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. 2009;189:243–263. doi: 10.1007/978-3-540-79086-0_9

Nucleic Acids-Based Therapeutics in the Battle Against Pathogenic Viruses

Joost Haasnoot 2, Ben Berkhout 2,✉
Editors: Hans-Georg Kräusslich1, Ralf Bartenschlager1
PMCID: PMC7119910  PMID: 19048203

Abstract

For almost three decades, researchers have studied the possibility to use nucleic acids as antiviral therapeutics. In theory, compounds such as antisense oligonucleotides, ribozymes, DNAzymes, and aptamers can be designed to trigger the sequence-specific inhibition of particular mRNA transcripts, including viral genomes. However, difficulties with their efficiency, off-target effects, toxicity, delivery, and stability halted the development of nucleic acid-based therapeutics that can be used in the clinic. So far, only a single antisense drug, Vitravene for the treatment of CMV-induced retinitis in AIDS patients, has made it to the clinic. Since the discovery of RNA interference (RNAi), there is a renewed interest in the development of nucleic acid-based therapeutics. Antiviral RNAi approaches are highly effective in vitro and in animal models and are currently being tested in clinical trials. Here we give an overview of antiviral nucleic acid-based therapeutics. We focus on antisense and RNAi-based compounds that have been shown to be effective in animal model systems.

Keywords: Respiratory Syncytial Virus, Peptide Nucleic Acid, Lock Nucleic Acid, Severe Acute Respiratory Syndrome, Viral Escape

Contributor Information

Hans-Georg Kräusslich, Email: hans-georg_kraeusslich@med.uni-heidelberg.de.

Ralf Bartenschlager, Email: ralf_bartenschlager@med.uni-heidelberg.de.

Ben Berkhout, Email: b.berkhout@amc.uva.nl.

