Source: http://www.asmscience.org/content/book/10.1128/9781555815561.ch20
Timestamp: 2019-04-21 00:21:13+00:00

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Genome and protein-coding organization of the Flaviviridae genera. The positions of the nontranslated region (NTR) and the polyprotein encoding the structural and non-structural (NS) proteins are shown. Cap denotes the 5′ cap present on Flavivirus genome RNA; IRES denotes the internal ribosome entry site found within the Hepacivirus and Pestivirus genome RNA. The positions of the mature viral proteins within each viral polyprotein are indicated. The structural proteins are abbreviated as follows: C, capsid; prM/M, membrane; E, envelope; E1, envelope protein 1; E2, envelope protein 2; ERNS, envelope. The NS proteins are designated 1 to 5 with A and B subtypes, as shown.
PRR signaling and viral control of the innate immune response to Flaviviridae infection. Viral RNA recognition by the TLR3 and RIG-I/MDA-5 pathways are shown. Recognition and binding of viral RNA products by TLRs, RIG-I, or MDA-5 induces downstream signaling of IRF3 and NF-κB activation, leading to the expression of a wide range of genes, including the production and secretion of IFN-β. The sites of regulation by BVDV Npro and HCV NS3/4A proteins are indicated. Ubq-Ubq, protein modification by virus-induced ubiquitin chain conjugation; P, protein phosphorylation; NEMO, NF-κB essential modulator.
Regulation of the Jak-Stat pathway during Flaviviridae infection. The two chains of the IFN-α/β receptor are shown associated with Tyk2 or Jak1. IFN binding to the receptor triggers the phosphorylation of receptor-associated Stat1 and Stat2, which form heterodimers that translocate to the cell nucleus for interaction with IRF9. The trimeric complex of Stat1, Stat2, and IRF9 binds to the ISRE of target genes to induce ISG expression. ISG products function to control virus replication and cell-to-cell virus spread, and have a major impact on tissue tropism. Sites of Jak-Stat pathway regulation by HCV core, NS5A, and E2 proteins are indicated. Control points imposed by WNV, DV, TBE/Langat virus, and JEV NS proteins are also shown. pY, protein tyrosine phosphorylation.
1. Alexander, W. S. 2002. Suppressors of cytokine signalling (SOCS) in the immune system. Nat. Rev. Immunol. 2: 410– 416.
2. Alter, M. J. 2007. Epidemiology of hepatitis C virus infection. World J. Gastroenterol. 13: 2436– 2441.
3. Alter, M. J. H.,, H. S. Margolis,, K. Krawczynski,, F. Judson,, A. Mares,, W. J. Alexander,, P.-Y. Hu,, J. K. Miller, et al. 1992. The natural history of community-acquired hepatitis C in the United States. N. Engl. J. Med. 321: 1494– 1500.
4. Au, W. C., and, P. M. Pitha. 2001. Recruitment of multiple interferon regulatory factors and histone acetyltransferase to the transcriptionally active interferon A promoters. J. Biol. Chem. 276: 41629– 41637.
5. Baigent, S. J.,, S. Goodbourn, and, J. W. McCauley. 2004. Differential activation of interferon regulatory factors-3 and -7 by non-cytopathogenic and cytopathogenic bovine viral diarrhoea virus. Vet. Immunol. Immunopathol. 100: 135– 144.
6. Baigent, S. J.,, G. Zhang,, M. D. Fray,, H. Flick-Smith,, S. Goodbourn, and, J. W. McCauley. 2002. Inhibition of beta interferon transcription by noncytopathogenic bovine viral diarrhea virus is through an interferon regulatory factor 3-dependent mechanism. J. Virol. 76: 8979– 8988.
7. Bauhofer, O.,, A. Summerfield,, Y. Sakoda,, J. D. Tratschin,, M. A. Hofmann, and, N. Ruggli. 2007. Classical swine fever virus N pro interacts with interferon regulatory factor 3 and induces its proteasomal degradation. J. Virol. 81: 3087– 3096.
8. Best, S. M.,, K. L. Morris,, J. G. Shannon,, S. J. Robertson,, D. N. Mitzel,, G. S. Park,, E. Boer,, J. B. Wolfinbarger, and, M. E. Bloom. 2005. Inhibition of interferon-stimulated JAK-Stat signaling by a tick-borne flavivirus and identification of NS5 as an interferon antagonist. J. Virol. 79: 12828– 12839.
9. Bialek, S. R., and, N. A. Terrault. 2006. The changing epidemiology and natural history of hepatitis C virus infection. Clin. Liver Dis. 10: 697– 715.
10. Bigger, C. B.,, K. M. Brasky, and, R. E. Lanford. 2001. DNA microarray analysis of chimpanzee liver during acute resolving hepatitis C virus infection. J. Virol. 75: 7059– 7066.
11. Blight, K. J.,, J. A. McKeating, and, C. M. Rice. 2002. Highly permissive cell lines for subgenomic and genomic hepatitis C virus RNA replication. J. Virol. 76: 13001– 13014.
