Chapter 13 : Antiviral Treatment of Flaviviruses

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $15.00

Preview this chapter:
Zoom in

Antiviral Treatment of Flaviviruses, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555815493/9781555814397_Chap13-1.gif /docserver/preview/fulltext/10.1128/9781555815493/9781555814397_Chap13-2.gif


This chapter discusses the key question of unavailability approved antiviral treatments for flavivirus pathogens which cause significant morbidity and mortality, examines the progress made in the development of therapies, identifies key targets of therapy, and reviews the challenges to overcome in the development of antiflaviviral disease treatments. It deals only with members of the genus, which include viruses of human concern, such as dengue virus (DV), yellow fever virus (YFV), West Nile virus (WNV), Japanese encephalitis virus (JEV), Murray Valley encephalitis virus (MVEV), Saint Louis encephalitis virus (SLEV), and tick-borne encephalitis virus (TBEV), all of which cause morbidity and mortality. A few flaviviruses, primarily DV and YFV, cause hemorrhagic manifestations in severe infection. The chapter investigates targets for the treatment of flaviviruses, including viral and host elements that may be effectively targeted for treatment. Important progress in the treatment of flavivirus infections has been made recently, bringing ever closer to fruition the important goal of developing a broad-spectrum agent that is effective after disease manifestation. New animal models of flaviviral disease would be important in developing a better understanding of basic virology and antiviral treatment. Epidemiological methods to detect and predict the severity and location of outbreaks would be beneficial in control of DV diseases, giving better chances to efficacy of antiflaviviral agents. Alerting physicians or veterinarians of emerging flaviviral outbreaks would also help improve the diagnosis and treatment of human or animal infections.

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13

Key Concept Ranking

Murray valley encephalitis virus
Japanese encephalitis virus
Yellow fever virus
Japanese encephalitis virus
Yellow fever virus
Japanese encephalitis virus
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of Figure 1.
Figure 1.

Key points of virus replication in regard to antiviral treatment are numbered in this outline of the flavivirus life cycle: 1, the virus attaches to the membrane of a host cell; 2, the virus enters the cell via endocytosis; 3, the endocytotic vesicle fuses with a lysosome, after which the virus is released into the cytoplasm; 4, viral RNA is released; 5, the positive-strand [(+)-strand] RNA genome is translated into a polyprotein by host cell machinery; 6, the polyprotein is cleaved by cellular and viral proteases; 7, viral enzymes replicate the viral RNA; 8, the viral RNA associates with NS proteins during assembly; 9, virus then may bud into the endoplasmic reticulum (ER); 10, virus matures and is released from the cell.

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 2.
Figure 2.

Diagrammatical representation of a typical flavivirus polyprotein. The 5’ end of the genome has a cap structure followed by an untranslated region (UTR). The genes coding for structural proteins, including nucleocapsid (C), Pre-M, and E, are located at the 5’ end of the coding region. NS proteins make up the last part of the coding sequence, followed by a 3’ UTR.

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 3.
Figure 3.

Structures of the DV (A) and WNV (B) NS5 polymerase proteins.

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 4.
Figure 4.

Chemical structures of T-1106 and T-705.

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 5.
Figure 5.

Chemical structure of ribavirin.

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 6.
Figure 6.

Structure of the NS3 protease protein of DV.

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 7.
Figure 7.

Helicase proteins from DV (A) and YFV (B).

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 8.
Figure 8.

E proteins from DV (A) and WNV (B).

