臺灣博碩士論文加值系統

中文摘要
C型肝炎病毒是造成非A非B型肝炎最重要的傳染源之一，目前治療C型肝炎的方法是以干擾素合併ribavirin，但只有對不到50%的病患有效。C型肝炎病毒的感染，通常會造成50-80%的患者變成慢性肝炎，在一段時間後其中30%左右的人即演變成肝硬化甚至肝癌。由於目前C型肝炎還無法有效治療，針對C型肝炎病毒致病及慢性感染機制的了解是非常重要的。
HCV的核心蛋白主要功能是當作核殼，用來包裹病毒的RNA，但近來發現它也具有調控宿主細胞內基因的表現以及促使細胞轉形、影響細胞凋亡反應等的能力，被認為是一個多功能的蛋白質。其中細胞凋亡是宿主本身遇到病毒感染時的一種免疫清除能力的表現，也因此核心蛋白極有可能是造成C型肝炎病毒持續性感染的重要因子之一。
本論文探討核心蛋白在宿主細胞對於細胞凋亡反應產生的影響，主要針對TNF-superfamily中之細胞凋亡誘導物及細胞凋亡中間反應物加以研究。實驗中使用HuH-7-7及HepG2這兩種人類肝癌細胞株。結果顯示，在含有核心蛋白的HuH-7細胞株中，經過α-Fas、TNF-α、TRAIL這些誘導物處理時均會促進引發細胞凋亡反應，其中α-Fas所引起的凋亡反應最微弱，其餘二種誘導物所引起之細胞凋亡則有明顯被促進的趨勢;而在HepG2細胞中則看不到這種對誘導物敏感的反應。進一步分析其內部發生細胞凋亡之相關caspase的活化狀況，推測核心蛋白所致敏之TNF-α、TRAIL pahthway應是不經粒線體那邊的type II路徑。而在觀察細胞凋亡中間反應物如FADD、FLIP、FLICE的總表現量時，發現三者無論核心蛋白存在與否皆不改變，此結果暗示在HuH-7細胞的凋亡反應受到核心蛋白影響的層次可能是在上游，且是影響其活化過程的產生，而不是量上面的改變。但此推論還需要進一步設計實驗加以證實，並尋找出實際與核心蛋白反應之分子，以便更瞭解C型肝炎的致病機轉及找出防治、治療之道。

Absctract
Hepatitis C virus (HCV) is the major causative agent of non-A, non-B hepatitis. Alfa interferon (IFN-α) and ribavirin combination therapy is currently the only effective therapy for hepatitis C. However, it only works on less than 50% of the patients. HCV infection often causes persistence in 50-80% of the patitients, 30% of them will eventually progress to cirrhosis and hepatocellular carcinoma. Therefore, it’s important to understand the mechanisms of the pathogenesis and chronicity of HCV infection.
The major function of HCV core protein is to serve as a component of nucleocapsid. However, it has been demonstrated that HCV core protein could regulate gene expression of host cell, induce cell transformation, and influence cell apoptosis. Apoptosis represents one of the abilities of host immunities to clear virus. So, core protein may be an important factor participating in the process of HCV persistent infection.
We evaluated the effects of HCV core protein on the apoptosis induced by the apoptotic inducing agents from TNF-superfamily. Two hepatima cell lines, HuH-7 and HepG2, were used. It was found that HCV core protein sensitized the HuH-7 cells to the α-Fas-, TNF-α-, and TRAIL-mediated apoptosis. The sensitization is less obvious in the α-Fas-induced apoptosis, but much more significant in the TNFα- or TRAIL-induced apoptosis. However, the phenomenon was not observed in core-expression HepG2 cells. Analysis of caspase activities in the apoptotic cells indicated that both caspase 8 and 3, but not caspase 9, activities were enhanced, thus excluding the possibility that the apoptosis is through the mitochondria-mediated pathway. Further Western blot analysis for the expression of FADD, FLICE, and FLIP indicated that the core protein did not affect the levels of these molecules. These results may suggest the HCV core protein sensitize the HuH-7 cells to the TNFα-or TRAIL-mediated apoptosis by enhancing the activation of the apoptosis-related complexes.