12. Blindenbacher, A.,, F. H. Duong,, L. Hunziker,, S. T. Stutvoet,, X. Wang,, L. Terracciano,, D. Moradpour,, H. E. Blum,, T. Alonzi,, M. Tripodi,, N. La Monica, and, M. H. Heim. 2003. Expression of hepatitis C virus proteins inhibits interferon alpha signaling in the liver of transgenic mice. Gastroenterology 124: 1465– 1475.
13. Bode, J. G.,, S. Ludwig,, C. Ehrhardt,, U. Albrecht,, A. Erhardt,, F. Schaper,, P. C. Heinrich, and, D. Haussinger. 2003. IFN-alpha antagonistic activity of HCV core protein involves induction of suppressor of cytokine signaling-3. FASEB J. 17: 488– 490.
14. Brackenbury, L. S.,, B. V. Carr,, Z. Stamataki,, H. Prentice,, E. A. Lefevre,, C. J. Howard, and, B. Charleston. 2005. Identification of a cell population that produces alpha/beta interferon in vitro and in vivo in response to noncytopathic bovine viral diarrhea virus. J. Virol. 79: 7738– 7744.
15. Brinton, M. A. 2002. The molecular biology of West Nile virus: a new invader of the Western hemisphere. Annu. Rev. Microbiol. 56: 371– 402.
16. Calisher, C. H., and, E. A. Gould. 2003. Taxonomy of the virus family Flaviviridae. Adv. Virus Res. 59: 1– 19.
17. Carson, P. J.,, P. Konewko,, K. S. Wold,, P. G. Mariani,, S. Goli,, P. Bergloff, and, R. D. Crosby. 2006. Long-term clinical and neuropsychological outcomes of West Nile virus infection. Clin. Infect. Dis. 43: 723– 730.
18. Chang, T. H.,, C. L. Liao, and, Y. L. Lin. 2006. Flavivirus induces interferon-beta gene expression through a pathway involving RIG-I-dependent IRF3 and PI3K-dependent NF-kappaB activation. Microbes Infect. 8: 157– 171.
19. Charleston, B.,, L. S. Brackenbury,, B. V. Carr,, M. D. Fray,, J. C. Hope,, C. J. Howard, and, W. I. Morrison. 2002. Alpha/beta and gamma interferons are induced by infection with noncytopathic bovine viral diarrhea virus in vivo. J. Virol. 76: 923– 927.
20. Chen, L.,, I. Borozan,, J. Feld,, J. Sun,, L. L. Tannis,, C. Coltescu,, J. Heathcote,, A. M. Edwards, and, I. D. McGilvray. 2005. Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection. Gastroenterology 128: 1437– 1444.
21. Chen, Z.,, R. Rijnbrand,, R. K. Jangra,, S. G. Devaraj,, L. Qu,, Y. Ma,, S. M. Lemon, and, K. Li. 2007. Ubiquitination and proteasomal degradation of interferon regulatory factor-3 induced by Npro from a cytopathic bovine viral diarrhea virus. Virology 366: 277– 292.
22. Choo, Q. L.,, G. Kuo,, A. J. Weiner,, L. R. Overby,, D. W. Bradley, and, M. Houghton. 1989. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244: 359– 362.
23. Cusson-Hermance, N.,, S. Khurana,, T. H. Lee,, K. A. Fitzgerald, and, M. A. Kelliher. 2005. Rip1 mediates the Trif-dependent toll-like receptor 3- and 4-induced NF-κB activation but does not contribute to interferon regulatory factor 3 activation. J. Biol. Chem. 280: 36560– 36566.
24. Daffis, S.,, M. A. Samuel,, B. C. Keller,, M. Gale, Jr., and, M. S. Diamond. 2007. Cell-specific IRF3 responses protect against West Nile virus infection by interferon-dependent and -independent mechanisms. PLoS Pathog. 3: e106.
25. Dansako, H.,, M. Ikeda, and, N. Kato. 2007. Limited suppression of the interferon-beta production by hepatitis C virus serine protease in cultured human hepatocytes. FEBS J. 274: 4161– 4176.
26. Dumpis, U.,, D. Crook, and, J. Oksi. 1999. Tick-borne encephalitis. Clin. Infect. Dis. 28: 882– 890.
27. Elco, C. P.,, J. M. Guenther,, B. R. Williams, and, G. C. Sen. 2005. Analysis of genes induced by Sendai virus infection of mutant cell lines reveals essential roles of interferon regulatory factor 3, NF-kappaB, and interferon but not Toll-like receptor 3. J. Virol. 79: 3920– 3929.
28. Evans, J. D., and, C. Seeger. 2007. Differential effects of mutations in NS4B on West Nile virus replication and inhibition of interferon signaling. J. Virol. 81: 11809– 11816.