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Altmeyer, R. 2004. Virus attachment and entry offer numerous targets for antiviral therapy. Curr. Pharm. Des. 10:37013712.
2. Bai, F.,, T. Town,, D. Pradhan,, J. Cox, Ashish,, M. Ledizet,, J. F. Anderson,, R. A. Flavell,, J. K. Krueger,, R. A. Koski, and, E. Fikrig. 2007. Antiviral peptides targeting the West Nile virus envelope protein. J. Virol. 81:20472055.
3. Bai, F.,, T. Wang,, U. Pal,, F. Bao,, L. H. Gould, and, E. Fikrig. 2005. Use of RNA interference to prevent lethal murine West Nile virus infection. J. Infect. Dis. 191:11481154.
4. Barrett, A. D.,, T. P. Monath,, V. Barban,, M. Niedrig, and, D. E. Teuwen. 2007. 17D yellow fever vaccines: new insights. A report of a workshop held during the World Congress on Medicine and Health in the Tropics, Marseille, France, Monday 12 September 2005. Vaccine 25:27582765.
5. Beckham, J. D.,, R. J. Goody,, P. Clarke,, C. Bonny, and, K. L. Tyler. 2007. Novel strategy for treatment of viral central nervous system infection by using a cell-permeating inhibitor of c-Jun N-terminal kinase. J. Virol. 81:69846992.
6. Bente, D. A., and, R. Rico-Hesse. 2006. Models of dengue virus infection. Drug Discov. Today 3:97103.
7. Bessaud, M.,, G. Grard,, C. N. Peyrefitte,, B. Pastorino,, D. Rolland,, R. N. Charrel,, X. de Lamballerie, and, H. J. Tolou. 2005. Identification and enzymatic characterization of NS2B-NS3 protease of Alkhurma virus, a class-4 flavivirus. Virus Res. 107:5762.
8. Borowski, P.,, M. Lang,, A. Haag,, H. Schmitz,, J. Choe,, H. M. Chen, and, R. S. Hosmane. 2002. Characterization of imidazo[4,5-d] pyridazine nucleosides as modulators of unwinding reaction mediated by West Nile virus nucleoside triphosphatase/helicase: evidence for activity on the level of substrate and/or enzyme. Antimicrob. Agents Chemother. 46:12311239.
9. Brinton, M. A. 2001. Host factors involved in West Nile virus replication. Ann. N. Y. Acad. Sci. 951:207219.
10. Brooks, T. J., and, R. J. Phillpotts. 1999. Interferon-alpha protects mice against lethal infection with St Louis encephalitis virus delivered by the aerosol and subcutaneous routes. Antivir. Res. 41:5764.
11. Chakravarti, A., and, R. Kumaria. 2006. Circulating levels of tumour necrosis factor-alpha & interferon-gamma in patients with dengue & dengue haemorrhagic fever during an outbreak. Indian J. Med. Res. 123:2530.
12. Chambers, T. J., and, M. S. Diamond. 2003. Pathogenesis of flavi-virus encephalitis. Adv. Virus Res. 60:273342.
13. Chan-Tack, K. M., and, G. Forrest. 2005. Failure of interferon alpha-2b in a patient with West Nile virus meningoencephalitis and acute flaccid paralysis. Scand. J. Infect. Dis. 37:944946.
14. Charlier, N.,, P. Leyssen,, E. De Clercq, and, J. Neyts. 2004. Rodent models for the study of therapy against flavivirus infections. Anti-vir. Res. 63:6777.
15. Charnsilpa, W.,, R. Takhampunya,, T. P. Endy,, M. P. Mammen, Jr.,, D. H. Libraty, and, S. Ubol. 2005. Nitric oxide radical suppresses replication of wild-type dengue 2 viruses in vitro. J. Med. Virol. 77:8995.
16. Chen, H. C.,, F. M. Hofman,, J. T. Kung,, Y. D. Lin, and, B. A. WuHsieh. 2007. Both virus and tumor necrosis factor alpha are critical for endothelium damage in a mouse model of dengue virus-induced hemorrhage. J. Virol. 81:55185526.
17. Chu, J. J., and, M. L. Ng. 2003. The mechanism of cell death during West Nile virus infection is dependent on initial infectious dose. J. Gen. Virol. 84:33053314.
18. Clyde, K.,, J. L. Kyle, and, E. Harris. 2006. Recent advances in deciphering viral and host determinants of dengue virus replication and pathogenesis. J. Virol. 80:1141811431.
19. Costa-Pereira, A. P.,, T. M. Williams,, B. Strobl,, D. Watling,, J. Briscoe, and, I. M. Kerr. 2002. The antiviral response to gamma inter-feron. J. Virol. 76:90609068.
20. Crance, J. M.,, N. Scaramozzino,, A. Jouan, and, D. Garin. 2003. Interferon, ribavirin, 6-azauridine and glycyrrhizin: antiviral compounds active against pathogenic flaviviruses. Antivir. Res. 58:7379.
21. Darman, J.,, S. Backovic,, S. Dike,, N. J. Maragakis,, C. Krishnan,, J. D. Rothstein,, D. N. Irani, and, D. A. Kerr. 2004. Viral-induced spinal motor neuron death is non-cell-autonomous and involves glutamate excitotoxicity. J. Neurosci. 24:75667575.
