Chapter 18 : Targeting the Interferon Response for Antiviral Therapy

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

Preview this chapter:
Zoom in

Targeting the Interferon Response for Antiviral Therapy, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555815493/9781555814397_Chap18-1.gif /docserver/preview/fulltext/10.1128/9781555815493/9781555814397_Chap18-2.gif


This chapter provides a general introduction and overview of the interferon (IFN) pathway. Separate sections of this chapter address the different types of IFN, activation of IFN-α/β expression, IFN-mediated signal transduction, antiviral mechanisms, and viral resistance to the IFN-α/β response. The IFNs are classified into three types (I, II, and III) based on receptor usage, sequence homology, and chromosome location of their genes. The chapter primarily focuses on the type I IFNs, as these cytokines are most closely associated with antiviral activity and therapeutic use. Like RNA, cytosolic DNA also induces the production of IFN-β. Therefore, in addition to RNA viruses, a mechanism also exists to detect the genomes from DNA viruses in the cytoplasm of infected cells. The Toll-like receptors (TLRs) are critical for recognizing different molecular patterns that are unique to viral or bacterial pathogens. As with the cytoplasmic sensors, specificity for pathogen-derived nucleic acids by the TLRs is at least in part provided at the level of nucleic acid modifications. IFN-α/β is important for certain aspects of the adaptive immune response and serves as one example of a bridge between innate and adaptive immunity. In addition to antiviral and immunomodulatory functions, IFN-α/β can also negatively influence cellular proliferation. Future research into improved IFN-based antiviral therapies might focus on improving the antiviral properties of these cytokines while decreasing the unwanted side effects. This goal might be accomplished in a number of distinct ways.

Citation: Robek M. 2009. Targeting the Interferon Response for Antiviral Therapy, p 317-332. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch18
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of Figure 1.
Figure 1.

IFN-β induction by dsRNA. Binding of dsRNA to TLR3 in endosomes leads to signaling through the TRIF adapter protein to activate the kinases TBK-1 and IKK-∊. Similarly, RNA binding to RIG-I or MDA5 in the cytoplasm leads to interaction with the mitochondrial protein IPS-1, followed by activation of the same kinases. These kinases in turn phosphorylate IRF-3, which then dimerizes, translocates to the nucleus, and activates IFN-β mRNA expression. IFN-β protein synthesized in the cytoplasm is then released from the cell. This process can be interrupted at various steps by viral proteins, including vaccinia virus E3L, which sequesters dsRNA; HCV NS3/4A, which cleaves IPS-1 and TRIF; KSHV vIRF, which inhibits IRF-3 function; and VSV matrix (M), which blocks mRNA export.

Citation: Robek M. 2009. Targeting the Interferon Response for Antiviral Therapy, p 317-332. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch18
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 2.
Figure 2.

IFN-α/β and IFN-γ receptor signaling. Binding of IFN-α/β or IFN-γ to their respective receptor activates Jak and Tyk tyrosine kinases to phosphorylate STAT proteins. After phosphorylation, the STATs dimerize and translocate to the nucleus, where they initiate transcription from specific promoter elements. The IFN-α/β receptor induces the activation of STAT-1/STAT-2 heterodimers, which when bound to IRF-9 activate IFN-stimulated gene expression from ISRE sequences. Likewise, the IFN-γ receptor induces the formation of STAT-1 homodimers, which bind and activate GAS elements. As with IFN-α/β induction, this process can be inhibited by viral proteins at multiple steps. Some examples include vaccinia virus B8R and B18R, which bind and neutralize extracellular IFN-α and IFN-γ; KSHV K3 and K5, which downregulate IFN-γ receptor from the cell surface; paramyxovirus V proteins, which inhibit STAT activation; and rabies P protein, which sequesters STAT proteins in the cytoplasm, preventing their nuclear import.

Citation: Robek M. 2009. Targeting the Interferon Response for Antiviral Therapy, p 317-332. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch18
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Ahmed, C. M.,, J. P. Martin, and, H. M. Johnson. 2007. IFN mimetic as a therapeutic for lethal vaccinia virus infection: possible effects on innate and adaptive immune responses. J. Immunol. 178: 45764583.
2. Alcami, A., and, G. L. Smith. 1995. Vaccinia, cowpox, and camel-pox viruses encode soluble gamma interferon receptors with novel broad species specificity. J. Virol. 69: 46334639.
3. Anderson, S. L.,, J. M. Carton,, J. Lou,, L. Xing, and, B. Y. Rubin. 1999. Interferon-induced guanylate binding protein-1 (GBP-1) mediates an antiviral effect against vesicular stomatitis virus and encephalomyocarditis virus. Virology 256: 814.