29. Fields, B. N. 1990. Virology. Raven Press, New York, NY.
30. Fitzgerald, K. A.,, S. M. McWhirter,, K. L. Faia,, D. C. Rowe,, E. Latz,, D. T. Golenbock,, A. J. Coyle,, S. M. Liao, and, T. Maniatis. 2003. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat. Immunol. 4: 491– 496.
31. Foy, E.,, K. Li,, C. Wang,, R. Sumpter,, M. Ikeda,, S. M. Lemon, and, M. Gale, Jr. 2003. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science 300: 1145– 1148.
32. Fredericksen, B. L., and, M. Gale, Jr. 2006. West Nile virus evades activation of interferon regulatory factor 3 through RIG-I-dependent and -independent pathways without antagonizing host defense signaling. J. Virol. 80: 2913– 2923.
33. Fredericksen, B. L.,, B. C. Keller,, J. Fornek,, M. G. Katze, and, M. Gale, Jr. 2008. Establishment and maintenance of the innate antiviral response to West Nile virus involves both RIG-I and MDA5 signaling through IPS-1. J. Virol. 82: 609– 616.
34. Fredericksen, B. L.,, M. Smith,, M. G. Katze,, P. Y. Shi, and, M. Gale, Jr. 2004. The host response to West Nile virus infection limits viral spread through the activation of the interferon regulatory factor 3 pathway. J. Virol. 78: 7737– 7747.
35. Gale, M., Jr.,, C. M. Blakely,, B. Kwieciszewski,, S.-L. Tan,, M. Dossett,, M. J. Korth,, S. J. Polyak,, D. R. Gretch, and, M. G. Katze. 1998. Control of PKR protein kinase by hepatitis C virus nonstructural 5A protein: molecular mechanisms of kinase regulation. Mol. Cell. Biol. 18: 5208– 5218.
36. Gale, M., Jr., and, E. M. Foy. 2005. Evasion of intracellular host defense by hepatitis C virus. Nature 436: 939– 945.
37. Gil, L. H.,, I. H. Ansari,, V. Vassilev,, D. Liang,, V. C. Lai,, W. Zhong,, Z. Hong,, E. J. Dubovi, and, R. O. Donis. 2006. The amino-terminal domain of bovine viral diarrhea virus N pro protein is necessary for alpha/beta interferon antagonism. J. Virol. 80: 900– 911.
38. Gilfoy, F. D. and,, P. W. Mason. 2007. West Nile virus-induced interferon production is mediated by the double-stranded RNA-dependent protein kinase PKR. J. Virol. 81: 11148– 11158.
40. Gritsun, T. S.,, V. A. Lashkevich, and, E. A. Gould. 2003. Tick-borne encephalitis. Antiviral Res. 57: 129– 146.
41. Gritsun, T. S.,, P. A. Nuttall, and, E. A. Gould. 2003. Tick-borne flaviviruses. Adv. Virus Res. 61: 317– 371.
42. Gubler, D. J. 2006. Dengue/dengue haemorrhagic fever: history and current Status. Novartis Found. Symp. 277: 3– 16.
43. Guo, J. T.,, J. Hayashi, and, C. Seeger. 2005. West Nile virus inhibits the signal transduction pathway of alpha interferon. J. Virol. 79: 1343– 1350.
44. Han, J. Q.,, G. Wroblewski,, Z. Xu,, R. H. Silverman, and, D. J. Barton. 2004. Sensitivity of hepatitis C virus RNA to the antiviral enzyme ribonuclease L is determined by a subset of efficient cleavage sites. J. Interferon Cytokine Res. 24: 664– 676.
45. Harris, E.,, K. L. Holden,, D. Edgil,, C. Polacek, and, K. Clyde. 2006. Molecular biology of flaviviruses. Novartis Found. Symp. 277: 23– 39.
46. Hayes, C. G. 2001. West Nile virus: Uganda, 1937, to New York City, 1999. Ann. N. Y. Acad. Sci. 951: 25– 37.
47. Hayes, E. B.,, N. Komar,, R. Nasci,, S. Montgomery,, D. O’Leary, and, G. Campbell. 2005. Epidemiology and transmission dynamics of West Nile virus disease. Emerg. Infect. Dis. 11: 1167– 1173.
48. Heim, M. H.,, D. Moradpour, and, H. E. Blum. 1999. Expression of hepatitis C virus proteins inhibits signal transduction through the Jak-Stat pathway. J. Virol. 73: 8469– 8475.
49. Hilton, L.,, K. Moganeradj,, G. Zhang,, Y. H. Chen,, R. E. Randall,, J. W. McCauley, and, S. Goodbourn. 2006. The NPro product of bovine viral diarrhea virus inhibits DNA binding by interferon regulatory factor 3 and targets it for proteasomal degradation. J. Virol. 80: 11723– 11732.
50. Ho, L. J.,, L. F. Hung,, C. Y. Weng,, W. L. Wu,, P. Chou,, Y. L. Lin,, D. M. Chang,, T. Y. Tai, and, J. H. Lai. 2005. Dengue virus type 2 antagonizes IFN-alpha but not IFN-gamma antiviral effect via down-regulating Tyk2-Stat signaling in the human dendritic cell. J. Immunol. 174: 8163– 8172.