22. Davis, L. E.,, R. DeBiasi,, D. E. Goade,, K. Y. Haaland,, J. A. Harrington,, J. B. Harnar,, S. A. Pergam,, M. K. King,, B. K. DeMasters, and, K. L. Tyler. 2006. West Nile virus neuroinvasive disease. Ann. Neurol. 60:286300.
23. Day, C. W.,, D. F. Smee,, J. G. Julander,, V. F. Yamshchikov,, R. W. Sidwell, and, J. D. Morrey. 2005. Error-prone replication of West Nile virus caused by ribavirin. Antivir. Res. 67:3845.
24. Deas, T. S.,, C. J. Bennett,, S. A. Jones,, M. Tilgner,, P. Ren,, M. J. Behr,, D. A. Stein,, P. L. Iversen,, L. D. Kramer,, K. A. Bernard, and, P. Y. Shi. 2007. In vitro resistance selection and in vivo efficacy of morpholino oligomers against West Nile virus. Antimicrob. Agents Chemother. 51:24702482.
25. Deas, T. S.,, I. Binduga-Gajewska,, M. Tilgner,, P. Ren,, D. A. Stein,, H. M. Moulton,, P. L. Iversen,, E. B. Kauffman,, L. D. Kramer, and, P. Y. Shi. 2005. Inhibition of flavivirus infections by antisense oligomers specifically suppressing viral translation and RNA replication. J. Virol. 79:45994609.
26. De Clercq, E. 2005. Recent highlights in the development of new antiviral drugs. Curr. Opin. Microbiol. 8:552560.
27. Diamond, M. S. 2003. Evasion of innate and adaptive immunity by flaviviruses. Immunol. Cell Biol. 81:196206.
28. Diamond, M. S., and, R. S. Klein. 2006. A genetic basis for human susceptibility to West Nile virus. Trends Microbiol. 14:287289.
29. Diamond, M. S.,, B. Shrestha,, E. Mehlhop,, E. Sitati, and, M. Engle. 2003. Innate and adaptive immune responses determine protection against disseminated infection by West Nile encephalitis virus. Viral Immunol. 16:259278.
30. Diamond, M. S.,, M. Zachariah, and, E. Harris. 2002. Mycophenolic acid inhibits dengue virus infection by preventing replication of viral RNA. Virology 304:211221.
31. Ding, S. W., and, O. Voinnet. 2007. Antiviral immunity directed by small RNAs. Cell 130:413426.
32. Edelman, R. 2007. Dengue vaccines approach the finish line. Clin. Infect. Dis. 45(Suppl. 1):S56S60.
33. Fitzner, J.,, D. Coulibaly,, D. E. Kouadio,, J. C. Yavo,, Y. G. Loukou,, P. O. Koudou, and, D. Coulombier. 2004. Safety of the yellow fever vaccine during the September 2001 mass vaccination campaign in Abidjan, Ivory Coast. Vaccine 23:156162.
34. Frick, D. N., and, A. M. Lam. 2006. Understanding helicases as a means of virus control. Curr. Pharm. Des. 12:13151338.
35. Furuta, Y.,, K. Takahashi,, M. Kuno-Maekawa,, H. Sangawa,, S. Uehara,, K. Kozaki,, N. Nomura,, H. Egawa, and, K. Shiraki. 2005. Mechanism of action of T-705 against influenza virus. Antimicrob. Agents Chemother. 49:981986.
36. Getts, D. R.,, I. Matsumoto,, M. Muller,, M. T. Getts,, J. Radford,, B. Shrestha,, I. L. Campbell, and, N. J. King. 2007. Role of IFN-gamma in an experimental murine model of West Nile virus-induced seizures. J. Neurochem. 103:10191030.
37. Glass, W. G.,, J. K. Lim,, R. Cholera,, A. G. Pletnev,, J. L. Gao, and, P. M. Murphy. 2005. Chemokine receptor CCR5 promotes leukocyte trafficking to the brain and survival in West Nile virus infection. J. Exp. Med. 202:10871098.
38. Goodell, J. R.,, F. Puig-Basagoiti,, B. M. Forshey,, P. Y. Shi, and, D. M. Ferguson. 2006. Identification of compounds with anti-West Nile Virus activity. J. Med. Chem. 49:21272137.
39. Green, S., and, A. Rothman. 2006. Immunopathological mechanisms in dengue and dengue hemorrhagic fever. Curr. Opin. Infect. Dis. 19:429436.
40. Griffin, D. E. 2005. Neuronal cell death in alphavirus encephalomyelitis. Curr. Top. Microbiol. Immunol. 289:5777.
41. Gu, B.,, P. Mason,, L. Wang,, P. Norton,, N. Bourne,, R. Moriarty,, A. Mehta,, M. Despande,, R. Shah, and, T. Block. 2007. Antiviral profiles of novel iminocyclitol compounds against bovine viral diarrhea virus, West Nile virus, dengue virus and hepatitis B virus. Antivir. Chem. Chemother. 18:4959.
42. Gu, B.,, S. Ouzunov,, L. Wang,, P. Mason,, N. Bourne,, A. Cuconati, and, T. M. Block. 2006. Discovery of small molecule inhibitors of West Nile virus using a high-throughput sub-genomic replicon screen. Antivir. Res. 70:3950.
43. Gubler, D. J. 2006. Dengue/dengue haemorrhagic fever: history and current status. Novartis Found. Symp. 277:316, 1622, 7173, 251253.
44. Halstead, S. B. 1979. In vivo enhancement of dengue virus infection in rhesus monkeys by passively transferred antibody. J. Infect. Dis. 140:527533.