4. Andoniou, C. E.,, S. L. van Dommelen,, V. Voigt,, D. M. Andrews,, G. Brizard,, C. Asselin-Paturel,, T. Delale,, K. J. Stacey,, G. Trinchieri, and, M. A. Degli-Esposti. 2005. Interaction between conventional dendritic cells and natural killer cells is integral to the activation of effective antiviral immunity. Nat. Immunol. 6: 10111019.
5. Ank, N.,, H. West,, C. Bartholdy,, K. Eriksson,, A. R. Thomsen, and, S. R. Paludan. 2006. Lambda interferon (IFN-lambda), a type III IFN, is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo. J. Virol. 80:4501– 4509.
6. Asaoka, K.,, K. Ikeda,, T. Hishinuma,, K. Horie-Inoue,, S. Takeda, and, S. Inoue. 2005. A retrovirus restriction factor TRIM5alpha is transcriptionally regulated by interferons. Biochem. Biophys. Res. Commun. 338: 19501956.
7. Balachandran, S.,, P. C. Roberts,, L. E. Brown,, H. Truong,, A. K. Pattnaik,, D. R. Archer, and, G. N. Barber. 2000. Essential role for the dsRNA-dependent protein kinase PKR in innate immunity to viral infection. Immunity 13: 129141.
8. Barchet, W.,, M. Cella,, B. Odermatt,, C. Asselin-Paturel,, M. Colonna, and, U. Kalinke. 2002. Virus-induced interferon alpha production by a dendritic cell subset in the absence of feedback signaling in vivo. J. Exp. Med. 195: 507516.
9. Barnes, B. J.,, P. A. Moore, and, P. M. Pitha. 2001. Virus-specific activation of a novel interferon regulatory factor, IRF-5, results in the induction of distinct interferon alpha genes. J. Biol. Chem. 276: 2338223390.
10. Barnes, B. J.,, J. Richards,, M. Mancl,, S. Hanash,, L. Beretta, and, P. M. Pitha. 2004. Global and distinct targets of IRF-5 and IRF-7 during innate response to viral infection. J. Biol. Chem. 279:45194– 45207.
11. Blatt, L. M.,, J. M. Davis,, S. B. Klein, and, M. W. Taylor. 1996. The biologic activity and molecular characterization of a novel synthetic interferon-alpha species, consensus interferon. J. Interferon Cytokine Res. 16: 489499.
12. Boehme, K. W.,, M. Guerrero, and, T. Compton. 2006. Human cytomegalovirus envelope glycoproteins B and H are necessary for TLR2 activation in permissive cells. J. Immunol. 177: 70947102.
13. Brideau-Andersen, A. D.,, X. Huang,, S. C. Sun,, T. T. Chen,, D. Stark,, I. J. Sas,, L. Zadik,, G. N. Dawes,, D. R. Guptill,, R. McCord,, S. Govindarajan,, A. Roy,, S. Yang,, J. Gao,, Y. H. Chen,, N. J. Skartved,, A. K. Pedersen,, D. Lin,, C. P. Locher,, I. Rebbapragada,, A. D. Jensen,, S. H. Bass,, T. L. Nissen,, S. Viswanathan,, G. R. Foster,, J. A. Symons, and, P. A. Patten. 2007. Directed evolution of gene-shuffled IFN-alpha molecules with activity profiles tailored for treatment of chronic viral diseases. Proc. Natl. Acad. Sci. USA 104: 82698274.
14. Brzozka, K.,, S. Finke, and, K. K. Conzelmann. 2006. Inhibition of interferon signaling by rabies virus phosphoprotein P: activation-dependent binding of STAT1 and STAT2. J. Virol. 80: 26752683.
15. Cederblad, B., and, G. V. Alm. 1990. Infrequent but efficient inter-feron-alpha-producing human mononuclear leukocytes induced by herpes simplex virus in vitro studied by immuno-plaque and limiting dilution assays. J. Interferon Res. 10: 6573.
16. Cheng, G.,, J. Zhong, and, F. V. Chisari. 2006. Inhibition of dsRNA-induced signaling in hepatitis C virus-infected cells by NS3 protease-dependent and -independent mechanisms. Proc. Natl. Acad. Sci. USA 103: 84998504.
17. Chi, B.,, H. L. Dickensheets,, K. M. Spann,, M. A. Alston,, C. Luongo,, L. Dumoutier,, J. Huang,, J. C. Renauld,, S. V. Kotenko,, M. Roederer,, J. A. Beeler,, R. P. Donnelly,, P. L. Collins, and, R. L. Rabin. 2006. Alpha and lambda interferon together mediate suppression of CD4 T cells induced by respiratory syncytial virus. J. Virol. 80: 50325040.