51. Hoebe, K.,, X. Du,, P. Georgel,, E. Janssen,, K. Tabeta,, S. O. Kim,, J. Goode,, P. Lin,, N. Mann,, S. Mudd,, K. Crozat,, S. Sovath,, J. Han, and, B. Beutler. 2003. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424: 743– 748.
52. Hornung, V.,, J. Ellegast,, S. Kim,, K. Brzózka,, A. Jung,, H. Kato,, H. Poeck,, S. Akira,, K. K. Conzelmann,, M. Schlee,, S. Endres, and, G. Hartmann. 2006. 5′-Triphosphate RNA is the ligand for RIG-I. Science 314: 994– 997.
53. Horscroft, N.,, D. Bellows,, I. Ansari,, V. C. Lai,, S. Dempsey,, D. Liang,, R. Donis,, W. Zhong, and, Z. Hong. 2005. Establishment of a subgenomic replicon for bovine viral diarrhea virus in Huh-7 cells and modulation of interferon-regulated factor 3-mediated antiviral response. J. Virol. 79: 2788– 2796.
54. Iqbal, M.,, E. Poole,, S. Goodbourn, and, J. W. McCauley. 2004. Role for bovine viral diarrhea virus E rns glyco-protein in the control of activation of beta interferon by double-stranded RNA. J. Virol. 78: 136– 145.
55. Janeway, C. A., Jr., and, R. Medzhitov. 2002. Innate immune recognition. Annu. Rev. Immunol. 20: 197– 216.
56. Johnson, C. L.,, D. M. Owen, and, M. Gale, Jr. 2007. Functional and therapeutic analysis of hepatitis C virus NS3/4A protease control of antiviral immune defense. J. Biol. Chem. 14: 10792– 10803.
57. Jones, M.,, A. Davidson,, L. Hibbert,, P. Gruenwald,, J. Schlaak,, S. Ball,, G. R. Foster, and, M. Jacobs. 2005. Dengue virus inhibits alpha interferon signaling by reducing STAT2 expression. J. Virol. 79: 5414– 5420.
58. Kajaste-Rudnitski, A.,, T. Mashimo,, M. P. Frenkiel,, J. L. Guenet,, M. Lucas, and, P. Despres. 2006. The 2′,5′-oligoadenylate synthetase 1b is a potent inhibitor of West Nile virus replication inside infected cells. J. Biol. Chem. 281: 4624– 4637.
59. Kato, H.,, S. Sato,, M. Yoneyama,, M. Yamamoto,, S. Uematsu,, K. Matsui,, T. Tsujimura,, K. Takeda,, T. Fujita,, O. Takeuchi, and, S. Akira. 2005. Cell type-specific involvement of RIG-I in antiviral response. Immunity 23: 19– 28.
60. Kato, H.,, O. Takeuchi,, S. Sato,, M. Yoneyama,, M. Yamamoto,, K. Matsui,, S. Uematsu,, A. Jung,, T. Kawai,, K. J. Ishii,, O. Yamaguchi,, K. Otsu,, T. Tsujimura,, C. S. Koh,, C. Reis e Sousa,, Y. Matsuura,, T. Fujita, and, S. Akira. 2006. Differential roles of MDA-5 and RIG-I helicases in the recognition of RNA viruses. Nature 441: 101– 105.
61. Katze, M. G.,, Y. He, and, M. Gale, Jr. 2002. Viruses and interferon: a fight for supremacy. Nature Reviews Immunology 2: 675– 667.
62. Kawai, T., and, S. Akira. 2006. Innate immune recognition of viral infection. Nat. Immunol. 7: 131– 137.
63. Kawai, T.,, K. Takahashi,, S. Sato,, C. Coban,, H. Kumar,, H. Kato,, K. J. Ishii,, O. Takeuchi, and, S. Akira. 2005. IPS-1, an adaptor triggering RIG-I- and MDA-5-mediated type I interferon induction. Nat. Immunol. 6: 981– 988.
64. Keller, B. C.,, B. L. Fredericksen,, M. A. Samuel,, R. E. Mock,, P. W. Mason,, M. S. Diamond, and, M. Gale, Jr. 2006. Resistance to alpha/beta interferon is a determinant of West Nile virus replication fitness and virulence. J. Virol. 80: 9424– 9434.
65. Khabar, K. S.,, F. Al Zoghaibi,, M. N. Al Ahdal,, T. Murayama,, M. Dhalla,, N. Mukaida,, M. Taha,, S. T. Al Sedairy,, Y. Siddiqui,, G. Kessie, and, K. Matsushima. 1997. The alpha chemokine, interleukin 8, inhibits the antiviral action of interferon alpha. J. Exp. Med. 186: 1077– 1085.