45. Harrison, T. J. 2006. Hepatitis B virus: molecular virology and common mutants. Semin. Liver Dis. 26:8796.
46. Hrobowski, Y. M.,, R. F. Garry, and, S. F. Michael. 2005. Peptide inhibitors of dengue virus and West Nile virus infectivity. Virol. J. 2:49.
47. Hsu, J. T.,, H. C. Wang,, G. W. Chen, and, S. R. Shih. 2006. Antiviral drug discovery targeting to viral proteases. Curr. Pharm. Des. 12:13011314.
48. Huggins, J. W. 1989. Prospects for treatment of viral hemorrhagic fevers with ribavirin, a broad-spectrum antiviral drug. Rev. Infect. Dis. 11(Suppl. 4):S750S761.
49. Huhn, G. D.,, J. Brown,, W. Perea,, A. Berthe,, H. Otero,, G. Li-Beau,, N. Maksha,, M. Sankoh,, S. Montgomery,, A. Marfin, and, M. Admassu. 2006. Vaccination coverage survey versus administrative data in the assessment of mass yellow fever immunization in internally displaced persons—Liberia, 2004. Vaccine 24:730737.
50. Jennings, A. D.,, C. A. Gibson,, B. R. Miller,, J. H. Mathews,, C. J. Mitchell,, J. T. Roehrig,, D. J. Wood,, F. Taffs,, B. K. Sil,, S. N. Whitby, et al. 1994. Analysis of a yellow fever virus isolated from a fatal case of vaccine-associated human encephalitis. J. Infect. Dis. 169:512518.
51. Julander, J. G.,, Y. Furuta,, K. Shafer, and, R. W. Sidwell. 2007. Activity of T-1106 in a hamster model of yellow fever virus infection. Antimicrob. Agents Chemother. 51:19621966.
52. Julander, J. G.,, J. W. Judge,, A. L. Olsen,, B. Rosenberg,, K. Schafer, and, R. W. Sidwell. 2006. Prophylactic treatment with recombinant Eimeria protein, alone or in combination with an agonist cocktail, protects mice from Banzi virus infection. Antivir. Res. 75:1419.
53. Julander, J. G.,, J. D. Morrey,, L. M. Blatt,, K. Shafer, and, R. W. Sidwell. 2007. Comparison of the inhibitory effects of interferon alfacon-1 and ribavirin on yellow fever virus infection in a hamster model. Antivir. Res. 73:140146.
54. Kalil, A. C.,, M. P. Devetten,, S. Singh,, B. Lesiak,, D. P. Poage,, K. Bargenquast,, P. Fayad, and, A. G. Freifeld. 2005. Use of inter-feron-alpha in patients with West Nile encephalitis: report of 2 cases. Clin. Infect. Dis. 40:764766.
55. Keller, T. H.,, Y. L. Chen,, J. E. Knox,, S. P. Lim,, N. L. Ma,, S. J. Patel,, A. Sampath,, Q. Y. Wang,, Z. Yin, and, S. G. Vasudevan. 2006. Finding new medicines for flaviviral targets. Novartis Found. Symp. 277:102114, 114119, 251253.
56. Kengsakul, K.,, K. Sathirapongsasuti, and, S. Punyagupta. 2002. Fatal myeloencephalitis following yellow fever vaccination in a case with HIV infection. J. Med. Assoc. Thai. 85:1311134.
57. Khromava, A. Y.,, R. B. Eidex,, L. H. Weld,, K. S. Kohl,, R. D. Bradshaw,, R. T. Chen, and, M. S. Cetron. 2005. Yellow fever vaccine: an updated assessment of advanced age as a risk factor for serious adverse events. Vaccine 23:32563263.
58. Khromykh, A. A.,, H. Meka,, K. J. Guyatt, and, E. G. Westaway. 2001. Essential role of cyclization sequences in flavivirus RNA replication. J. Virol. 75:67196728.
59. King, N. J.,, D. R. Getts,, M. T. Getts,, S. Rana,, B. Shrestha, and, A. M. Kesson. 2007. Immunopathology of flavivirus infections. Immunol. Cell Biol. 85:3342.
60. Kinney, R. M.,, C. Y. Huang,, B. C. Rose,, A. D. Kroeker,, T. W. Dreher,, P. L. Iversen, and, D. A. Stein. 2005. Inhibition of dengue virus serotypes 1 to 4 in Vero cell cultures with morpholino oligomers. J. Virol. 79:51165128.
61. Kleiter, I.,, A. Steinbrecher,, D. Flugel,, U. Bogdahn, and, W. Schulte-Mattler. 2006. Autonomic involvement in tick-borne encephalitis (TBE): report of five cases. Eur. J. Med. Res. 11:261265.
62. Kumar, P.,, S. K. Lee,, P. Shankar, and, N. Manjunath. 2006. A single siRNA suppresses fatal encephalitis induced by two different flaviviruses. PLoS Med. 3:e96.
63. Kumar, P.,, H. Wu,, J. L. McBride,, K. E. Jung,, M. H. Kim,, B. L. Davidson,, S. K. Lee,, P. Shankar, and, N. Manjunath. 2007. Transvascular delivery of small interfering RNA to the central nervous system. Nature 448:3943.
64. Kurane, I. 2007. Dengue hemorrhagic fever with special emphasis on immunopathogenesis. Comp. Immunol. Microbiol. Infect. Dis. 30:329340.