18. Coccia, E. M.,, M. Severa,, E. Giacomini,, D. Monneron,, M. E. Remoli,, I. Julkunen,, M. Cella,, R. Lande, and, G. Uze. 2004. Viral infection and Toll-like receptor agonists induce a differential expression of type I and lambda interferons in human plasmacytoid and monocyte-derived dendritic cells. Eur. J. Immunol. 34: 796805.
19. Colamonici, O. R.,, P. Domanski,, S. M. Sweitzer,, A. Larner, and, R. M. Buller. 1995. Vaccinia virus B18R gene encodes a type I interferon-binding protein that blocks interferon alpha transmembrane signaling. J. Biol. Chem. 270: 1597415978.
20. Dai, J.,, N. J. Megjugorac,, S. B. Amrute, and, P. Fitzgerald-Bocarsly. 2004. Regulation of IFN regulatory factor-7 and IFN-alpha production by enveloped virus and lipopolysaccharide in human plasmacytoid dendritic cells. J. Immunol. 173: 15351548.
21. Dave, R. S.,, J. P. McGettigan,, T. Qureshi,, M. J. Schnell,, G. Nunnari, and, R. J. Pomerantz. 2006. siRNA targeting vaccinia virus double-stranded RNA binding protein [E3L] exerts potent antiviral effects. Virology 348: 489497.
22. Decker, T., and, P. Kovarik. 2000. Serine phosphorylation of STATs. Oncogene 19: 26282637.
23. Der, S. D.,, A. Zhou,, B. R. Williams, and, R. H. Silverman. 1998. Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays. Proc. Natl. Acad. Sci. USA 95: 1562315628.
24. de Veer, M. J.,, M. Holko,, M. Frevel,, E. Walker,, S. Der,, J. M. Paranjape,, R. H. Silverman, and, B. R. Williams. 2001. Functional classification of interferon-stimulated genes identified using microar-rays. J. Leukoc. Biol. 69: 912920.
25. D’Onofrio, C.,, O. Franzese,, A. Puglianiello,, E. Peci,, G. Lanzilli, and, E. Bonmassar. 1992. Antiviral activity of individual versus combined treatments with interferon alpha, beta and gamma on early infection with HTLV-I in vitro. Int. J. Immunopharmacol. 14: 10691079.
26. Doyle, S. E.,, H. Schreckhise,, K. Khuu-Duong,, K. Henderson,, R. Rosler,, H. Storey,, L. Yao,, H. Liu,, F. Barahmand-pour,, P. Siva-kumar,, C. Chan,, C. Birks,, D. Foster,, C. H. Clegg,, P. Wietzke-Braun,, S. Mihm, and, K. M. Klucher. 2006. Interleukin-29 uses a type 1 interferon-like program to promote antiviral responses in human hepatocytes. Hepatology 44: 896906.
27. Du, Z.,, L. Wei,, A. Murti,, S. R. Pfeffer,, M. Fan,, C. H. Yang, and, L. M. Pfeffer. 2007. Non-conventional signal transduction by type 1 interferons: the NF-kappaB pathway. J. Cell. Biochem. 102: 10871094.
28. Enninga, J.,, D. E. Levy,, G. Blobel, and, B. M. Fontoura. 2002. Role of nucleoporin induction in releasing an mRNA nuclear export block. Science 295: 15231525.
29. Espert, L.,, G. Degols,, C. Gongora,, D. Blondel,, B. R. Williams,, R. H. Silverman, and, N. Mechti. 2003. ISG20, a new interferon-induced RNase specific for single-stranded RNA, defines an alternative antiviral pathway against RNA genomic viruses. J. Biol. Chem. 278: 1615116158.
30. Feld, J. J., and, J. H. Hoofnagle. 2005. Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature 436: 967972.
31. Feldman, S. B.,, M. Ferraro,, H. M. Zheng,, N. Patel,, S. Gould-Fogerite, and, P. Fitzgerald-Bocarsly. 1994. Viral induction of low frequency interferon-alpha producing cells. Virology 204: 17.
32. Ferrantini, M.,, I. Capone, and, F. Belardelli. 2007. Interferon-alpha and cancer: mechanisms of action and new perspectives of clinical use. Biochimie 89: 884893.
33. Fitzgerald-Bocarsly, P., and, D. Feng. 2007. The role of type I interferon production by dendritic cells in host defense. Biochimie 89: 843855.
34. Fujita, T.,, K. Onoguchi,, K. Onomoto,, R. Hirai, and, M. Yoneyama. 2007. Triggering antiviral response by RIG-I-related RNA heli-cases. Biochimie 89: 754760.
35. Gale, M., Jr., and, E. M. Foy. 2005. Evasion of intracellular host defence by hepatitis C virus. Nature 436: 939945.
36. Ganem, D., and, A. M. Prince. 2004. Hepatitis B virus infection— natural history and clinical consequences. N. Engl. J. Med. 350: 11181129.