目 錄
目錄 頁碼
中文摘要………………………………………………………………... i
英文摘要………………………………………………………………… ii
壹、 緒論…………………………………………………….………..… 1
一、 C型肝炎
二、 C型肝炎病毒
三、 C型肝炎病毒的各蛋白產物
四、 細胞凋亡的簡介
五、 研究方向及目的
貳、 材料與方法……………………………………………………..… 12
一、 穩定細胞株(stable cell line)的細胞凋亡反應實驗
二、 表現HCV核心蛋白的重組腺病毒(Adenovirus)大量製備
及感染
三、 核心蛋白對T細胞毒殺能力之影響
參、 結果……………………………………………………………..… 19
一、 核心蛋白對不同誘導物引發細胞凋亡之影響
(1) 穩定表現核心蛋白之細胞株內的細胞凋亡反應
(2) 核心蛋白參與之細胞凋亡路徑的探討
二、 利用重組腺病毒載體製備核心蛋白表現細胞株及分析其
對細胞凋亡的反應
(1) 重組腺病毒的製備
(2) 細胞凋亡的誘導
三、 核心蛋白對毒殺性T細胞之毒殺能力的影響
肆、 討論……………………………………………………………..… 29
一、 核心蛋白對TNF-superfamily這類誘導物所引發之細胞凋
亡反應之影響
二、 腺病毒之製備及感染
三、 核心蛋白影響T細胞毒殺能力
伍、 圖及表…………………………………………………………..… 35
陸、 參考文獻………………………………………………………..… 53
柒、 附錄……………………………………………………………….. 63

陸、參考文獻
Ali, N., and Siddiqui, A. (1995). Interaction of polypyrimidine tract-binding protein with the 5' noncoding region of the hepatitis C virus RNA genome and its functional requirement in internal initiation of translation. J Virol 69, 6367-75.
Ali, N., and Siddiqui, A. (1997). The La antigen binds 5' noncoding region of the hepatitis C virus RNA in the context of the initiator AUG codon and stimulates internal ribosome entry site-mediated translation. Proc Natl Acad Sci USA 94, 2249-54.
Asabe, S. I., Tanji, Y., Satoh, S., Kaneko, T., Kimura, K., and Shimotohno, K. (1997). THe N-terminal region of hepatitis C virus-encoded NS5A is important for NS4A-dependent phosphorylation. J Virol 71, 790-6.
Barba, G., Harper, F., Kohara, M., Goulinet, S., Matsuura, Y., Eder, G., Schaff, Z., Chapman, M. J., Miyamura, T., and Brechot, C. (1997). Hepatitis C virus core protein shows a cytoplasmic localization and association to cellular lipid storage droplet. PNAS 94, 1200-1205.
Bartenschlager, R., Ahlborn-Laake, L., Mous, J., and Jacobsen, H. (1994). Kinetic and structural analyses of hepatitis C virus polyprotein processing. J Virol 68, 5045-55.
Bukh, J., Miller, R. H., and Purcell, R. H. (1995). Genetic heterogeneity of hepatitis C virus: quasispecies and genotypes. Semin Liver Dis 15.
Bukh, J., Purcell, R. H., and Miller, R. H. (1993). At least 12 genotypes of hepatitis C virus predicted by sequence analysis of the putative E1 gene of isolates collected worldwide. Proc Natl Acad Sci U S A 90, 8234-8238.
Chamberlain, R. W., Adams, N., Saeed, A. A., Simmonds, P., and Elliott, R. M. (1997). Complete nucleotide sequence of a type 4 hepatitis C virus variant, the predominant genotype in the Middle East. J Gen Virol 78, 1341-7.
Chang, S. C., Yen, J. H., Kang, H. Y., Jang, M. H., and Cnahg, M. F. (1994). Nuclear localization signals in the core protein of hepatitis C virus. Biochem Biophys Res Commun 205.
Chen, C., You, L., Hwang, L., and Lee, Y. (1997). Direct interaction of hepatitis C virus core protein with the cellular lymphotoxin-beta receptor modulates the signal pathway of the lymphotoxin-beta receptor. J. Virol. 71, 9417-9426.
