登革病毒(Dengue virus)每年約造成一億人口的感染，其所造成的疾病可以由輕微的登革熱(Dengue fever)到較嚴重的登革出血熱(Dengue haemorrhagic fever)以及登革休克症候群(Dengue shock syndrome) ，甚至死亡。最近的研究指出登革病毒感染會誘發自噬現象(autophagy)，其是一種細胞中的恆定反應，主要負責清除累積於細胞質當中聚集、半衰期長的蛋白，以及一些受損的胞器。登革病毒所引發的自噬現象可以調控脂肪代謝並且加強病毒的複製。然而，對於病毒本身以及病毒NS1蛋白在登革病毒誘發的自噬現象中是否有所影響，以及是否在活體中登革病毒也可以誘發自噬現象是我們所想探討的。我們的研究利用質體ptfLC3 (tandem fluorescent-tagged microtubule-associated protein 1 light chain 3)以及質體pRLucC124A-LC3wt證實登革病毒會驅使完整的自噬流體現象(autophagic flux)。進一步利用曠時螢光顯微鏡方式，觀察質體ptfLC3在登革病毒感染的Huh7細胞中的變化。我們發現在登革病毒感染早期誘發短週期的自噬流體(約三小時)，而在感染晚期則會有延長週期的現象(約六小時)。此外，我們發現登革病毒的NS1蛋白並不會隨著自噬流體現象而被分解。先前的研究指出NS1蛋白會和LC3蛋白有共處(co-localization)的情形，並且參與病毒的複製。大量表現NS1蛋白並不會誘發自噬現象。然而，登革病毒的非結構性蛋白會參與病毒的複製。登革病毒複製子(replicon)，其只具有非結構性蛋白，即會誘發自噬現象，顯示病毒的複製以及非結構性蛋白與誘發自噬現象有關。先前的研究指出C型肝炎病毒會經由不完全摺疊蛋白反應(unfolded protein response)而誘發自噬現象。登革病毒已經被報導會引起內質網壓力(ER stress)。我們證實了登革病毒感染Huh7細胞會引發內質網壓力。在給予內質網壓力的抑制劑(4-phenyl butyric acid)後，登革病毒所引發自噬現象也被抑制了，此結果顯示登革病毒所引起的內質網壓力參與在病毒造成的自噬現象當中。動物實驗的研究中，我們將登革病毒以顱內注射的方式感染出生六天大的仔鼠。研究結果顯示在登革病毒感染後五天的小鼠腦中可以觀察到LC3 II的增加並且與NS1有共處的情形。此外，利用穿透式電子顯微鏡觀察到有類自噬泡(autophagosome like vesicles)的存在，皆證實了登革病毒在活體中會引起自噬現象。最後我們證實利用自噬現象的抑制劑(3-methyladenine)抑制自噬現象的發生，會減緩登革病毒感染造成小鼠病程的發展，並且伴隨著NS1蛋白表現下降以及病毒量的減少。總而言之，此研究證實登革病毒的感染會引發多重週期的自噬流體現象，並且內質網壓力參與在誘發自噬現象的發生，而NS1則沒有。最後證實登革病毒感染在活體中會引起自噬現象，此現象會影響疾病病程的發展。

