein 5 
1 lipoproteins structure 5 
2 lipoprotein function 6 
3 Lipoproteins impact HCV life cycle 7
Apolipoproteins 8 -----------
1 Apolipoproteins 8 
2 Apolipoproteins play crucial role in lipid and lipoproteins metabolism 8
3 Apolipoproteins and HCV 9
Direct-acting antiviral agents (DAAs) 11
1 DAAs and it treatments until now 11 
2 Sofosbuvir (PSI-7977) 12 
3 Daclastavir (BMS-790052) 12 
4 Ledipasvir (GS-5885) 13 
5 Grazoprevir (MK-5172) 13 
6 lipoprotein profile of HCV treatment in clinical research 14 
Study goal 14 
Chapter 2 : Materials and methods 15 
Cell culture 17 
1 Huh7.5-SEAP cell line 17 
2 cell culture system 17 
3 Preparation of frozen cells 18
4 Defrozen cells 20 
Infection Huh7.5-SEAP cells with HCVcc 20 
1 subculture cells in 24 well high binding plates 20 
2 infected Huh7.5-SEAP cells with HCVcc and treatments of DAAs 21 
3 treatments of DAAs prepare 22 
Western blot 22 
1 sample proteins concentration determination 22 
2 sample preparation 23 
3 Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) 24 
4 Proteins transfer and blotting 25 
SEAP activity 26 
1 principle of SEAP activity 26 
2 sample preparation 26 
MTS assay 27 
1 sample preparation 27 
HCV purification 28 
1 Virus collection and J15 cell line keeping 28 
2 virus precipitating and purification 29 
3 virus titer determinate(IFA) 30 
4 virus titer determinate(TCID50) 31 
Chapter 3 : Results 32 
Screening IC50 of direct Acting antiviral agents in Huh7.5-SEAP system 33 
The cell viability in high dosages of direct acting antiviral agents treatments. 33
The DAAs showed the anti-viral activity in five treatments 34 
PSI-7977, a HCV NS5B inhibitor, inhibited the HCV viral proteins expression 34 
BMS-790052, a HCV NS5A inhibitor, inhibited the HCV viral proteins expression 35 
GS5885, a HCV NS5A inhibitor, inhibited the HCV viral proteins expression 35 
MK-5172, a HCV NS3/4A inhibitor, inhibited the HCV viral proteins expression 36 
PSI-7977 reversed the evaluation of apolipoproteins, caused by HCV infection 36 
BMS-790052 reversed the evaluation of apolipoproteins, caused by HCV infection 37
GS-5885 reversed the evaluation of apolipoproteins, caused by HCV infection 38 
MK-5172 reversed the evaluation of apolipoproteins, caused by HCV infection 38 
Chapter 4 : Discussion 39 
Could we use the SEAP system to monitor the viral activity and screen for IC50 ? 40
The apolipoproteins play important role in HCV life cycle and could be used as the
biomarker for treatments of DAAs 41 
Were the difference of viral proteins reduction cause by the proteins itself or drug target? 43 
Conclusion: 44 
References 45 
Tables And Figures 58
                                    

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