Choo, Q. L., Kuo, G., Weiner, A. J., Overby, L. R., Bradley, D. W., and Houghton, M. (1990). Hepatitis C virus : the majou causative agent of viral non-A,non-B hepatitis. Br. Med. Bull. 46, 423-442.
Choo, Q. L., Kuo, G., Weiner, A. J., Overby, L. R., Bradley, D. W., and houghton, M. (1989). Isolation of a c-DNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244, 359-362.
Chu, C. M., Yeh, C. T., and Liaw, Y. F. (1999). Fulminant hepatic failure in acute hepatitis C: increased risk in chronic carriers of hepatitis B virus. Gut 45, 613-7.
Denecker, G., Vercammen, D., Declercq, W., and Vandenabeele, P. (2001). Apoptotic and necrotic cell death induced by death domain receptors. Cellular and Molecular Life Sciences 58, 356-370.
Eckart, M. R., Selby, M., Masiarz, F., Lee, C., Berger, K., Crawford, K., Kuo, C., Kuo, G., Houghton, M., and Choo, Q. L. (1993). The hepatitis C virus encodes a serine protease involved in processing of the putative nonstructural proteins from the viral polyprotein precursor. Biochem Biophys Res Commun 192, 399-406.
Failla, C., Tomei, L., and De Francesco, R. (1994). Both NS3 and NS4A are required for proteolytic processing of hepatitis C virus nonstructural proteins. J Virol 68, 3753-60.
Farci, P., Shimoda, A., Wong, D., Cabezon, T., De Gioannis, D., Strazzera, A., Shimizu, Y., Shapiro, M., Alter, H. J., and Purcell, R. H. (1996). Prevention of hepatitis C virus infection in chimpanzees by hyperimmune serum against the hypervariable region 1 of the envelope 2 protein. Proc Natl Acad Sci USA 93, 15394-9.
Fukushi, S., Katayama, K., Kurihara, C., Ishiyama, N., Hoshino, F. B., Ando, T., and Oya, A. (1994). Complete 5' noncoding region is necessary for the efficient internal initiation of hepatitis C virus RNA. Bio Phy Res Commun 199, 425-432.
Fukushi, S., Kurihara, C., Ishiyama, N., Hoshino, F. B., Oya, A., and Katayama, K. (1997). The sequence element of the internal ribosome entry site and a 25-kilodalton cellular protein contribute to efficient internal initiation of translation of hepatitis C virus RNA. J Virol 71, 1662-66.
Gale, M. J., Korth, M. J., Tang, N. M., Tan, S. L., Hopkins, D. A., Dever, T. E., Polyak, S. J., Gretch, D. R., and Katze, M. G. (1997). Evidence that hepatitic C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. virology 230, 217-227.
Gale, M. J., Kwieciszewski, B., Dossett, M., Nakao, H., and Katze, M. G. (1999). Antiapoptotic and oncogenic potentials of hepatitis C virus are linked to interferon resistance by viral repression of the PKR protein kinase. Journal of Virology 73, 6506-6516.
Grakoui, A., McCourt, D. W., Wychowski, C., Feinstone, S. M., and Rice, C. M. (1993). A second hepatitis C virus-encoded proteinase. Proc Natl Acad Sci U S A 90, 10583-7.
Hahm, B., Kim, Y. K., Kim, J. H., Kim, T. Y., and Jang, S. K. (1998). Heterogeneous nuclear ribonucleoprotein L interacts with the 3' border of the internal ribosomal entry site of hepatitis C virus. J Virol 72, 8782-88.
Harada, S., Watanabe, Y., Takeuchi, K., Suzuki, T., Katayama, T., Takebe, Y., Saito, I., and Miyamura, T. (1991). Expression of processed core protein of hepatitis C virus in mammalian cells. J Virol 65, 3075-21.
He, T.-C., Zhou, S., da Costa, L. T., Yu, J., Kinzler, K. W., and Vogelstein, B. (1998). A simplified system for generating recombinant adenoviruses. PNAS 95, 2509-2514.
Hijikata, M., Mizushima, H., Akagi, T., Mori, S., Kakiuchi, N., Kato, N., Tanaka, T., Kimura, K., and Shimotohno, K. (1993). Two distinct proteinase activities required for the processing of a putative nonstructural precursor protein of hepatitis C virus. J Virol 67, 4665-75.