Dengue virus (DV) causes about 100 million people infection every year. DV disease ranges from mild dengue fever (DF) to severe dengue haemorrhagic fever (DHF), dengue shock syndrome (DSS) and death. DV infection induces a cellular homeostasis response, autophagy, which is responsible for the degradation of long-lived proteins, aggregated proteins and damaged organelles. DV induced-autophagy regulates lipid metabolism of the host cell to enhance its replication. However, how DV induces autophagy, whether DV NS1 gene can induce autophagy and whether DV2 infection induces autophagy in vivo remain unclear. We demonstrated that DV2 infection triggered the complete autophagic flux by using a ptfLC3 (tandem fluorescent-tagged microtubule-associated protein 1 light chain 3) plasmid and a pRLucC124A-LC3wt plasmid. Furthermore, time lapse recording was conducted to demonstrate that DV2 infection induced multiple autophagic flux cycles including a short cycle (about 3 h) at early stage and a prolonged cycle (about 6 h) at the late stages of infection. Despite DV2 infection triggering complete autophagic progression, DV2 nonstructural protein 1 (NS1) protein was not degraded in the process. Previous study showed colocalization of NS1 and LC3 in autophagosomes in DV2 infected cells and NS1 is a component of DV replication complex. Furthermore, overexpression of NS1 (pCMVTaq3B-NS1) was not able to induce autophagy. DV has seven nonstructural proteins. We demonstrated that DV2 replicon (pD2R2A), which only contains nonstructural genes, induced autophagy, indicating that DV2 nonstructural proteins besides NS1 is involved in autophagy induction. Previous study showed that Hepatitis C virus induced autophagy via unfolded protein response (UPR). DV has been reported can induce ER stress. Our data showed that DV2 infection induced ER stress in Huh7 cells. After the treatment of an ER stress inhibitor 4-phenyl butyric acid (4-PBA), DV2 induced autophagy was inhibited demonstrated by decreased LC3 II expression, suggesting that DV2 infection induces ER stress which participates in DV2 induced autophagy. In animal study, DV2 was intracranially inoculated into six-day-old ICR suckling mice. Our data showed that in the DV-infected mouse brain, LC3 II expression was increased and NS1 was colocalized with inLC3 at day 5 post infections. Furthermore, in DV2 infected brain tissue the double-membrane autophagosome like vesicles were also detected under a transmission electronic microscope (TEM). It suggests that DV2 infection induces autophagy in vivo. Finally, we demonstrated that inhibition of autophagy by 3-methyladenine (3-MA) decreased the DV2 infection-related disease symptoms accompanied with decreased NS1 expression and viral titer. In summary, this study reveals that DV2 infection induces multiple autophagic flux cycles, ER stress participates in increased autophagy but NS1 does not, and finally DV2 infection induces autophagy in vivo, which affects disease symptoms.

Alcon-LePoder, S., Drouet, M. T., Roux, P., Frenkiel, M. P., Arborio, M., Durand-Schneider, A. M., Maurice, M., Le Blanc, I., Gruenberg, J., and Flamand, M. (2005). The secreted form of dengue virus nonstructural protein NS1 is endocytosed by hepatocytes and accumulates in late endosomes: implications for viral infectivity. J Virol 79(17), 11403-11.

Alexander, D. E., and Leib, D. A. (2008). Xenophagy in herpes simplex virus replication and pathogenesis. Autophagy 4(1), 101-3.

Benarroch, D., Egloff, M. P., Mulard, L., Guerreiro, C., Romette, J. L., and Canard, B. (2004). A structural basis for the inhibition of the NS5 dengue virus mRNA 2'-O-methyltransferase domain by ribavirin 5'-triphosphate. J Biol Chem 279(34), 35638-43.

Chang, C. J., Luh, H. W., Wang, S. H., Lin, H. J., Lee, S. C., and Hu, S. T. (2001). The heterogeneous nuclear ribonucleoprotein K (hnRNP K) interacts with dengue virus core protein. DNA Cell Biol 20(9), 569-77.

Cheng, H. J., Lei, H. Y., Lin, C. F., Luo, Y. H., Wan, S. W., Liu, H. S., Yeh, T. M., and Lin, Y. S. (2009). Anti-dengue virus nonstructural protein 1 antibodies recognize protein disulfide isomerase on platelets and inhibit platelet aggregation. Mol Immunol 47(2-3), 398-406.

Crooks, A. J., Lee, J. M., Easterbrook, L. M., Timofeev, A. V., and Stephenson, J. R. (1994). The NS1 protein of tick-borne encephalitis virus forms multimeric species upon secretion from the host cell. J Gen Virol 75 ( Pt 12), 3453-60.

Deen, J. L., Harris, E., Wills, B., Balmaseda, A., Hammond, S. N., Rocha, C., Dung, N. M., Hung, N. T., Hien, T. T., and Farrar, J. J. (2006). The WHO dengue classification and case definitions: time for a reassessment. Lancet 368(9530), 170-3.