65. Lanciotti, R. S.,, J. T. Roehrig,, V. Deubel,, J. Smith,, M. Parker,, K. Steele,, B. Crise,, K. E. Volpe,, M. B. Crabtree,, J. H. Scherret,, R. A. Hall,, J. S. MacKenzie,, C. B. Cropp,, B. Panigrahy,, E. Ost-lund,, B. Schmitt,, M. Malkinson,, C. Banet,, J. Weissman,, N. Komar,, H. M. Savage,, W. Stone,, T. McNamara, and, D. J. Gubler. 1999. Origin of the West Nile virus responsible for an outbreak of encephalitis in the northeastern United States. Science 286:23332337.
66. Lee, E.,, M. Pavy,, N. Young,, C. Freeman, and, M. Lobigs. 2006. Antiviral effect of the heparan sulfate mimetic, PI-88, against dengue and encephalitic flaviviruses. Antivir. Res. 69:3138.
67. Lei, H. Y.,, T. M. Yeh,, H. S. Liu,, Y. S. Lin,, S. H. Chen, and, C. C. Liu. 2001. Immunopathogenesis of dengue virus infection. J. Biomed. Sci. 8:377388.
68. Lemasters, J. J. 1999. V. Necrapoptosis and the mitochondrial permeability transition: shared pathways to necrosis and apoptosis. Am. J. Physiol. 276:G1G6.
69. Lemasters, J. J.,, T. Qian,, C. A. Bradham,, D. A. Brenner,, W. E. Cascio,, L. C. Trost,, Y. Nishimura,, A. L. Nieminen, and, B. Herman. 1999. Mitochondrial dysfunction in the pathogenesis of necrotic and apoptotic cell death. J. Bioenerg. Biomembr. 31:305319.
70. Lewis, M., and, J. R. Amsden. 2007. Successful treatment of West Nile virus infection after approximately 3 weeks into the disease course. Pharmacotherapy 27:455458.
71. Leyssen, P.,, J. Balzarini,, E. De Clercq, and, J. Neyts. 2005. The predominant mechanism by which ribavirin exerts its antiviral activity in vitro against flaviviruses and paramyxoviruses is mediated by inhibition of IMP dehydrogenase. J. Virol. 79:19431947.
72. Leyssen, P.,, E. De Clercq, and, J. Neyts. 2000. Perspectives for the treatment of infections with Flaviviridae. Clin. Microbiol. Rev. 13:6782.
73. Leyssen, P.,, E. De Clercq, and, J. Neyts. 2006. The anti-yellow fever virus activity of ribavirin is independent of error-prone replication. Mol. Pharmacol. 69:14611467.
74. Leyssen, P.,, C. Drosten,, M. Paning,, N. Charlier,, J. Paeshuyse,, E. De Clercq, and, J. Neyts. 2003. Interferons, interferon inducers, and interferon-ribavirin in treatment of flavivirus-induced encephalitis in mice. Antimicrob. Agents Chemother. 47:777782.
75. Lin, C. C.,, L. T. Yeh,, T. Luu,, D. Lourenco, and, J. Y. Lau. 2003. Pharmacokinetics and metabolism of [(14)C]ribavirin in rats and cynomolgus monkeys. Antimicrob. Agents Chemother. 47:13951398.
76. Lipsitch, M.,, T. Cohen,, M. Murray, and, B. R. Levin. 2007. Antiviral resistance and the control of pandemic influenza. PLoS Med. 4:e15.
77. 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. 80:23962404.
78. Lohr, K.,, J. E. Knox,, W. Y. Phong,, N. L. Ma,, Z. Yin,, A. Sampath,, S. J. Patel,, W. L. Wang,, W. L. Chan,, K. R. Rao,, G. Wang,, S. G. Vasudevan,, T. H. Keller, and, S. P. Lim. 2007. Yellow fever virus NS3 protease: peptide-inhibition studies. J. Gen. Virol. 88:22232227.
79. Lok, A. S.,, F. Zoulim,, S. Locarnini,, A. Bartholomeusz,, M. G. Ghany,, J. M. Pawlotsky,, Y. F. Liaw,, M. Mizokami, and, C. Kuiken. 2007. Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management. Hepatology 46:254265.
80. Lum, L. C.,, S. K. Lam,, Y. S. Choy,, R. George, and, F. Harun. 1996. Dengue encephalitis: a true entity? Am. J. Trop. Med. Hyg. 54:256259.
81. Malet, H.,, M. P. Egloff,, B. Selisko,, R. E. Butcher,, P. J. Wright,, M. Roberts,, A. Gruez,, G. Sulzenbacher,, C. Vonrhein,, G. Bricogne,, J. M. Mackenzie,, A. A. Khromykh,, A. D. Davidson, and, B. Canard. 2007. Crystal structure of the RNA polymerase domain of the West Nile virus non-structural protein 5. J. Biol. Chem. 282:1067810689.
82. Malinoski, F. J.,, S. E. Hasty,, M. A. Ussery, and, J. M. Dalrymple. 1990. Prophylactic ribavirin treatment of dengue type 1 infection in rhesus monkeys. Antivir. Res. 13:139149.
83. Marchette, N. J.,, T. O’Rourke, and, S. B. Halstead. 1980. Studies on dengue 2 virus infection in cyclophosphamide-treated rhesus monkeys. Med. Microbiol. Immunol. 168:3547.
84. Mason, R. A.,, N. M. Tauraso,, R. K. Ginn,, T. C. O’Brien, and, R. W. Trimmer. 1972. Yellow fever vaccine. V. Antibody response in monkeys inoculated with graded doses of the 17D vaccine. Appl. Microbiol. 23:908913.
85. Mason, R. A.,, N. M. Tauraso,, R. O. Spertzel, and, R. K. Ginn. 1973. Yellow fever vaccine: direct challenge of monkeys given graded doses of 17D vaccine. Appl. Microbiol. 25:539544.