66. Klee, A. L.,, B. Maidin,, B. Edwin,, I. Poshni,, F. Mostashari,, A. Fine,, M. Layton, and, D. Nash. 2004. Long-term prognosis for clinical West Nile virus infection. Emerg. Infect. Dis. 10: 1405– 1411.
67. Kramer, L. D.,, J. Li, and, P. Y. Shi. 2007. West Nile virus. Lancet Neurol. 6: 171– 181.
68. Kroeger, A.,, M. Nathan, and, J. Hombach. 2004. Dengue. Nat. Rev. Microbiol. 2: 360– 361.
69. Kumar, A.,, J. Haque,, J. Lacoste,, J. Hiscott, and, B. R. G. Williams. 1994. Double-stranded RNA-dependent protein kinase activates transcription factor NF-κB by phosphorylating IkB. Proc. Natl. Acad. Sci. USA 91: 6288– 6292.
70. Kumar, A.,, Y.-L. Yang,, V. Flati,, S. Der,, S. Kadereit,, A. Deb,, J. Haque,, L. Reis,, C. Weissmann, and, B. R. G. Williams. 1997. Deficient cytokine signaling in mouse embryo fibroblasts with a targeted deletion in the PKR gene: role of IRF-1 and NF-kB. EMBO J. 16: 406– 416.
71. La Rocca, S. A.,, R. J. Herbert,, H. Crooke,, T. W. Drew,, T. E. Wileman, and, P. P. Powell. 2005. Loss of interferon regulatory factor 3 in cells infected with classical swine fever virus involves the N-terminal protease, N pro. J. Virol. 79: 7239– 7247.
72. Lenschow, D. J.,, C. Lai,, N. Frias-Staheli,, N. V. Giannakopoulos,, A. Lutz,, T. Wolff,, A. Osiak,, B. Levine,, R. E. Schmidt,, A. Garcia-Sastre,, D. A. Leib,, A. Pekosz,, K. P. Knobeloch,, I. Horak, and, H. W. Virgin IV. 2007. IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses. Proc. Natl. Acad. Sci. USA 104: 1371– 1376.
73. Li, K.,, E. Foy,, J. C. Ferreon,, M. Nakamura,, A. C. Ferreon,, M. Ikeda,, S. C. Ray,, M. Gale, Jr., and, S. M. Lemon. 2005. Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proc. Natl. Acad. Sci. USA 102: 2992– 2997.
74. Ligon, B. L. 2005. Dengue fever and dengue hemorrhagic fever: a review of the history, transmission, treatment, and prevention. Semin. Pediatr. Infect. Dis. 16: 60– 65.
75. Lin, R.,, C. Heylbroeck,, P. M. Pitha, and, J. Hiscott. 1998. Virus-dependent phosphorylation of the IRF3 transcription factor regulates nuclear translocation, transactivation potential, and proteasome-mediated degradation. Mol. Cell. Biol. 18: 2986– 2996.
76. Lin, R.,, Y. Mamane, and, J. Hiscott. 1999. Structural and functional analysis of interferon regulatory factor 3: localization of the transactivation and autoinhibitory domains. Mol. Cell. Biol. 19: 2465– 2474.
77. Lin, R. J.,, B. L. Chang,, H. P. Yu,, C. L. Liao, and, Y. L. Lin. 2006. Blocking of interferon-induced Jak-Stat signaling by Japanese encephalitis virus NS5 through a protein tyrosine phosphatase-mediated mechanism. J. Virol. 80: 5908– 5918.
78. Lin, R. J.,, C. L. Liao,, E. Lin, and, Y. L. Lin. 2004. Blocking of the alpha interferon-induced Jak-Stat signaling pathway by Japanese encephalitis virus infection. J. Virol. 78: 9285– 9294.
79. Lindenbach, B. D., and, C. M. Rice. 2005. Unravelling hepatitis C virus replication from genome to function. Nature 436: 933– 938.
80. Liu, W. J.,, X. J. Wang,, D. C. Clark,, M. Lobigs,, R. A. Hall, and, A. A. Khromykh. 2006. A single amino acid substitution in the West Nile virus nonstructural protein NS2A disables its ability to inhibit alpha/beta interferon induction and attenuates virus virulence in mice. J. Virol. 80: 2396– 2404.
81. Liu, W. J.,, X. J. Wang,, V. V. Mokhonov,, P. Y. Shi,, R. Randall, and, A. A. Khromykh. 2005. Inhibition of interferon signaling by the New York 99 strain and Kunjin subtype of West Nile virus involves blockage of Stat1 and Stat2 activation by nonstructural proteins. J. Virol. 79: 1934– 1942.
82. Loo, Y. M.,, J. Fornek,, N. Crochet,, G. Bajwa,, O. Perwistasari,, L. Martinez-Sobrido,, S. Akira,, M. A. Gill,, A. García-Sastre,, M. G. Katze, and, M. J. Gale. 2008. Distinct RIG-I and MDA-5 signaling by RNA viruses in innate immunity. J. Virol. 82: 335– 345.