Hijikata, M., Shimizu, Y. K., Kato, H., Iwamoto, A., Shih, J. W., Alter, H. J., Purcell, R. H., and Yoshikura, H. (1993). Equilibrium centrifugation studies of hepatitis C virus : evidence for circulating immune complexes. J Virol 67, 1953-8.
Honda, M., Beard, M. R., Ping, L. H., and Lemon, S. M. (1999). A phylogenetically conserved stem-loop structure at the 5' border of the internal ribosome entry site of hepatitis C virus is required for cap-independent viral translation. J Virol 73, 1165-74.
Honda, M., Beard, M. R., Ping, L.-H., and Lemon, S. M. (1999). A Phylogenetically Conserved Stem-Loop Structure at the 5' Border of the Internal Ribosome Entry Site of Hepatitis C Virus Is Required for Cap-Independent Viral Translation. J. Virol. 73, 1165-1174.
Honda, M., Ping, L. H., Rijnbrand, R. C., Amphlett, E., Clarke, B., Rowlands, D., and Lemon, S. M. (1996). Structural requirements for initiation of translation by internal ribosome entry within genome-length hepatitis C virus RNA. Virology 222.
Hoofnagle, J. H., and di Bisceglie, A. M. (1997). The treatment of chronic viral hepatitis. N Engl J Med 336, 347-56.
Hsieh, T.-Y., Matsumoto, M., Chou, H.-C., Schneider, R., Hwang, S. B., Lee, A. S., and Lai, M. M. C. (1998). Hepatitis C Virus Core Protein Interacts with Heterogeneous Nuclear Ribonucleoprotein K. J. Biol. Chem. 273, 17651-17659.
Hussy, P., Langen, H., Mous, J., and Jacobsen, H. (1996). Hepatitis C virus core protein : carboxy-terminus boundayies of two precessed species sugguest cleavage by a signal peptide peptidase. Virology 224, 93-104.
Hwang, S. B., Park, K. J., Kim, Y. S., Sung, Y. C., and Lai, M. M. (1997). Hepatitis C virus NS5B protein is a membrane-associated phosphoprotein with a predominantly perinuclear localization. Virology 227, 439-46.
Iino, S., Hino, K., and Yasuda, K. (1994). Current state of interferon therapy for chronic hepatitis C. Intervirology 37, 87-100.
Ito, T., and Lai, M. (1997). Determination of the secondary structure of and cellular protein binding to the 3'-untranslated region of the hepatitis C virus RNA genome. J. Virol. 71, 8698-8706.
Ito, T., and Lai, M. M. (1997). Determination of the secondary structure of and cellular protein binding to the 3'-untranslated region of the hepatitis C virus RNA genome. J Virol 71, 8698-8706.
Ito, T., Tahara, S. M., and Lai, M. M. (1998). The 3'-untranslated region of hepatitis C virus RNA enhances translation from an internal ribosomal entry site. J Virol 72, 8789-96.
Kato, N., Ootsuyama, Y., Ohkoshi, S., Nakazawa, T., Sekiya, H., Hijikata, M., and Shimotohno, K. (1992). Characterization of hypervariable regions in the putative envelope protein of hepatitis C virus. Biochem Biophys Res Commun 189, 119-27.
Kim, D. W., Gwck, Y., Han, J. H., and Choe, J. (1995). C-Terminal domain of the hepatitis C virus NS3 protein contains an RNA helicase activity. Biochem Biophys Res Commun 215, 160-6.
Kolykhalov, A. A., Fienstone, S. M., and Rice, C. M. (1996). Identification of highly conserved sequence element of the 3' terminus of hepatitis C virus genome RNA. J Virol 70, 3363-71.
Lai, M. Y., Kao, J. H., Yang, P. M., Chen, P. J., Chan, K. W., Chu, J. S., and Chen, D. S. (1996). Long-term efficacy of ribavirin plus interferon alfa in the treatment of chronic hepatitis C. Gastroenterology 111, 1307-1312.
Lin, C., Pragai, B. M., Grakoui, A., Xu, J., and Rice, C. M. (1994). Hepatitis C virus NS3 serine proteinase: trans-cleavage requirements and processing kinetics. J Virol 68, 8147-57.