86. McMinn, P. C. 1997. The molecular basis of virulence of the encephalitogenic flaviviruses. J. Gen. Virol. 78(Pt. 11):27112722.
87. Michaelis, M.,, M. C. Kleinschmidt,, H. W. Doerr, and, J. Cinatl, Jr. 2007. Minocycline inhibits West Nile virus replication and apoptosis in human neuronal cells. J. Antimicrob. Chemother. 60:981986.
88. Mizutani, T.,, M. Kobayashi,, Y. Eshita,, K. Shirato,, T. Kimura,, Y. Ako,, H. Miyoshi,, T. Takasaki,, I. Kurane,, H. Kariwa,, T. Umemura, and, I. Takashima. 2003. Involvement of the JNK-like protein of the Aedes albopictus mosquito cell line, C6/36, in phagocytosis, endocytosis and infection of West Nile virus. Insect Mol. Biol. 12:491499.
89. Monath, T. P. 2006. Yellow fever as an endemic/epidemic disease and priorities for vaccination. Bull. Soc. Pathol. Exot. 99:341347.
90. Monath, T. P. 2005. Yellow fever vaccine. Expert Rev. Vaccines 4:553574.
91. Morrey, J. D.,, C. W. Day,, J. G. Julander,, L. M. Blatt,, D. F. Smee, and, R. W. Sidwell. 2004. Effect of interferon-alpha and interferoninducers on West Nile virus in mouse and hamster animal models. Antivir. Chem. Chemother. 15:6775.
92. Morrey, J. D.,, C. W. Day,, J. G. Julander,, A. L. Olsen,, R. W. Sidwell,, C. D. Cheney, and, L. M. Blatt. 2004. Modeling hamsters for evaluating West Nile virus therapies. Antivir. Res. 63:4150.
93. Morrey, J. D.,, V. Siddharthan,, A. L. Olsen,, G. Y. Roper,, H. Wang,, T. J. Baldwin,, S. Koenig,, S. Johnson,, J. L. Nordstrom, and, M. S. Diamond. 2006. Humanized monoclonal antibody against West Nile virus envelope protein administered after neuronal infection protects against lethal encephalitis in hamsters. J. Infect. Dis. 194:13001308.
94. Morrey, J. D.,, V. Siddharthan,, A. L. Olsen,, H. Wang,, J. G. Ju-lander,, J. O. Hall,, H. Li,, J. L. Nordstrom,, S. Koenig,, S. Johnson, and, M. S. Diamond. 2007. Defining limits of treatment with humanized neutralizing monoclonal antibody for West Nile virus neurological infection in a hamster model. Antimicrob. Agents Chemother. 51:23962402.
95. Mueller, N. H.,, C. Yon,, V. K. Ganesh, and, R. Padmanabhan. 2007. Characterization of the West Nile virus protease substrate specificity and inhibitors. Int. J. Biochem. Cell Biol. 39:606614.
96. Neyts, J. 2006. Selective inhibitors of hepatitis C virus replication. Antivir. Res. 71:363371.
97. Ng, C. Y.,, F. Gu,, W. Y. Phong,, Y. L. Chen,, S. P. Lim,, A. Davidson, and, S. G. Vasudevan. 2007. Construction and characterization of a stable subgenomic dengue virus type 2 replicon system for antiviral compound and siRNA testing. Antivir. Res. 76:222231.
98. Noueiry, A. O.,, P. D. Olivo,, U. Slomczynska,, Y. Zhou,, B. Buscher,, B. Geiss,, M. Engle,, R. M. Roth,, K. M. Chung,, M. Samuel, and, M. S. Diamond. 2007. The identification of novel small-molecule inhibitors of West Nile virus infection. J. Virol. 76:119921204.
99. Oishi, K.,, M. Saito,, C. A. Mapua, and, F. F. Natividad. 2007. Dengue illness: clinical features and pathogenesis. J. Infect. Che-mother. 13:125133.
100. Ojwang, J. O.,, S. Ali,, D. F. Smee,, J. D. Morrey,, C. D. Shimasaki, and, R. W. Sidwell. 2005. Broad-spectrum inhibitor of viruses in the Flaviviridae family. Antivir. Res. 68:4955.
101. O’Leary, D. M.,, V. Movsesyan,, S. Vicini, and, A. I. Faden. 2000. Selective mGluR5 antagonists MPEP and SIB-1893 decrease NMDA or glutamate-mediated neuronal toxicity through actions that reflect NMDA receptor antagonism. Br. J. Pharmacol. 131:14291437.
102. Oliphant, T., and, M. S. Diamond. 2007. The molecular basis of antibody-mediated neutralization of West Nile virus. Expert Opin. Biol. Ther. 7:885892.
103. Oliphant, T.,, M. Engle,, G. E. Nybakken,, C. Doane,, S. Johnson,, L. Huang,, S. Gorlatov,, E. Mehlhop,, A. Marri,, K. M. Chung,, G. D. Ebel,, L. D. Kramer,, D. H. Fremont, and, M. S. Diamond. 2005. Development of a humanized monoclonal antibody with therapeutic potential against West Nile virus. Nat. Med. 11:522530.
104. Ong, S. P.,, B. G. Choo,, J. J. Chu, and, M. L. Ng. 2006. Expression of vector-based small interfering RNA against West Nile virus effectively inhibits virus replication. Antivir. Res. 72:216223.