Dreux, M., Gastaminza, P., Wieland, S. F., and Chisari, F. V. (2009). The autophagy machinery is required to initiate hepatitis C virus replication. Proc Natl Acad Sci U S A 106(33), 14046-51.

English, L., Chemali, M., Duron, J., Rondeau, C., Laplante, A., Gingras, D., Alexander, D., Leib, D., Norbury, C., Lippe, R., and Desjardins, M. (2009). Autophagy enhances the presentation of endogenous viral antigens on MHC class I molecules during HSV-1 infection. Nat Immunol 10(5), 480-7.

Falgout, B., and Markoff, L. (1995). Evidence that flavivirus NS1-NS2A cleavage is mediated by a membrane-bound host protease in the endoplasmic reticulum. J Virol 69(11), 7232-43.

Falgout, B., Pethel, M., Zhang, Y. M., and Lai, C. J. (1991). Both nonstructural proteins NS2B and NS3 are required for the proteolytic processing of dengue virus nonstructural proteins. J Virol 65(5), 2467-75.

Farkas, T., Hoyer-Hansen, M., and Jaattela, M. (2009). Identification of novel autophagy regulators by a luciferase-based assay for the kinetics of autophagic flux. Autophagy 5(7), 1018-25.

Ferraris, P., Blanchard, E., and Roingeard, P. (2010). Ultrastructural and biochemical analyses of hepatitis C virus-associated host cell membranes. J Gen Virol 91(Pt 9), 2230-7.

Gannage, M., Dormann, D., Albrecht, R., Dengjel, J., Torossi, T., Ramer, P. C., Lee, M., Strowig, T., Arrey, F., Conenello, G., Pypaert, M., Andersen, J., Garcia-Sastre, A., and Munz, C. (2009). Matrix protein 2 of influenza A virus blocks autophagosome fusion with lysosomes. Cell Host Microbe 6(4), 367-80.

Guevin, C., Manna, D., Belanger, C., Konan, K. V., Mak, P., and Labonte, P. (2010). Autophagy protein ATG5 interacts transiently with the hepatitis C virus RNA polymerase (NS5B) early during infection. Virology 405(1), 1-7.

Heaton, N. S., Perera, R., Berger, K. L., Khadka, S., Lacount, D. J., Kuhn, R. J., and Randall, G. (2010). Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis. Proc Natl Acad Sci U S A 107(40), 17345-50.

Heaton, N. S., and Randall, G. (2010). Dengue virus-induced autophagy regulates lipid metabolism. Cell Host Microbe 8(5), 422-32.

Henchal, E. A., and Putnak, J. R. (1990). The dengue viruses. Clin Microbiol Rev 3(4), 376-96.

Hosokawa, N., Hara, T., Kaizuka, T., Kishi, C., Takamura, A., Miura, Y., Iemura, S., Natsume, T., Takehana, K., Yamada, N., Guan, J. L., Oshiro, N., and Mizushima, N. (2009). Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell 20(7), 1981-91.

Huang, S. C., Chang, C. L., Wang, P. S., Tsai, Y., and Liu, H. S. (2009). Enterovirus 71-induced autophagy detected in vitro and in vivo promotes viral replication. J Med Virol 81(7), 1241-52.

Jackson, W. T., Giddings, T. H., Jr., Taylor, M. P., Mulinyawe, S., Rabinovitch, M., Kopito, R. R., and Kirkegaard, K. (2005). Subversion of cellular autophagosomal machinery by RNA viruses. PLoS Biol 3(5), e156.

Jacobs, M. G., Robinson, P. J., Bletchly, C., Mackenzie, J. M., and Young, P. R. (2000). Dengue virus nonstructural protein 1 is expressed in a glycosyl-phosphatidylinositol-linked form that is capable of signal transduction. FASEB J 14(11), 1603-10.