83. Loo, Y. M.,, D. M. Owen,, K. Li,, A. K. Erickson,, C. L. Johnson,, P. M. Fish,, D. S. Carney,, T. Wang,, H. Ishida,, M. Yoneyama,, T. Fujita,, T. Saito,, W. M. Lee,, C. H. Hagedorn,, D. T. Lau,, S. A. Weinman,, S. M. Lemon, and, M. Gale, Jr. 2006. Viral and therapeutic control of IFN-beta promoter stimulator 1 during hepatitis C virus infection. Proc. Natl. Acad. Sci. USA 103: 6001– 6006.
84. Macdonald, A., and, M. Harris. 2004. Hepatitis C virus NS5A: tales of a promiscuous protein. J. Gen. Virol. 85: 2485– 2502.
85. Mackenzie, J. S.,, D. J. Gubler, and, L. R. Petersen. 2004. Emerging flaviviruses: the spread and resurgence of Japanese encephalitis, West Nile and dengue viruses. Nat. Med. 10: S98– S109.
86. Malathi, K.,, B. Dong,, M. Gale, Jr., and, R. H. Silverman. 2007. Small self-RNA generated by RNase L amplifies antiviral innate immunity. Nature 448: 816– 819.
87. Mashimo, T.,, M. Lucas,, D. Simon-Chazottes,, M. P. Frenkiel,, X. Montagutelli,, P. E. Ceccaldi,, V. Deubel,, J. L. Guenet, and, P. Despres. 2002. A nonsense mutation in the gene encoding 2′-5′-oligoadenylate synthetase/L1 isoform is associated with West Nile virus susceptibility in laboratory mice. Proc. Natl. Acad. Sci. USA 99: 11311– 11316.
88. McHutchison, J. G. 2004. Understanding hepatitis C. Am. J. Manag. Care 10: S21- S29.
89. McHutchison, J. G., and, K. Patel. 2002. Future therapy of hepatitis C. Hepatology 36: S245- S252.
90. Meylan, E.,, J. Curran,, K. Hofmann,, D. Moradpour,, M. Binder,, R. Bartenschlager, and, J. Tschopp. 2005. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437: 1167– 1172.
91. Mibayashi, M.,, L. Martinez-Sobrido,, Y. M. Loo,, W. B. Cardenas,, M. Gale, Jr., and, A. Garcia-Sastre. 2007. Inhibition of retinoic acid-inducible gene I-mediated induction of beta interferon by the NS1 protein of influenza A virus. J. Virol. 81: 514– 524.
92. Munoz-Jordan, J. L.,, M. Laurent-Rolle,, J. Ashour,, L. Martinez-Sobrido,, M. Ashok,, W. I. Lipkin, and, A. Garcia-Sastre. 2005. Inhibition of alpha/beta interferon signaling by the NS4B protein of flaviviruses. J. Virol. 79: 8004– 8013.
93. Munoz-Jordan, J. L.,, G. G. Sanchez-Burgos,, M. Laurent-Rolle, and, A. Garcia-Sastre. 2003. Inhibition of interferon signaling by dengue virus. Proc. Natl. Acad. Sci. USA 100: 14333– 14338.
94. Navarro, L.,, K. Mowen,, S. Rodems,, B. Weaver,, N. Reich,, D. Spector, and, M. David. 1998. Cytomegalovirus activates interferon immediate-early response gene expression and an interferon regulatory factor 3-containing interferon-stimulated response element-binding complex. Mol. Cell. Biol. 18: 3796– 3802.
95. Noguchi, T.,, S. Satoh,, T. Noshi,, E. Hatada,, R. Fukuda,, A. Kawai,, S. Ikeda,, M. Hijikata, and, K. Shimotohno. 2001. Effects of mutation in hepatitis C virus nonstructural protein 5A on interferon resistance mediated by inhibition of PKR kinase activity in mammalian cells. Microbiol. Immunol. 45: 829– 840.
96. Onomoto, K.,, M. Yoneyama, and, T. Fujita. 2007. Regulation of antiviral innate immune responses by RIG-I family of RNA helicases. Curr. Top. Microbiol. Immunol. 316: 193– 205.
97. Oshiumi, H.,, M. Matsumoto,, K. Funami,, T. Akazawa, and, T. Seya. 2003. TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction. Nat. Immunol. 4: 161– 167.
98. Park, G. S.,, K. L. Morris,, R. G. Hallett,, M. E. Bloom, and, S. M. Best. 2007. Identification of residues critical for the interferon antagonist function of Langat virus NS5 reveals a role for the RNA-dependent RNA polymerase domain. J. Virol. 81: 6936– 6946.
99. Perelygin, A. A.,, S. V. Scherbik,, I. B. Zhulin,, B. M. Stockman,, Y. Li, and, M. A. Brinton. 2002. Positional cloning of the murine flavivirus resistance gene. Proc. Natl. Acad. Sci. USA 99: 9322– 9327.
100. Petersen, L. R., and, J. T. Roehrig. 2001. West Nile virus: a reemerging global pathogen. Emerg. Infect. Dis. 7: 611– 614.