37. Garcia, M. A.,, E. F. Meurs, and, M. Esteban. 2007. The dsRNA protein kinase PKR: virus and cell control. Biochimie 89: 799811.
38. Gerosa, F.,, A. Gobbi,, P. Zorzi,, S. Burg,, F. Briere,, G. Carra, and, G. Trinchieri. 2005. The reciprocal interaction of NK cells with plasmacytoid or myeloid dendritic cells profoundly affects innate resistance functions. J. Immunol. 174: 727734.
39. Gil, M. P.,, E. Bohn,, A. K. O’Guin,, C. V. Ramana,, B. Levine,, G. R. Stark,, H. W. Virgin, and, R. D. Schreiber. 2001. Biologic consequences of Stat1-independent IFN signaling. Proc. Natl. Acad. Sci. USA 98: 66806685.
40. Gitlin, L.,, W. Barchet,, S. Gilfillan,, M. Cella,, B. Beutler,, R. A. Flavell,, M. S. Diamond, and, M. Colonna. 2006. Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. Proc. Natl. Acad. Sci. USA 103: 84598464.
41. Guidotti, L. G., and, F. V. Chisari. 1999. Cytokine-induced viral purging—role in viral pathogenesis. Curr. Opin. Microbiol. 2: 388391.
42. Guidotti, L. G.,, R. Rochford,, J. Chung,, M. Shapiro,, R. Purcell, and, F. V. Chisari. 1999. Viral clearance without destruction of infected cells during acute HBV infection. Science 284: 825829.
43. Haller, O.,, G. Kochs, and, F. Weber. 2007. Interferon, Mx, and viral countermeasures. Cytokine Growth Factor Rev. 18: 425433.
44. Hershey, J. W. 1991. Translational control in mammalian cells. Annu. Rev. Biochem. 60: 717755.
45. Honda, K.,, H. Yanai,, H. Negishi,, M. Asagiri,, M. Sato,, T. Mizutani,, N. Shimada,, Y. Ohba,, A. Takaoka,, N. Yoshida, and, T. Taniguchi. 2005. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434: 772777.
46. Hornung, V.,, J. Ellegast,, S. Kim,, K. Brzozka,, 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 RIGI. Science 314: 994997.
47. Horsmans, Y.,, T. Berg,, J. P. Desager,, T. Mueller,, E. Schott,, S. P. Fletcher,, K. R. Steffy,, L. A. Bauman,, B. M. Kerr, and, D. R. Averett. 2005. Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infection. Hepatology 42: 724731.
48. Hovanessian, A. G., and, J. Justesen. 2007. The human 2’-5’oligoadenylate synthetase family: unique interferon-inducible enzymes catalyzing 2’-5’ instead of 3’-5’ phosphodiester bond formation. Biochimie 89: 779788.
49. Huang, J.,, S. V. Smirnov,, A. Lewis-Antes,, M. Balan,, W. Li,, S. Tang,, G. V. Silke,, M. M. Putz,, G. L. Smith, and, S. V. Kotenko. 2007. Inhibition of type I and type III interferons by a secreted glycoprotein from Yaba-like disease virus. Proc. Natl. Acad. Sci. USA 104: 98229827.
50. Isaacs, A., and, J. Lindenmann. 1957. Virus interference. I. The interferon. Proc. R. Soc. Lond. B 147: 258267.
51. Ishii, K. J.,, C. Coban,, H. Kato,, K. Takahashi,, Y. Torii,, F. Takeshita,, H. Ludwig,, G. Sutter,, K. Suzuki,, H. Hemmi,, S. Sato,, M. Yamamoto,, S. Uematsu,, T. Kawai,, O. Takeuchi, and, S. Akira. 2006. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nat. Immunol. 7: 4048.
52. Isogawa, M.,, M. D. Robek,, Y. Furuichi, and, F. V. Chisari. 2005. Toll-like receptor signaling inhibits hepatitis B virus replication in vivo. J. Virol. 79: 72697272.
53. Iwasaki, A. 2007. Role of autophagy in innate viral recognition. Autophagy 3: 354356.
54. 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. 282: 1079210803.
55. Jordan, W. J.,, J. Eskdale,, S. Srinivas,, V. Pekarek,, D. Kelner,, M. Rodia, and, G. Gallagher. 2007. Human interferon lambda-1 (IFN-lambda1/IL-29) modulates the Th1/Th2 response. Genes Immun. 8: 254261.
56. Kalie, E.,, D. A. Jaitin,, R. Abramovich, and, G. Schreiber. 2007. An interferon alpha2 mutant optimized by phage display for IFNAR1 binding confers specifically enhanced antitumor activities. J. Biol. Chem. 282: 1160211611.
57. 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 MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441: 101105.