Liu, Q., Tackney, C., Bhat, R. A., Prince, A. M., and Zhang, P. (1997). Regulated processing of hepatitis C virus core protein is linked to subcellular localization. J Virol 71, 657-62.
Lo, S. Y., Masiarz, F., Hwang, S. B., Lai, M. M. C., and Ou, J. H. (1995). Differential subcellular localization of hepatitis C virus core gene product. Virology 213, 455-61.
Lo, S. Y., Selby, M., Tong, M., and Ou, J. H. (1994). Comparative studies of the core gene products of two different hepatitis C virus isolates: two alternative forms determined by a single amino acid substitution. Virology 199, 124-31.
Mamiya, N., and Worman, H. J. (1999). Hepatitis C Virus Core Protein Binds to a DEAD Box RNA Helicase. J. Biol. Chem. 274, 15751-15756.
Marcellin, P. (1999). Hepatitis C: the clinical spectrum of the disease. J Hepatol 31, 9-16.
Marusawa, H., Hijikata, M., Chiba, T., and Shimotohno, K. (1999). Hepatitis C Virus Core Protein Inhibits Fas- and Tumor Necrosis Factor Alpha-Mediated Apoptosis via NF-kappa B Activation. J. Virol. 73, 4713-4720.
Matsumoto, M., Hsieh, T., Zhu, N., VanArsdale, T., Hwang, S., Jeng, K., Gorbalenya, A., Lo, S., Ou, J., Ware, C., and Lai, M. (1997). Hepatitis C virus core protein interacts with the cytoplasmic tail of lymphotoxin-beta receptor. J. Virol. 71, 1301-1309.
Merrick, W. C., and Hershey, J. W. B. (1996). . In Translational Control, J. Hershey, M. Mathews and M. Sonenberg, eds. (Cold Spring Harbor, NY.: Cold Spring Harbor Laboratory), pp. 31-70.
Mizushima, H., Hijikata, M., Tanji, Y., Kimura, K., and Shimotohno, K. (1994). Analysis of N-terminal processing of hepatitis C virus nonstructural protein 2. Virology 68, 2731-4.
Moradpour, D., Englert, C., Wakita, T., and Wands, J. R. (1996). Characterization of cell lines allowing tighly regulated expression of hepatitis C virus core protein. Virology 222, 51-63.
Nagata, S. (1997). Apoptosis by death factor. Cell 88, 355-365.
Otsuka, M., Kato, N., Lan, K.-H., Yoshida, H., Kato, J., Goto, T., Shiratori, Y., and Omata, M. (2000). Hepatitis C Virus Core Protein Enhances p53 Function through Augmentation of DNA Binding Affinity and Transcriptional Ability. J. Biol. Chem. 275, 34122-34130.
Owsianka, A. M., and Patel, A. H. (1999). Hepatitis C virus core protein interacts with a human DEAD box protein DDX3. Virology 257, 330-340.
Pestova, T. V., Shatsky, I. N., Fletcher, S. P., Jackson, R. J., and Hellen, C. U. T. (1998). A prokaryotic-like mode of cytoplasmatic eukaryotic ribosome binding to the initiation codon during internal translation of hepatitis C virus and classical swine fever virus RNAs. Genes Dev 12, 67-83.
Polyak, S. J., Paschal, D. M., McArdle, S., Gale, M. J., Moradpour, D., and Gretch, D. R. (1999). Characterization of the effects of hepatitis C virus nonstructural 5A protein expression in human cell lines and on interferon-sensitive virus replication. Hepatology 29, 1262-1271.
Ravaggi, A., Natoli, G., Promi, D., Albertini, A., Levrero, M., and Cariani, E. (1994). Intracellular localization of full-length and truncated hepatitis C virus core protein expressed in mammalian cells. J Hepatol 20, 833-6.
Ray, R. B., Lagging, L. M., Meyer, K., Steele, R., and Ray, R. (1995). Transcriptional regulation of cellular and viral promoters by the hepatitis C virus core protein. Virus Reserch 37, 209-220.
Ray, R. B., Meyer, K., and Ray, R. (1996). Suppression of Apoptotic Cell Death by Hepatitis C Virus Core Protein. Virology 226, 176-182.