Jager, S., Bucci, C., Tanida, I., Ueno, T., Kominami, E., Saftig, P., and Eskelinen, E. L. (2004). Role for Rab7 in maturation of late autophagic vacuoles. J Cell Sci 117(Pt 20), 4837-48.

Ke, P. Y., and Chen, S. S. (2011). Activation of the unfolded protein response and autophagy after hepatitis C virus infection suppresses innate antiviral immunity in vitro. J Clin Invest 121(1), 37-56.

Khakpoor, A., Panyasrivanit, M., Wikan, N., and Smith, D. R. (2009). A role for autophagolysosomes in dengue virus 3 production in HepG2 cells. J Gen Virol 90(Pt 5), 1093-103.

Kim, H. J., Lee, S., and Jung, J. U. (2010). When autophagy meets viruses: a double-edged sword with functions in defense and offense. Semin Immunopathol 32(4), 323-41.

Kimura, S., Noda, T., and Yoshimori, T. (2007). Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3. Autophagy 3(5), 452-60.

Kirkegaard, K., and Jackson, W. T. (2005). Topology of double-membraned vesicles and the opportunity for non-lytic release of cytoplasm. Autophagy 1(3), 182-4.

Kyei, G. B., Dinkins, C., Davis, A. S., Roberts, E., Singh, S. B., Dong, C., Wu, L., Kominami, E., Ueno, T., Yamamoto, A., Federico, M., Panganiban, A., Vergne, I., and Deretic, V. (2009). Autophagy pathway intersects with HIV-1 biosynthesis and regulates viral yields in macrophages. J Cell Biol 186(2), 255-68.

Lamark, T., Kirkin, V., Dikic, I., and Johansen, T. (2009). NBR1 and p62 as cargo receptors for selective autophagy of ubiquitinated targets. Cell Cycle 8(13), 1986-90.

Law, A. H., Lee, D. C., Yuen, K. Y., Peiris, M., and Lau, A. S. (2010). Cellular response to influenza virus infection: a potential role for autophagy in CXCL10 and interferon-alpha induction. Cell Mol Immunol 7(4), 263-70.

Lee, T. C., Lin, Y. L., Liao, J. T., Su, C. M., Lin, C. C., Lin, W. P., and Liao, C. L. (2010). Utilizing liver-specific microRNA-122 to modulate replication of dengue virus replicon. Biochem Biophys Res Commun 396(3), 596-601.

Lee, Y. R., Huang, K. J., Lei, H. Y., Chen, S. H., Lin, Y. S., Yeh, T. M., and Liu, H. S. (2005). Suckling mice were used to detect infectious dengue-2 viruses by intracerebral injection of the full-length RNA transcript. Intervirology 48(2-3), 161-6.

Lee, Y. R., Lei, H. Y., Liu, M. T., Wang, J. R., Chen, S. H., Jiang-Shieh, Y. F., Lin, Y. S., Yeh, T. M., Liu, C. C., and Liu, H. S. (2008). Autophagic machinery activated by dengue virus enhances virus replication. Virology 374(2), 240-8.

Levine, B., and Kroemer, G. (2008). Autophagy in the pathogenesis of disease. Cell 132(1), 27-42.

Li, J., Liu, Y., Wang, Z., Liu, K., Wang, Y., Liu, J., Ding, H., and Yuan, Z. (2011a). Subversion of cellular autophagy machinery by hepatitis B virus for viral envelopment. J Virol 85(13), 6319-33.

Li, J. C., Au, K. Y., Fang, J. W., Yim, H. C., Chow, K. H., Ho, P. L., and Lau, A. S. (2011b). HIV-1 trans-activator protein dysregulates IFN-gamma signaling and contributes to the suppression of autophagy induction. AIDS 25(1), 15-25.

Liang, C., Feng, P., Ku, B., Dotan, I., Canaani, D., Oh, B. H., and Jung, J. U. (2006). Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nat Cell Biol 8(7), 688-99.

Liang, C., Lee, J. S., Inn, K. S., Gack, M. U., Li, Q., Roberts, E. A., Vergne, I., Deretic, V., Feng, P., Akazawa, C., and Jung, J. U. (2008). Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nat Cell Biol 10(7), 776-87.