58. Kawai, T., and, S. Akira. 2006. Innate immune recognition of viral infection. Nat. Immunol. 7: 131137.
59. Kotenko, S. V.,, G. Gallagher,, V. V. Baurin,, A. Lewis-Antes,, M. Shen,, N. K. Shah,, J. A. Langer,, F. Sheikh,, H. Dickensheets, and, R. P. Donnelly. 2003. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat. Immunol. 4: 6977.
60. Krieg, A. M. 2007. Antiinfective applications of toll-like receptor 9 agonists. Proc. Am. Thorac. Soc. 4: 289294.
61. Kroger, A.,, M. Koster,, K. Schroeder,, H. Hauser, and, P. P. Mueller. 2002. Activities of IRF-1. J. Interferon Cytokine Res. 22: 514.
62. LaFleur, D. W.,, B. Nardelli,, T. Tsareva,, D. Mather,, P. Feng,, M. Semenuk,, K. Taylor,, M. Buergin,, D. Chinchilla,, V. Roshke,, G. Chen,, S. M. Ruben,, P. M. Pitha,, T. A. Coleman, and, P. A. Moore. 2001. Interferon-kappa, a novel type I interferon expressed in human keratinocytes. J. Biol. Chem. 276: 3976539771.
63. Langland, J. O.,, J. M. Cameron,, M. C. Heck,, J. K. Jancovich, and, B. L. Jacobs. 2006. Inhibition of PKR by RNA and DNA viruses. Virus Res. 119: 100110.
64. Larkin, J.,, L. Jin,, M. Farmen,, D. Venable,, Y. Huang,, S. L. Tan, and, J. I. Glass. 2003. Synergistic antiviral activity of human interferon combinations in the hepatitis C virus replicon system. J. Interferon Cytokine Res. 23: 247257.
65. Lee, S. B.,, Z. Melkova,, W. Yan,, B. R. Williams,, A. G. Hovanes-sian, and, M. Esteban. 1993. The interferon-induced double-stranded RNA-activated human p68 protein kinase potently inhibits protein synthesis in cultured cells. Virology 192: 380385.
66. Lefevre, F.,, M. Guillomot,, S. D’Andrea,, S. Battegay, and, C. La Bonnardiere. 1998. Interferon-delta: the first member of a novel type I interferon family. Biochimie 80: 779788.
67. 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: 13711376.
68. 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: 29922997.
69. Li, Q.,, R. Means,, S. Lang, and, J. U. Jung. 2007. Downregulation of gamma interferon receptor 1 by Kaposi’s sarcoma-associated herpesvirus K3 and K5. J. Virol. 81: 21172127.
70. Lin, R.,, P. Genin,, Y. Mamane,, M. Sgarbanti,, A. Battistini,, W. J. Harrington, Jr.,, G. N. Barber, and, J. Hiscott. 2001. HHV-8 encoded vIRF-1 represses the interferon antiviral response by blocking IRF-3 recruitment of the CBP/p300 coactivators. Oncogene 20: 800811.
71. Look, D. C.,, W. T. Roswit,, A. G. Frick,, Y. Gris-Alevy,, D. M. Dickhaus,, M. J. Walter, and, M. J. Holtzman. 1998. Direct suppression of Stat1 function during adenoviral infection. Immunity 9: 871880.
72. Macdonald, M. R.,, E. S. Machlin,, O. R. Albin, and, D. E. Levy. 2007. The zinc-finger antiviral protein acts synergistically with an interferon-induced factor for maximal activity against alphaviruses. J. Virol. 81: 1350913518.
73. 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: 816819.
74. Marcello, T.,, A. Grakoui,, G. Barba-Spaeth,, E. S. Machlin,, S. V. Kotenko,, M. R. MacDonald, and, C. M. Rice. 2006. Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics. Gastroenterology 131: 18871898.
75. Mark, K. E.,, L. Corey,, T. C. Meng,, A. S. Magaret,, M. L. Huang,, S. Selke,, H. B. Slade,, S. K. Tyring,, T. Warren,, S. L. Sacks,, P. Leone,, V. A. Bergland, and, A. Wald. 2007. Topical resiquimod 0.01% gel decreases herpes simplex virus type 2 genital shedding: a randomized, controlled trial. J. Infect. Dis. 195: 13241331.
76. Martin, E.,, C. Nathan, and, Q. W. Xie. 1994. Role of interferon regulatory factor 1 in induction of nitric oxide synthase. J. Exp. Med. 180: 977984.
77. Meager, A.,, K. Visvalingam,, P. Dilger,, D. Bryan, and, M. Wadhwa. 2005. Biological activity of interleukins-28 and -29: comparison with type I interferons. Cytokine 31: 109118.
78. Moro, A.,, A. Santos,, M. J. Arana, and, S. E. Perea. 2000. Activation of the human p27(Kip1) promoter by IFNalpha 2b. Biochem. Biophys. Res. Commun. 269: 3134.