105. Ono, L.,, W. Wollinger,, I. M. Rocco,, T. L. Coimbra,, P. A. Gorin, and, M. R. Sierakowski. 2003. In vitro and in vivo antiviral properties of sulfated galactomannans against yellow fever virus (BeH111 strain) and dengue 1 virus (Hawaii strain). Antivir. Res. 60:201208.
106. Padmanabhan, R.,, N. Mueller,, E. Reichert,, C. Yon,, T. Teramoto,, Y. Kono,, R. Takhampunya,, S. Ubol,, N. Pattabiraman,, B. Fal-gout,, V. K. Ganesh, and, K. Murthy. 2006. Multiple enzyme activities of flavivirus proteins. Novartis Found. Symp. 277:7484, 8486, 251253.
107. Pang, T.,, M. J. Cardosa, and, M. G. Guzman. 2007. Of cascades and perfect storms: the immunopathogenesis of dengue haemorrhagic fever-dengue shock syndrome (DHF/DSS). Immunol. Cell Biol. 85:4345.
108. 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. 81:69366946.
109. Petersen, L. R., and, A. A. Marfin. 2005. Shifting epidemiology of Flaviviridae. J. Travel Med. 12(Suppl. 1):S3S11.
110. Phillpotts, R. J.,, L. D. Jones,, R. A. Lukaszewski,, C. Lawrie, and, T. J. Brooks. 2003. Antibody and interleukin-12 treatment in murine models of encephalitogenic flavivirus (St. Louis encephalitis, tick-borne encephalitis) and alphavirus (Venezuelan equine encephalitis) infection. J. Interferon Cytokine Res. 23:4750.
111. Prow, N. A., and, D. N. Irani. 2007. The opioid receptor antagonist, naloxone, protects spinal motor neurons in a murine model of alphavirus encephalomyelitis. Exp. Neurol. 205:461470.
112. Puig-Basagoiti, F.,, M. Tilgner,, B. M. Forshey,, S. M. Philpott,, N. G. Espina,, D. E. Wentworth,, S. J. Goebel,, P. S. Masters,, B. Falgout,, P. Ren,, D. M. Ferguson, and, P. Y. Shi. 2006. Triaryl pyrazoline compound inhibits flavivirus RNA replication. Anti-microb. Agents Chemother. 50:13201329.
113. Rahal, J. J.,, J. Anderson,, C. Rosenberg,, T. Reagan, and, L. L. Thompson. 2004. Effect of interferon-alpha2b therapy on St. Louis viral meningoencephalitis: clinical and laboratory results of a pilot study. J. Infect. Dis. 190:10841087.
114. Rothman, A. L. 2004. Dengue: defining protective versus pathologic immunity. J. Clin. Investig. 113:946951.
115. Russmann, S.,, I. Grattagliano,, P. Portincasa,, V. O. Palmieri, and, G. Palasciano. 2006. Ribavirin-induced anemia: mechanisms, risk factors and related targets for future research. Curr. Med. Chem. 13:33513357.
116. Samuel, M. A.,, J. D. Morrey, and, M. S. Diamond. 2007. Caspase 3-dependent cell death of neurons contributes to the pathogenesis of West Nile virus encephalitis. J. Virol. 81:26142623.
117. Samuel, M. A.,, H. Wang,, V. Siddharthan,, J. D. Morrey, and, M. S. Diamond. 2007. Axonal transport mediates West Nile virus entry into the central nervous system and induces acute flaccid paralysis. Proc. Natl. Acad. Sci. USA 104:1714017145.
118. Sbrana, E.,, S. Y. Xiao,, H. Guzman,, M. Ye,, A. P. Travassos da Rosa, and, R. B. Tesh. 2004. Efficacy of post-exposure treatment of yellow fever with ribavirin in a hamster model of the disease. Am. J. Trop. Med. Hyg. 71:306312.
119. Sbrana, E.,, S. Y. Xiao,, V. L. Popov,, P. C. Newman, and, R. B. Tesh. 2006. Experimental yellow fever virus infection in the golden hamster (Mesocricetus auratus) III. Clinical laboratory values. Am. J. Trop. Med. Hyg. 74:10841089.
120. 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 342:7787.
121. Shresta, S.,, K. L. Sharar,, D. M. Prigozhin,, P. R. Beatty, and, E. Harris. 2006. Murine model for dengue virus-induced lethal disease with increased vascular permeability. J. Virol. 80:1020810217.
122. Shrestha, B., and, M. S. Diamond. 2004. Role of CD8+ T cells in control of West Nile virus infection. J. Virol. 78:83128321.
123. Shrestha, B.,, T. Wang,, M. A. Samuel,, K. Whitby,, J. Craft,, E. Fikrig, and, M. S. Diamond. 2006. Gamma interferon plays a crucial early antiviral role in protection against West Nile virus infection. J. Virol. 80:53385348.
124. Sidwell, R. W.,, D. L. Barnard,, C. W. Day,, D. F. Smee,, K. W. Bailey,, M. H. Wong,, J. D. Morrey, and, Y. Furuta. 2007. Efficacy of orally administered T-705 on lethal avian influenza A (H5N1) virus infections in mice. Antimicrob. Agents Chemother. 51:845851.
125. Sidwell, R. W., and, J. H. Huffman. 1971. Use of disposable micro tissue culture plates for antiviral and interferon induction studies. Appl. Microbiol. 22:797801.