Liang, X. H., Jackson, S., Seaman, M., Brown, K., Kempkes, B., Hibshoosh, H., and Levine, B. (1999). Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402(6762), 672-6.

Lin, C. C., Huang, Y. H., Shu, P. Y., Wu, H. S., Lin, Y. S., Yeh, T. M., Liu, H. S., Liu, C. C., and Lei, H. Y. (2010). Characteristic of dengue disease in Taiwan: 2002-2007. Am J Trop Med Hyg 82(4), 731-9.

Lin, C. F., Lei, H. Y., Shiau, A. L., Liu, C. C., Liu, H. S., Yeh, T. M., Chen, S. H., and Lin, Y. S. (2003). Antibodies from dengue patient sera cross-react with endothelial cells and induce damage. J Med Virol 69(1), 82-90.

Lindenbach, B. D., and Rice, C. M. (1999). Genetic interaction of flavivirus nonstructural proteins NS1 and NS4A as a determinant of replicase function. J Virol 73(6), 4611-21.

Lindmo, K., and Stenmark, H. (2006). Regulation of membrane traffic by phosphoinositide 3-kinases. J Cell Sci 119(Pt 4), 605-14.

Mackenzie, J. M., Jones, M. K., and Young, P. R. (1996). Immunolocalization of the dengue virus nonstructural glycoprotein NS1 suggests a role in viral RNA replication. Virology 220(1), 232-40.

Martina, B. E., Koraka, P., and Osterhaus, A. D. (2009). Dengue virus pathogenesis: an integrated view. Clin Microbiol Rev 22(4), 564-81.

Matsunaga, K., Saitoh, T., Tabata, K., Omori, H., Satoh, T., Kurotori, N., Maejima, I., Shirahama-Noda, K., Ichimura, T., Isobe, T., Akira, S., Noda, T., and Yoshimori, T. (2009). Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol 11(4), 385-96.

McLean, J. E., Wudzinska, A., Datan, E., Quaglino, D., and Zakeri, Z. (2011). Flavivirus NS4A-induced autophagy protects cells against death and enhances virus replication. J Biol Chem.

Medin, C. L., Fitzgerald, K. A., and Rothman, A. L. (2005). Dengue virus nonstructural protein NS5 induces interleukin-8 transcription and secretion. J Virol 79(17), 11053-61.

Miller, S., Kastner, S., Krijnse-Locker, J., Buhler, S., and Bartenschlager, R. (2007). The non-structural protein 4A of dengue virus is an integral membrane protein inducing membrane alterations in a 2K-regulated manner. J Biol Chem 282(12), 8873-82.

Munoz-Jordan, J. L., Laurent-Rolle, M., Ashour, J., Martinez-Sobrido, L., Ashok, M., Lipkin, W. I., and Garcia-Sastre, A. (2005). Inhibition of alpha/beta interferon signaling by the NS4B protein of flaviviruses. J Virol 79(13), 8004-13.

Munoz-Jordan, J. L., Sanchez-Burgos, G. G., Laurent-Rolle, M., and Garcia-Sastre, A. (2003). Inhibition of interferon signaling by dengue virus. Proc Natl Acad Sci U S A 100(24), 14333-8.

Nara, A., Mizushima, N., Yamamoto, A., Kabeya, Y., Ohsumi, Y., and Yoshimori, T. (2002). SKD1 AAA ATPase-dependent endosomal transport is involved in autolysosome formation. Cell Struct Funct 27(1), 29-37.

Nishida, Y., Arakawa, S., Fujitani, K., Yamaguchi, H., Mizuta, T., Kanaseki, T., Komatsu, M., Otsu, K., Tsujimoto, Y., and Shimizu, S. (2009). Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature 461(7264), 654-8.

Noda, T., Fujita, N., and Yoshimori, T. (2008). The Ubi brothers reunited. Autophagy 4(4), 540-1.