79. Mundt, E. 2007. Human MxA protein confers resistance to double-stranded RNA viruses of two virus families. J. Gen. Virol. 88: 13191323.
80. Numasaki, M.,, M. Tagawa,, F. Iwata,, T. Suzuki,, A. Nakamura,, M. Okada,, Y. Iwakura,, S. Aiba, and, M. Yamaya. 2007. IL-28 elicits antitumor responses against murine fibrosarcoma. J. Immunol. 178: 50865098.
81. Okuse, C.,, J. A. Rinaudo,, K. Farrar,, F. Wells, and, B. E. Korba. 2005. Enhancement of antiviral activity against hepatitis C virus in vitro by interferon combination therapy. Antivir. Res. 65: 2334.
82. Oritani, K.,, K. L. Medina,, Y. Tomiyama,, J. Ishikawa,, Y. Okajima,, M. Ogawa,, T. Yokota,, K. Aoyama,, I. Takahashi,, P. W. Kincade, and, Y. Matsuzawa. 2000. Limitin: an interferon-like cytokine that preferentially influences B-lymphocyte precursors. Nat. Med. 6: 659666.
83. Ortaldo, J. R.,, R. B. Herberman,, C. Harvey,, P. Osheroff,, Y. C. Pan,, B. Kelder, and, S. Pestka. 1984. A species of human alpha interferon that lacks the ability to boost human natural killer activity. Proc. Natl. Acad. Sci. USA 81: 49264929.
84. Ortaldo, J. R.,, A. Mantovani,, D. Hobbs,, M. Rubinstein,, S. Pestka, and, R. B. Herberman. 1983. Effects of several species of human leukocyte interferon on cytotoxic activity of NK cells and monocytes. Int. J. Cancer 31: 285289.
85. Paun, A., and, P. M. Pitha. 2007. The IRF family, revisited. Biochimie 89: 744753.
86. Pestka, S. 2007. The interferons: 50 years after their discovery, there is much more to learn. J. Biol. Chem. 282: 2004720051.
87. Pestka, S.,, C. D. Krause, and, M. R. Walter. 2004. Interferons, inter-feron-like cytokines, and their receptors. Immunol. Rev. 202: 832.
88. Pichlmair, A., and, C. Reis e Sousa. 2007. Innate recognition of viruses. Immunity 27: 370383.
89. Pichlmair, A.,, O. Schulz,, C. P. Tan,, T. I. Naslund,, P. Liljestrom,, F. Weber, and, C. Reis e Sousa. 2006. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5’-phosphates. Science 314: 9971001.
90. Platanias, L. C. 2005. Mechanisms of type-I- and type-II-inter-feron-mediated signalling. Nat. Rev. Immunol. 5: 375386.
91. Ramana, C. V.,, M. P. Gil,, Y. Han,, R. M. Ransohoff,, R. D. Schreiber, and, G. R. Stark. 2001. Stat1-independent regulation of gene expression in response to IFN-gamma. Proc. Natl. Acad. Sci. USA 98: 66746679.
92. Reid, L. E.,, A. H. Brasnett,, C. S. Gilbert,, A. C. Porter,, D. R. Gewert,, G. R. Stark, and, I. M. Kerr. 1989. A single DNA response element can confer inducibility by both alpha- and gamma-inter-ferons. Proc. Natl. Acad. Sci. USA 86: 840844.
93. Roberts, R. M.,, J. C. Cross, and, D. W. Leaman. 1991. Unique features of the trophoblast interferons. Pharmacol. Ther. 51: 329345.
94. Romerio, F., and, D. Zella. 2002. MEK and ERK inhibitors enhance the anti-proliferative effect of interferon-alpha2b. FASEB J. 16: 16801682.
95. Ronco, L. V.,, A. Y. Karpova,, M. Vidal, and, P. M. Howley. 1998. Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity. Genes Dev. 12: 20612072.
96. Runkel, L.,, L. Pfeffer,, M. Lewerenz,, D. Monneron,, C. H. Yang,, A. Murti,, S. Pellegrini,, S. Goelz,, G. Uze, and, K. Mogensen. 1998. Differences in activity between alpha and beta type I interferons explored by mutational analysis. J. Biol. Chem. 273: 80038008.
97. Sainz, B., Jr., and, W. P. Halford. 2002. Alpha/beta interferon and gamma interferon synergize to inhibit the replication of herpes simplex virus type 1. J. Virol. 76: 1154111550.
98. Sainz, B., Jr.,, H. L. LaMarca,, R. F. Garry, and, C. A. Morris. 2005. Synergistic inhibition of human cytomegalovirus replication by interferon-alpha/beta and interferon-gamma. Virol. J. 2:14.