101. Pichlmair, A.,, O. Schulz,, C. P. Tan,, T. I. Näslund,, P. Liljeström,, F. Weber, and, C. Reis e Sousa. 2006. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science 314: 997– 1001.
102. Polyak, S. J.,, K. S. Khabar,, D. M. Paschal,, H. J. Ezelle,, G. Duverlie,, G. N. Barber,, D. E. Levy,, N. Mukaida, and, D. R. Gretch. 2001. Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response. J. Virol. 75: 6095– 6106.
103. Polyak, S. J.,, K. S. Khabar,, M. Rezeiq, and, D. R. Gretch. 2001. Elevated levels of interleukin-8 in serum are associated with hepatitis C virus infection and resistance to interferon therapy. J. Virol. 75: 6209– 6211.
104. Preston, C. M.,, A. N. Harman, and, M. J. Nicholl. 2001. Activation of interferon response factor-3 in human cells infected with herpes simplex virus type 1 or human cytomegalovirus. J. Virol. 75: 8909– 8916.
105. Randall, G.,, L. Chen,, M. Panis,, A. K. Fischer,, B. D. Lindenbach,, J. Sun,, J. Heathcote,, C. M. Rice,, A. M. Edwards, and, I. D. McGilvray. 2006. Silencing of USP18 potentiates the antiviral activity of interferon against hepatitis C virus infection. Gastroenterology 131: 1584– 1591.
106. Rehermann, B., and, M. Nascimbeni. 2005. Immunology of hepatitis B virus and hepatitis C virus infection. Nat. Rev. Immunol. 5: 215– 229.
107. Ruggli, N.,, J. D. Tratschin,, M. Schweizer,, K. C. McCullough,, M. A. Hofmann, and, A. Summerfield. 2003. Classical swine fever virus interferes with cellular antiviral defense: evidence for a novel function of N pro. J. Virol. 77: 7645– 7654.
108. Sadler, A. J., and, B. R. Williams. 2007. Structure and function of the protein kinase R. Curr. Top. Microbiol. Immunol. 316: 253– 292.
109. Saito, T., and, M. Gale, Jr. 2006. Principles of intracellular viral recognition. Curr. Opin. Immunol. 19: 17– 23.
110. Saito, T.,, R. Hirai,, Y. M. Loo,, D. Owen,, C. L. Johnson,, S. C. Sinha,, S. Akira,, T. Fujita, and, M. Gale, Jr. 2006. Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2. Proc. Natl. Acad. Sci. USA. 104: 582– 587.
111. Samuel, M. A., and, M. S. Diamond. 2005. Alpha/beta interferon protects against lethal West Nile virus infection by restricting cellular tropism and enhancing neuronal survival. J. Virol. 79: 13350– 13361.
112. Samuel, M. A., and, M. S. Diamond. 2006. Pathogensis of West Nile virus infection: a balance between virulence, innate and adaptive immunity, and viral evasion. J. Virol. 80: 9349– 9360.
113. Samuel, M. A.,, K. Whitby,, B. C. Keller,, A. Marri,, W. Barchet,, B. R. Williams,, R. H. Silverman,, M. Gale, Jr., and, M. S. Diamond. 2006. PKR and RNase L contribute to protection against lethal West Nile Virus infection by controlling early viral spread in the periphery and replication in neurons. J. Virol. 80: 7009– 7019.
114. Sato, M.,, H. Suemori,, N. Hata,, M. Asagiri,, K. Ogasawara,, K. Nakao,, T. Nakaya,, M. Katsuki,, S. Noguchi,, N. Tanaka, and, T. Taniguchi. 2000. Distinct and essential roles of transcription factors IRF3 and IRF-7 in response to viruses for IFN-alpha/beta gene induction. Immunity 13: 539– 548.
115. Scherbik, S. V.,, J. M. Paranjape,, B. M. Stockman,, R. H. Silverman, and, M. A. Brinton. 2006. RNase L plays a role in the antiviral response to West Nile virus. J. Virol. 80: 2987– 2999.
116. Scholle, F., and, P. W. Mason. 2005. West Nile virus replication interferes with both poly(I:C)-induced interferon gene transcription and response to interferon treatment. Virology 342: 77– 87.
117. Schweizer, M.,, P. Matzener,, G. Pfaffen,, H. Stalder, and, E. Peterhans. 2006. “Self” and “nonself” manipulation of interferon defense during persistent infection: bovine viral diarrhea virus resists alpha/beta interferon without blocking antiviral activity against unrelated viruses replicating in its host cells. J. Virol. 80: 6926– 6935.
118. Seago, J.,, L. Hilton,, E. Reid,, V. Doceul,, J. Jeyatheesan,, K. Moganeradj,, J. McCauley,, B. Charleston, and, S. Goodbourn. 2007. The N pro product of classical swine fever virus and bovine viral diarrhea virus uses a conserved mechanism to target interferon regulatory factor-3. J. Gen. Virol. 88: 3002– 3006.