126. Siirin, M. T.,, T. Duan,, H. Lei,, H. Guzman,, A. P. da Rosa,, D. M. Watts,, S. Y. Xiao, and, R. B. Tesh. 2007. Chronic St. Louis encephalitis virus infection in the golden hamster (Mesocricetus auratus). Am. J. Trop. Med. Hyg. 76:299306.
127. Solomon, T.,, N. M. Dung,, B. Wills,, R. Kneen,, M. Gainsborough,, T. V. Diet,, T. T. Thuy,, H. T. Loan,, V. C. Khanh,, D. W. Vaughn,, N. J. White, and, J. J. Farrar. 2003. Interferon alfa-2a in Japanese encephalitis: a randomised double-blind placebo-controlled trial. Lancet 361:821826.
128. Strazielle, N., and, J. F. Ghersi-Egea. 2005. Factors affecting delivery of antiviral drugs to the brain. Rev. Med. Virol. 15:105133.
129. Takhampunya, R.,, R. Padmanabhan, and, S. Ubol. 2006. Antiviral action of nitric oxide on dengue virus type 2 replication. J. Gen. Virol. 87:30033011.
130. Takhampunya, R.,, S. Ubol,, H. S. Houng,, C. E. Cameron, and, R. Padmanabhan. 2006. Inhibition of dengue virus replication by mycophenolic acid and ribavirin. J. Gen. Virol. 87:19471952.
131. Tesh, R. B.,, H. Guzman,, A. P. da Rosa,, P. F. Vasconcelos,, L. B. Dias,, J. E. Bunnell,, H. Zhang, and, S. Y. Xiao. 2001. Experimental yellow fever virus infection in the golden hamster (Mesocricetus auratus). I. Virologic, biochemical, and immunologic studies. J. Infect. Dis. 183:14311436.
132. Tomei, L.,, S. Altamura,, G. Paonessa,, R. De Francesco, and, G. Migliaccio. 2005. HCV antiviral resistance: the impact of in vitro studies on the development of antiviral agents targeting the viral NS5B polymerase. Antivir. Chem. Chemother. 16:225245.
133. Tomori, O. 2004. Yellow fever: the recurring plague. Crit. Rev. Clin. Lab. Sci. 41:391427.
134. Ujjinamatada, R. K.,, Y. S. Agasimundin,, P. Zhang,, R. S. Hos-mane,, R. Schuessler,, P. Borowski,, K. Kalicharran, and, A. Fattom. 2005. A novel imidazole nucleoside containing a diaminodihydro-S-triazine as a substituent: inhibitory activity against the West Nile virus NTPase/helicase. Nucleosides Nucleotides Nucleic Acids 24:17751788.
135. Ujjinamatada, R. K.,, A. Baier,, P. Borowski, and, R. S. Hosmane. 2007. An analogue of AICAR with dual inhibitory activity against WNV and HCV NTPase/helicase: synthesis and in vitro screening of 4-carbamoyl-5-(4,6-diamino-2,5-dihydro-1,3,5-triazin-2-yl)imidazole-1-beta-D-ribofuranoside. Bioorg. Med. Chem. Lett. 17:22852288.
136. Van Laethem, K., and, A. M. Vandamme. 2006. Interpreting resistance data for HIV-1 therapy management—know the limitations. AIDS Rev. 8:3743.
137. Wang, Y.,, M. Lobigs,, E. Lee,, A. Koskinen, and, A. Mullbacher. 2006. CD8(+) T cell-mediated immune responses in West Nile virus (Sarafend strain) encephalitis are independent of gamma interferon. J. Gen. Virol. 87:35993609.
138. Whitby, K.,, T. C. Pierson,, B. Geiss,, K. Lane,, M. Engle,, Y. Zhou,, R. W. Doms, and, M. S. Diamond. 2005. Castanospermine, a potent inhibitor of dengue virus infection in vitro and in vivo. J. Virol. 79:86988706.
139. Witayathawornwong, P. 2005. Fatal dengue encephalitis. Southeast Asian J. Trop. Med. Public Health 36:200202.
140. Wolf, R. F.,, J. F. Papin,, R. Hines-Boykin,, M. Chavez-Suarez,, G. L. White,, M. Sakalian, and, D. P. Dittmer. 2006. Baboon model for West Nile virus infection and vaccine evaluation. Virology 355:4451.
141. Wu, J.,, A. K. Bera,, R. J. Kuhn, and, J. L. Smith. 2005. Structure of the Flavivirus helicase: implications for catalytic activity, protein interactions, and proteolytic processing. J. Virol. 79:1026810277.
142. Xiao, S. Y.,, H. Zhang,, H. Guzman, and, R. B. Tesh. 2001. Experimental yellow fever virus infection in the golden hamster (Mesocricetus auratus). II. Pathology. J. Infect. Dis. 183:14371444.


Generic image for table
Table 1.

Cases of WNV disease reported in the United States from 1999 through 25 September 2007

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13
Generic image for table
Table 2.

Compounds efficacious in the treatment of flaviviruses in various cell culture models

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13
Generic image for table
Table 3.

Select compounds with activity against flaviviruses in various animal models of disease

Citation: Julander J. 2009. Antiviral Treatment of Flaviviruses, p 223-240. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch13

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error