99. Samuel, C. E. 2001. Antiviral actions of interferons. Clin. Micro-biol. Rev. 14: 778809.
100. Sato, A.,, M. Ohtsuki,, M. Hata,, E. Kobayashi, and, T. Murakami. 2006. Antitumor activity of IFN-lambda in murine tumor models. J. Immunol. 176: 76867694.
101. 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 IRF-3 and IRF-7 in response to viruses for IFN-alpha/ beta gene induction. Immunity 13: 539548.
102. Schoenemeyer, A.,, B. J. Barnes,, M. E. Mancl,, E. Latz,, N. Gout-agny,, P. M. Pitha,, K. A. Fitzgerald, and, D. T. Golenbock. 2005. The interferon regulatory factor, IRF5, is a central mediator of Toll-like receptor 7 signaling. J. Biol. Chem. 280: 1700517012.
103. Severa, M.,, M. E. Remoli,, E. Giacomini,, J. Ragimbeau,, R. Lande,, G. Uze,, S. Pellegrini, and, E. M. Coccia. 2006. Differential responsiveness to IFN-alpha and IFN-beta of human mature DC through modulation of IFNAR expression. J. Leukoc. Biol. 79: 12861294.
104. Sheppard, P.,, W. Kindsvogel,, W. Xu,, K. Henderson,, S. Schluts-meyer,, T. E. Whitmore,, R. Kuestner,, U. Garrigues,, C. Birks,, J. Roraback,, C. Ostrander,, D. Dong,, J. Shin,, S. Presnell,, B. Fox,, B. Haldeman,, E. Cooper,, D. Taft,, T. Gilbert,, F. J. Grant,, M. Tack-ett,, W. Krivan,, G. McKnight,, C. Clegg,, D. Foster, and, K. M. Klucher. 2003. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat. Immunol. 4: 6368.
105. Stark, G. R.,, I. M. Kerr,, B. R. Williams,, R. H. Silverman, and, R. D. Schreiber. 1998. How cells respond to interferons. Annu. Rev. Biochem. 67: 227264.
106. Stetson, D. B., and, R. Medzhitov. 2006. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 24: 93103.
107. Symons, J. A.,, A. Alcami, and, G. L. Smith. 1995. Vaccinia virus encodes a soluble type I interferon receptor of novel structure and broad species specificity. Cell 81: 551560.
108. Takaoka, A.,, Z. Wang,, M. K. Choi,, H. Yanai,, H. Negishi,, T. Ban,, Y. Lu,, M. Miyagishi,, T. Kodama,, K. Honda,, Y. Ohba, and, T. Taniguchi. 2007. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448: 501505.
109. Takaoka, A.,, H. Yanai,, S. Kondo,, G. Duncan,, H. Negishi,, T. Mizutani,, S. Kano,, K. Honda,, Y. Ohba,, T. W. Mak, and, T. Taniguchi. 2005. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434: 243249.
110. Tanaka, Y.,, H. Marusawa,, H. Seno,, Y. Matsumoto,, Y. Ueda,, Y. Kodama,, Y. Endo,, J. Yamauchi,, T. Matsumoto,, A. Takaori-Kondo,, I. Ikai, and, T. Chiba. 2006. Anti-viral protein APOBEC3G is induced by interferon-alpha stimulation in human hepatocytes. Biochem. Biophys. Res. Commun. 341: 314319.
111. Thakur, C. S.,, B. K. Jha,, B. Dong,, J. Das Gupta,, K. M. Silverman,, H. Mao,, H. Sawai,, A. O. Nakamura,, A. K. Banerjee,, A. Gudkov, and, R. H. Silverman. 2007. Small-molecule activators of RNase L with broad-spectrum antiviral activity. Proc. Natl. Acad. Sci. USA 104: 95859590.
112. Uprichard, S. L. 2005. The therapeutic potential of RNA interference. FEBS Lett. 579: 59966007.
113. Uze, G., and, D. Monneron. 2007. IL-28 and IL-29: newcomers to the interferon family. Biochimie 89: 729734.
114. Vlotides, G.,, A. S. Sorensen,, F. Kopp,, K. Zitzmann,, N. Cengic,, S. Brand,, R. Zachoval, and, C. J. Auernhammer. 2004. SOCS-1 and SOCS-3 inhibit IFN-alpha-induced expression of the antiviral proteins 2, 5-OAS and MxA. Biochem. Biophys. Res. Commun. 320: 10071014.
115. von Kobbe, C.,, J. M. van Deursen,, J. P. Rodrigues,, D. Sitterlin,, A. Bachi,, X. Wu,, M. Wilm,, M. Carmo-Fonseca, and, E. Izaurralde. 2000. Vesicular stomatitis virus matrix protein inhibits host cell gene expression by targeting the nucleoporin Nup98. Mol. Cell 6: 12431252.