Ray, R. B., Steele, R., Meyer, K., and Ray, R. (1998). Hepatitis C virus core protein represses p21WAF/Cip1/Sid1 promoter activity. Gene 208, 331-336.
Ray, R. B., Steele, R., Meyer, K., and Ray, R. (1997). Transcritional repression of p53 promoter by hepatitis C virus core protein. J. Biol. Chem. 272, 10983-10986.
Reynolds, J. E., Kaminski, A., Kettinen, H. J., Carroll, A. R., Rowlands, D. J., and Jackson, R. J. (1995). Unique features of internal initiation of hepatitis C virus RNAtranslation. EMBO J 14, 6010-20.
Rice, C. M. (1996). Flaviviridae: the virus and their replication. In Field viology, B.N.Fields, d. M. Kuipe and P. M. Howley, eds. (New York: Raven press), pp. 931-60.
Rijnbrand, R., and Bredenbeek, P. (1995). Almost the entire 5' non-translated region of hepatitis C virus is required for cap-independent translation. FEBS Lett 365, 115-119.
Ruggieri, A., Harada, T., Matsuura, Y., and Miyamura, T. (1997). Sensitization to Fas-Mediated Apoptosis by Hepatitis C Virus Core Protein. Virology 229, 68-76.
Santolini, E., Migliaccio, G., and La Monica, N. (1994). Biosynthesis and biochemical properties of the hepatitis C virus core protein. J Virol 68, 3631-41.
Santolini, E., Pacini, L., Fipaldini, C., Migliaccio, G., and Monica, N. (1995). The NS2 protein of hepatitis C virus is a transmembrane polypeptide. J Virol 69, 7461-71.
Seeff, L. B., Miller, R. N., Rabkin, C. S., Buskell-Bales, Z., Straley-Eason, K. D., Smoak, B. L., Johnson, L. D., Lee, S. R., and Kaplan, E. L. (2000). 45-year follow-up of hepatitis C virus infection in healthy young adults. Ann Intern Med 132, 105-11.
Shih, C. M., Lo, S. J., Miyamura, T., Chen, S. Y., and Lee, Y. H. W. (1993). Supression of hepatitis B virus Expression and replication by hepatitis C virus core protein in HuH-7 cell. J Virol 67, 5823-32.
Simmonds, P. (2001). 2000 Fleming Lecture. The origin and evolution of hepatitis viruses in humans. J Gen Virol 82, 693-712.
Simmonds, P., Alberti, A., Alter, H. J., Bonino, F., Bradley, D. W., Brechot, C., Brouwer, J. T., Cnah, S. W., Chayama, K., and Chen, D. S. (1994). A proposed system for the nomenclature of hepatitis C viral genotypes [letter]. Hepatology 19, 1321-1324.
Simmonds, P., and Smith, D. B. (1999). Structural constraints on RNA virus evolution. Journal of Virology 73, 5787-5794.
Sizova, D. V., Kolupaeva, V. G., Pestova, T. V., Shatsky, I. N., and Hellen, C. U. T. (1998). Specific interaction of eukaryotic translation initiation factor 3 with the 5'nontranslated regions of hepatitis C virus and classical swine fever virus RNAs. J Virol 72, 4775-82.
Smith, D. B., Mellor, J., Jarvis, L. M., Davidson, F., Kolberg, J., Urdea, M., Yap, P. L., and Simmonds, P. (1995). Variation of the hepatitis C virus 5' non-coding region: implications for secondary structure, virus detection and typing. The International HCV Collaborative Study Group. J Gen Virol 76, 1749-61.
Spaete, R. R., Alexander, D., Rugroden, M. E., Choo, Q. L., Berger, K., Crawford, K., Kuo, C., Leng, S., Lee, C., Ralston, R., Thudirm, K., Tung, J. W., Kuo, G., and Houghton, M. (1992). Characterization of the hepatitis C virus E2/NS1 gene product expressed in mammalian cells. Virology 188, 819-30.
Suzuki, R., Matsuura, Y., Suzuki, T., Ando, A., Chiba, J., Harada, T., Santo, L., and Miyamura, T. (1995). Nuclear localization of the truncated hepatitis C virus core protein with its hydrophobic C terminus deleted. J Gen Virol 76, 53-61.