119. Sen, G. C. 2001. Viruses and interferons. Annu. Rev. Microbiol. 55: 255– 281.
120. Servant, M. J.,, B. tenOever,, C. LePage,, L. Conti,, S. Gessani,, I. Juljunen,, R. Lin, and, J. Hiscott. 2001. Identification of distinct signaling pathways leading to the phosphorylation of interferon regulatory factor 3. J. Biol. Chem. 276: 355– 363.
121. Seth, R. B.,, L. Sun,, C. K. Ea, and, Z. J. Chen. 2005. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NFkappaB and IRF 3. Cell 122: 669– 682.
122. Silverman, R. H. 2007. Viral encounters with OAS and RNase L during the IFN antiviral response. J. Virol. 81: 12720– 12729.
123. Smith, E. J.,, I. Marie,, A. Prakash,, A. Garcia-Sastre, and, D. E. Levy. 2001. IRF3 and IRF7 phosphorylation in virus-infected cells does not require double-stranded RNA-dependent protein kinase R or Ikappa B kinase but is blocked by vaccinia virus E3L protein. J. Biol. Chem. 276: 8951– 8957.
124. Solomon, T., and, P. M. Winter. 2004. Neurovirulence and host factors in flavivirus encephalitis—evidence from clinical epidemiology. Arch. Virol. Suppl. 2004: 161– 170.
125. Sumpter, R.,, Y.-M. Loo,, E. Foy,, K. Li,, M. Yoneyama,, T. Fujita,, S. M. Lemon, and, M. J. Gale. 2005. Regulating intracellular anti-viral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I. J. Virol. 79: 2689– 2699.
126. Taylor, D. R.,, S. T. Shi,, P. R. Romano,, G. N. Barber, and, M. M. C. Lai. 1999. Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. Science 285: 107– 110.
127. tenOever, B. R.,, M. J. Servant,, N. Grandvaux,, R. Lin, and, J. Hiscott. 2002. Recognition of the measles virus nucleocapsid as a mechanism of IRF3 activation. J. Virol. 76: 3659– 3669.
128. Trinchet, J. C.,, N. Ganne-Carrie,, P. Nahon,, G. N’kontchou, and, M. Beaugrand. 2007. Hepatocellular carcinoma in patients with hepatitis C virus-related chronic liver disease. World J. Gastroenterol. 13: 2455– 2460.
129. Tsuchihara, K.,, T. Tanaka,, M. Hijikata,, S. Kuge,, H. Toyoda,, A. Nomoto,, N. Yamamoto, and, K. Shimotohno. 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– 6726.
130. Venter, M.,, T. G. Myers,, M. A. Wilson,, T. J. Kindt,, J. T. Paweska,, F. J. Burt,, P. A. Leman, and, R. Swanepoel. 2005. Gene expression in mice infected with West Nile virus strains of different neurovirulence. Virology 342: 119– 140.
131. Wang, T.,, T. Town,, L. Alexopoulou,, J. F. Anderson,, E. Fikrig, and, R. A. Flavell. 2004. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat. Med. 10: 1366– 1373.
132. Xu, L. G.,, Y. Y. Wang,, K. J. Han,, L. Y. Li,, Z. Zhai, and, H. B. Shu. 2005. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol. Cell 19: 727– 740.
133. Yamamoto, M.,, S. Sato,, H. Hemmi,, K. Hoshino,, T. Kaisho,, H. Sanjo,, O. Takeuchi,, M. Sugiyama,, M. Okabe,, K. Takeda, and, S. Akira. 2003. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 301: 640– 643.
134. Yamamoto, M.,, S. Sato,, K. Mori,, K. Hoshino,, O. Takeuchi,, K. Takeda, and, S. Akira. 2002. Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. J. Immunol. 169: 6668– 6672.
135. Yang, Y.,, Y. Liang,, L. Qu,, Z. Chen,, M. Yi,, K. Li, and, S. M. Lemon. 2007. Disruption of innate immunity due to mitochondrial targeting of a picornaviral protease precursor. Proc. Natl. Acad. Sci. USA 104: 7253– 7258.
136. Yoneyama, M., and, T. Fujita. 2007. RIG-I family RNA helicases: cytoplasmic sensor for antiviral innate immunity. Cytokine Growth Factor Rev. 18: 545– 551.
137. Yoneyama, M.,, M. Kikuchi,, T. Natsukawa,, N. Shinobu,, T. Imaizumi,, M. Miyagishi,, K. Taira,, S. Akira, and, T. Fujita. 2004. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5: 730– 737.
138. Yoneyama, M.,, W. Suhara, and, T. Fujita. 2002. Control of IRF3 activation by phosphorylation. J. Interferon Cytokine Res. 22: 73– 76.
139. Yoneyama, M.,, W. Suhara,, Y. Fukuhara,, M. Fukuda,, E. Nishida, and, T. Fujita. 1998. Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF3 and CBP/p300. EMBO J. 17: 1087– 1095.

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