116. Wang, X.,, M. Li,, H. Zheng,, T. Muster,, P. Palese,, A. A. Beg, and, A. Garcia-Sastre. 2000. Influenza A virus NS1 protein prevents activation of NF-kappaB and induction of alpha/beta interferon. J. Virol. 74: 1156611573.
117. Watson, J. C.,, H. W. Chang, and, B. L. Jacobs. 1991. Characterization of a vaccinia virus-encoded double-stranded RNA-binding protein that may be involved in inhibition of the double-stranded RNA-dependent protein kinase. Virology 185: 206216.
118. Weber, F., and, O. Haller. 2007. Viral suppression of the inter-feron system. Biochimie 89: 836842.
119. Wesoly, J.,, Z. Szweykowska-Kulinska, and, H. A. Bluyssen. 2007. STAT activation and differential complex formation dictate selectivity of interferon responses. Acta Biochim. Pol. 54: 2738.
120. Wieland, S.,, R. Thimme,, R. H. Purcell, and, F. V. Chisari. 2004. Genomic analysis of the host response to hepatitis B virus infection. Proc. Natl. Acad. Sci. USA 101: 66696674.
121. Wieland, S. F., and, F. V. Chisari. 2005. Stealth and cunning: hepatitis B and hepatitis C viruses. J. Virol. 79: 93699380.
122. Williams, B. R. 2001. Signal integration via PKR. Sci. STKE 2001:RE2.
123. Wolk, K., and, R. Sabat. 2006. Interleukin-22: a novel T- and NK-cell derived cytokine that regulates the biology of tissue cells. Cytokine Growth Factor Rev. 17: 367380.
124. Wollmann, G.,, M. D. Robek, and, A. N. van den Pol. 2007. Variable deficiencies in the interferon response enhance susceptibility to vesicular stomatitis virus oncolytic actions in glioblastoma cells but not in normal human glial cells. J. Virol. 81: 14791491.
125. Yang, Y. L.,, L. F. Reis,, J. Pavlovic,, A. Aguzzi,, R. Schafer,, A. Kumar,, B. R. Williams,, M. Aguet, and, C. Weissmann. 1995. Deficient signaling in mice devoid of double-stranded RNA-dependent protein kinase. EMBO J. 14: 60956106.
126. 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: 730737.
127. Yoshimura, A.,, T. Naka, and, M. Kubo. 2007. SOCS proteins, cytokine signalling and immune regulation. Nat. Rev. Immunol. 7: 454465.
128. Yuan, W., and, R. M. Krug. 2001. Influenza B virus NS1 protein inhibits conjugation of the interferon (IFN)-induced ubiquitin-like ISG15 protein. EMBO J. 20: 362371.
129. Zhou, A.,, J. M. Paranjape,, S. D. Der,, B. R. Williams, and, R. H. Silverman. 1999. Interferon action in triply deficient mice reveals the existence of alternative antiviral pathways. Virology 258: 435440.
130. Zhou, Y.,, S. Wang,, A. Gobl, and, K. Oberg. 1999. Inhibition of CDK2, CDK4 and cyclin E and increased expression of p27Kip1 during treatment with interferon-alpha in carcinoid tumor cells. J. Biol. Regul. Homeost. Agents 13: 207215.
131. Zhou, Z.,, O. J. Hamming,, N. Ank,, S. R. Paludan,, A. L. Nielsen, and, R. Hartmann. 2007. Type III interferon (IFN) induces a type I IFN-like response in a restricted subset of cells through signaling pathways involving both the Jak-STAT pathway and the mitogen-activated protein kinases. J. Virol. 81: 77497758.
132. Zhu, H.,, M. Butera,, D. R. Nelson, and, C. Liu. 2005. Novel type I interferon IL-28A suppresses hepatitis C viral RNA replication. Virol. J. 2:80.
133. Zhu, H.,, X. Shang,, N. Terada, and, C. Liu. 2004. STAT3 induces anti-hepatitis C viral activity in liver cells. Biochem. Biophys. Res. Commun. 324: 518528.
134. Zhu, H.,, H. Zhao,, C. D. Collins,, S. E. Eckenrode,, Q. Run,, R. A. McIndoe,, J. M. Crawford,, D. R. Nelson,, J. X. She, and, C. Liu. 2003. Gene expression associated with interferon alfa antiviral activity in an HCV replicon cell line. Hepatology 37: 11801188.
135. Zitzmann, K.,, S. Brand,, S. Baehs,, B. Goke,, J. Meinecke,, G. Spottl,, H. Meyer, and, C. J. Auernhammer. 2006. Novel interferon-lambdas induce antiproliferative effects in neuroendocrine tumor cells. Biochem. Biophys. Res. Commun. 344:1334– 1341.

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