O'Donnell, V., Pacheco, J. M., LaRocco, M., Burrage, T., Jackson, W., Rodriguez, L. L., Borca, M. V., and Baxt, B. (2011). Foot-and-mouth disease virus utilizes an autophagic pathway during viral replication. Virology 410(1), 142-50.

Orvedahl, A., Alexander, D., Talloczy, Z., Sun, Q., Wei, Y., Zhang, W., Burns, D., Leib, D. A., and Levine, B. (2007). HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein. Cell Host Microbe 1(1), 23-35.

Panyasrivanit, M., Khakpoor, A., Wikan, N., and Smith, D. R. (2009). Co-localization of constituents of the dengue virus translation and replication machinery with amphisomes. J Gen Virol 90(Pt 2), 448-56.

Pena, J., and Harris, E. (2011). Dengue virus modulates the unfolded protein response in a time-dependent manner. J Biol Chem 286(16), 14226-36.

Preugschat, F., Yao, C. W., and Strauss, J. H. (1990). In vitro processing of dengue virus type 2 nonstructural proteins NS2A, NS2B, and NS3. J Virol 64(9), 4364-74.

Sampath, A., Xu, T., Chao, A., Luo, D., Lescar, J., and Vasudevan, S. G. (2006). Structure-based mutational analysis of the NS3 helicase from dengue virus. J Virol 80(13), 6686-90.

Shafee, N., and AbuBakar, S. (2003). Dengue virus type 2 NS3 protease and NS2B-NS3 protease precursor induce apoptosis. J Gen Virol 84(Pt 8), 2191-5.

Shrivastava, S., Raychoudhuri, A., Steele, R., Ray, R., and Ray, R. B. (2011). Knockdown of autophagy enhances the innate immune response in hepatitis C virus-infected hepatocytes. Hepatology 53(2), 406-14.

Sir, D., Chen, W. L., Choi, J., Wakita, T., Yen, T. S., and Ou, J. H. (2008). Induction of incomplete autophagic response by hepatitis C virus via the unfolded protein response. Hepatology 48(4), 1054-61.

Sir, D., Tian, Y., Chen, W. L., Ann, D. K., Yen, T. S., and Ou, J. H. (2010). The early autophagic pathway is activated by hepatitis B virus and required for viral DNA replication. Proc Natl Acad Sci U S A 107(9), 4383-8.

Suhy, D. A., Giddings, T. H., Jr., and Kirkegaard, K. (2000). Remodeling the endoplasmic reticulum by poliovirus infection and by individual viral proteins: an autophagy-like origin for virus-induced vesicles. J Virol 74(19), 8953-65.

Sun, Q., Fan, W., Chen, K., Ding, X., Chen, S., and Zhong, Q. (2008). Identification of Barkor as a mammalian autophagy-specific factor for Beclin 1 and class III phosphatidylinositol 3-kinase. Proc Natl Acad Sci U S A 105(49), 19211-6.

Takahashi, Y., Coppola, D., Matsushita, N., Cualing, H. D., Sun, M., Sato, Y., Liang, C., Jung, J. U., Cheng, J. Q., Mule, J. J., Pledger, W. J., and Wang, H. G. (2007). Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol 9(10), 1142-51.

Talloczy, Z., Virgin, H. W. t., and Levine, B. (2006). PKR-dependent autophagic degradation of herpes simplex virus type 1. Autophagy 2(1), 24-9.

Tamai, K., Tanaka, N., Nara, A., Yamamoto, A., Nakagawa, I., Yoshimori, T., Ueno, Y., Shimosegawa, T., and Sugamura, K. (2007). Role of Hrs in maturation of autophagosomes in mammalian cells. Biochem Biophys Res Commun 360(4), 721-7.

Tan, B. H., Fu, J., Sugrue, R. J., Yap, E. H., Chan, Y. C., and Tan, Y. H. (1996). Recombinant dengue type 1 virus NS5 protein expressed in Escherichia coli exhibits RNA-dependent RNA polymerase activity. Virology 216(2), 317-25.