Tai, C., Chi, W., Chen, D., and Hwang, L. (1996). The helicase activity associated with hepatitis C virus nonstructural protein 3 (NS3). J. Virol. 70, 8477-8484.
Tanaka, T., Kato, N., Cho, M. J., Sugiyama, K., and Shimotohno, K. (1996). Structure of the 3' terminus of the hepatitis C virus genome. J Virol 70, 3307-12.
Tanji, Y., Hijikata, M., Satoh, S., Kaneko, T., and Shimotohno, K. (1995a). Hepatitis C virus-encoded nonstructural protein NS4A has versatile functions in viral protein processing. J Virol 69, 1575-81.
Tanji, Y., Kaneko, T., Satoh, S., and Shimotohno, K. (1995b). Phosphorylation of hepatitis C virus-encoded nonstructural protein NS5A. J Virol 69, 3980-6.
Taylor, D. R., Shi, S. T., Romano, P. R., Barber, G. N., and Lai, M. M. (1999). Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein [see comments]. Science 185, 107-10.
Taylor, D. R., Tian, B., Romano, T. R., Hinnebusch, A. G., Lai, M. M. C., and Mathews, M. B. (2001). Hepatitis C virus envelope protein E2 does not inhibit PKR by simple competition with autophosphorylation sites in the RNA-binding domain. Journal of Virology 75, 1265-1273.
Tewar, M., Telford, W. G., Miller, R. A., and Dixit, V. M. (1995). CrmA, a poxvirus-encoded serpin, inhibits cytotoxic T-lymphocyte-mediated apoptosis. J. Biol. Chem. 270, 22725-22758.
Thornberry, N. A., and Lazebink, Y. (1998). Caspases: enemies within. Science 281, 1312-1316.
Tomei, L., Failla, C., Santolini, E., De Francesco, R., and La Monica, N. (1993). NS3 is a serin protease required for processing of hepatitis C virus polyprotein. J Virol 67, 4017-26.
Tsuchihara, K., Tanaka, T., Hijikata, M., Kuge, S., Toyoda, H., Nomoto, A., Yamamoto, N., and Shimotohno, K. (1997). Specific interaction of polypyrimidine tract-binding protein with the extreme 3'-terminal structure of the hepatitis C virus genome, the 3'X. J Virol 71, 6720-6.
Tsukiyama-Kohara, K., Iizuka, N., Kohara, M., and Nomoto, A. (1992). Internal ribosome entry site within hepatitis C virus RNA. J Virol 66, 1476-83.
Wang, C., Sarnow, P., and Siddiqui, A. (1993). Translation of human hepatitis C virus RNA in cultured cells is mediated by an internal ribosome-binding mechanism. J Virol 67, 3338-44.
Weiner, A. J., Brauer, M. J., Rosenblatt, J., Richman, K. H., Tung, J., Crawford, K., Bonino, F., Saracco, G., Choo, Q. L., and Houghton, M. (1991). Variable and hypervariable domains are found in the regions of HCV corresponding to the flavivirus envelope and NS1 proteins and the pestivirus envelope glycoproteins. Virology 180, 842-8.
Yasui, K., Wakita, T., Tsukiyama-Kohara, K., Funahashi, S. I., Ichikawa, M., Kajita, T., Moradpour, D., Wands, J. R., and Kohara, M. (1998). The native form and maturation process of hepatitis C virus core protein. J Virol 72, 6048-55.
You, L.-R., Chen, C.-M., Yeh, T.-S., Tsai, T.-Y., Mai, R.-T., Lin, C.-H., and Lee, Y.-H. W. (1999). Hepatitis C Virus Core Protein Interacts with Cellular Putative RNA Helicase. J. Virol. 73, 2841-2853.
Zhu, N., Khoshnan, A., Schneider, R., Matsumoto, M., Dennert, G., Ware, C., and Lai, M. M. C. (1998). Hepatitis C Virus Core Protein Binds to the Cytoplasmic Domain of Tumor Necrosis Factor (TNF) Receptor 1nd Enhances TNF-Induced Apoptosis. J. Virol. 72, 3691-3697.