Tang, H., Da, L., Mao, Y., Li, Y., Li, D., Xu, Z., Li, F., Wang, Y., Tiollais, P., Li, T., and Zhao, M. (2009). Hepatitis B virus X protein sensitizes cells to starvation-induced autophagy via up-regulation of beclin 1 expression. Hepatology 49(1), 60-71.

Tanida, I., Fukasawa, M., Ueno, T., Kominami, E., Wakita, T., and Hanada, K. (2009). Knockdown of autophagy-related gene decreases the production of infectious hepatitis C virus particles. Autophagy 5(7), 937-45.

Taylor, M. P., Burgon, T. B., Kirkegaard, K., and Jackson, W. T. (2009). Role of microtubules in extracellular release of poliovirus. J Virol 83(13), 6599-609.

Taylor, M. P., and Kirkegaard, K. (2007). Modification of cellular autophagy protein LC3 by poliovirus. J Virol 81(22), 12543-53.

Umareddy, I., Pluquet, O., Wang, Q. Y., Vasudevan, S. G., Chevet, E., and Gu, F. (2007). Dengue virus serotype infection specifies the activation of the unfolded protein response. Virol J 4, 91.

Wang, C. C., Huang, Z. S., Chiang, P. L., Chen, C. T., and Wu, H. N. (2009). Analysis of the nucleoside triphosphatase, RNA triphosphatase, and unwinding activities of the helicase domain of dengue virus NS3 protein. FEBS Lett 583(4), 691-6.

Wang, J., Shi, Y., and Yang, H. (2010). [Infection with hepatitis B virus enhances basal autophagy]. Wei Sheng Wu Xue Bao 50(12), 1651-6.

Wang, S. H., Syu, W. J., Huang, K. J., Lei, H. Y., Yao, C. W., King, C. C., and Hu, S. T. (2002). Intracellular localization and determination of a nuclear localization signal of the core protein of dengue virus. J Gen Virol 83(Pt 12), 3093-102.

Wengler, G., and Gross, H. J. (1978). Studies on virus-specific nucleic acids synthesized in vertebrate and mosquito cells infected with flaviviruses. Virology 89(2), 423-37.

Wu, Y. T., Tan, H. L., Shui, G., Bauvy, C., Huang, Q., Wenk, M. R., Ong, C. N., Codogno, P., and Shen, H. M. (2010). Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase. J Biol Chem 285(14), 10850-61.

Xie, Z., and Klionsky, D. J. (2007). Autophagosome formation: core machinery and adaptations. Nat Cell Biol 9(10), 1102-9.

Xu, T., Sampath, A., Chao, A., Wen, D., Nanao, M., Chene, P., Vasudevan, S. G., and Lescar, J. (2005). Structure of the Dengue virus helicase/nucleoside triphosphatase catalytic domain at a resolution of 2.4 A. J Virol 79(16), 10278-88.

Yan, Y., Flinn, R. J., Wu, H., Schnur, R. S., and Backer, J. M. (2009). hVps15, but not Ca2+/CaM, is required for the activity and regulation of hVps34 in mammalian cells. Biochem J 417(3), 747-55.

Yon, C., Teramoto, T., Mueller, N., Phelan, J., Ganesh, V. K., Murthy, K. H., and Padmanabhan, R. (2005). Modulation of the nucleoside triphosphatase/RNA helicase and 5'-RNA triphosphatase activities of Dengue virus type 2 nonstructural protein 3 (NS3) by interaction with NS5, the RNA-dependent RNA polymerase. J Biol Chem 280(29), 27412-9.

Zhang, Y., Zhang, W., Ogata, S., Clements, D., Strauss, J. H., Baker, T. S., Kuhn, R. J., and Rossmann, M. G. (2004). Conformational changes of the flavivirus E glycoprotein. Structure 12(9), 1607-18.

Zhou, Z., Jiang, X., Liu, D., Fan, Z., Hu, X., Yan, J., Wang, M., and Gao, G. F. (2009). Autophagy is involved in influenza A virus replication. Autophagy 5(3), 321-8.