References

  1. Akashi H, Miyagishi M, Yokota T, Watanabe H, Hino T, Nishina K, Kohara M, Taira K. Escape from the interferon response associated with RNA interference using vectors that encode long modified hairpin—RNA. Molecular BioSystems. 2005;1:382–390. doi: 10.1039/b510159j. [DOI] [PubMed] [Google Scholar]
  2. Anderson J, Li MJ, Palmer B, Remling L, Li S, Yam P, Yee JK, Rossi J, Zaia J, Akkina R. Safety and efficacy of a lentiviral vector containing three anti—HIV genes—CCR5 ribozyme, Tat-rev siRNA, and TAR decoy—in SCID—hu mouse–derived T Cells. Mol Ther. 2007;5:1182–1188. doi: 10.1038/sj.mt.6300157. [DOI] [PubMed] [Google Scholar]
  3. Andersson MG, Haasnoot PCJ, Xu N, Berenjian S, Berkhout B, Akusjarvi G. Suppression of RNA interference by adenovirus virus-associated RNA. J Virol. 2005;79:9556–9565. doi: 10.1128/JVI.79.15.9556-9565.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Arrighi JF, Pion M, Garcia E, Escola JM, van Kooyk Y, Geijtenbeek TB, Piguet V. DC-SIGN-mediated infectious synapse formation enhances X4 HIV-1 transmission from dendritic cells to T cells. J Exp Med. 2004a;200:1279–1288. doi: 10.1084/jem.20041356. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Arrighi JF, Pion M, Wiznerowicz M, Geijtenbeek TB, Garcia E, Abraham S, Leuba F, Dutoit V, Ducrey-Rundquist O, van Kooyk Y, Trono D, Piguet V. Lentivirus-mediated RNA interference of DC—SIGN expression inhibits human immunodeficiency virus transmission from dendritic cells to T cells. J Virol. 2004b;78:10848–10855. doi: 10.1128/JVI.78.20.10848-10855.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bahner I, Kearns K, Hao QL, Smogorzewska EM, Kohn DB. Transduction of human CD34+ hematopoietic progenitor cells by a retroviral vector expressing an RRE decoy inhibits human immunodeficiency virus type 1 replication in myelomonocytic cells produced in long-term culture. J Virol. 1996;70:4352–4360. doi: 10.1128/jvi.70.7.4352-4360.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Barichievy S, Saayman S, von Eije KJ, Morris KV, Arbuthnot P, Weinberg MS. The inhibitory efficacy of RNA POL III-expressed long hairpin RNAs targeted to untranslated regions of the HIV-1 5′ long terminal repeat. Oligonucleotides. 2007;17:419–431. doi: 10.1089/oli.2007.0095. [DOI] [PubMed] [Google Scholar]
  8. Bellecave P, Andreola ML, Ventura M, Tarrago-Litvak L, Litvak S, Astier-Gin T. Selection of DNA aptamers that bind the RNA-dependent RNA polymerase of hepatitis C virus and inhibit viral RNA synthesis in vitro. Oligonucleotides. 2003;13:455–463. doi: 10.1089/154545703322860771. [DOI] [PubMed] [Google Scholar]
  9. Bennasser Y, Le SY, Benkirane M, Jeang KT. Evidence that HIV—1 encodes an siRNA and a suppressor of RNA silencing. Immunity. 2005;22:607–619. doi: 10.1016/j.immuni.2005.03.010. [DOI] [PubMed] [Google Scholar]
  10. Berkhout B. RNA interference as an antiviral approach: targeting HIV-1 Curr. Opin Mol Ther. 2005;6:141–145. [PubMed] [Google Scholar]
  11. Birmingham A, Anderson EM, Reynolds A, Ilsley-Tyree D, Leake D, Fedorov Y, Baskerville S, Maksimova E, Robinson K, Karpilow J, Marshall WS, Khvorova A. 3′ UTR seed matches, but not overall identity, are associated with RNAi off—targets. Nat Methods. 2006;3:199–204. doi: 10.1038/nmeth854. [DOI] [PubMed] [Google Scholar]
  12. Bitko V, Barik S. Phenotypic silencing of cytoplasmic genes using sequence—specific double-stranded short interfering RNA and its application in the reverse genetics of wild type negative-strand RNA viruses. BMC Microbiol. 2001;1:34. doi: 10.1186/1471-2180-1-34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Bitko V, Musiyenko A, Shulyayeva O, Barik S. Inhibition of respiratory viruses by nasally administered siRNA. Nat Med. 2005;11:50–55. doi: 10.1038/nm1164. [DOI] [PubMed] [Google Scholar]
  14. Boden D, Pusch O, Lee F, Tucker L, Ramratnam B. Human immunodeficiency virus type 1 escape from RNA interference. J Virol. 2003;77:11531–11535. doi: 10.1128/JVI.77.21.11531-11535.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Boden D, Pusch O, Silbermann R, Lee F, Tucker L, Ramratnam B. Enhanced gene silencing of HIV-1 specific siRNA using microRNA designed hairpins. Nucleic Acids Res. 2004;32:1154–1158. doi: 10.1093/nar/gkh278. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Bramsen JB, Laursen MB, Damgaard CK, Lena SW, Babu BR, Wengel J, Kjems J. Improved silencing properties using small internally segmented interfering RNAs. Nucleic Acids Res. 2007;35:5886–5897. doi: 10.1093/nar/gkm548. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Brass AL, Dykxhoorn DM, Benita Y, Yan N, Engelman A, Xavier RJ, Lieberman J, Elledge SJ. Identification of host proteins required for HIV infection through a functional genomic screen. Science. 2008;319:921–926. doi: 10.1126/science.1152725. [DOI] [PubMed] [Google Scholar]
  18. Bridge AJ, Pebernard S, Ducraux A, Nicoulaz AL, Iggo R. Induction of an interferon response by RNAi vectors in mammalian cells. Nat Genet. 2003;34:263–264. doi: 10.1038/ng1173. [DOI] [PubMed] [Google Scholar]
  19. Brummelkamp TR, Bernards R, Agami R. A system for stable expression of short interfering RNAs in mammalian cells. Science. 2002;296:550–553. doi: 10.1126/science.1068999. [DOI] [PubMed] [Google Scholar]
  20. Burke DH, Scates L, Andrews K, Gold L. Bent pseudoknots and novel RNA inhibitors of type 1 human immunodeficiency virus (HIV—1) reverse transcriptase. J Mol Biol. 1996;264:650–666. doi: 10.1006/jmbi.1996.0667. [DOI] [PubMed] [Google Scholar]
  21. Burrer R, Neuman BW, Ting JP, Stein DA, Moulton HM, Iversen PL, Kuhn P, Buchmeier MJ. Antiviral effects of antisense morpholino oligomers in murine coronavirus infection models. J Virol. 2007;81:5637–5648. doi: 10.1128/JVI.02360-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Carmona S, Ely A, Crowther C, Moolla N, Salazar FH, Marion PL, Ferry N, Weinberg MS, Arbuthnot P. Effective inhibition of HBV replication in vivo by anti-HBx short hairpin RNAs. Mol Ther. 2006;13:411–421. doi: 10.1016/j.ymthe.2005.10.013. [DOI] [PubMed] [Google Scholar]
  23. Chen CC, Ko TM, Ma HI, Wu HL, Xiao X, Li J, Chang CM, Wu PY, Chen CH, Han JM, Yu CP, Jeng KS, Hu CP, Tao MH. Long-term inhibition of hepatitis B virus in transgenic mice by double-stranded adeno-associated virus 8-delivered short hairpin RNA. Gene Ther. 2007;14:11–19. doi: 10.1038/sj.gt.3302846. [DOI] [PubMed] [Google Scholar]
  24. Cheng TL, Chang WW, Su IJ, Lai MD, Huang W, Lei HY, Chang WT. Therapeutic inhibition of hepatitis B virus surface antigen expression by RNA interference. Biochem Biophys Res Commun. 2005;336:820–830. doi: 10.1016/j.bbrc.2005.08.173. [DOI] [PubMed] [Google Scholar]
  25. Cullen BR. Is RNA interference involved in intrinsic antiviral immunity in mammals? Nat Immunol. 2006;7:563–567. doi: 10.1038/ni1352. [DOI] [PubMed] [Google Scholar]
  26. Czauderna F, Fechtner M, Dames S, Aygun H, Klippel A, Pronk GJ, Giese K, Kaufmann J. Structural variations and stabilising modifications of synthetic siRNAs in mammalian cells. Nucleic Acids Res. 2003;31:2705–2716. doi: 10.1093/nar/gkg393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Das AT, Brummelkamp TR, Westerhout EM, Vink M, Madiredjo M, Bernards R, Berkhout B. Human immunodeficiency virus type 1 escapes from RNA interference—mediated inhibition. J Virol. 2004;78:2601–2605. doi: 10.1128/JVI.78.5.2601-2605.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. DeVincenzo J, Cehelsky JE, Alvarez R, Elbashir S, Harborth J, Toudjarska I, Nechev L, Murugaiah V, Van Vliet A, Vaishnaw AK, Meyers R. Evaluation of the safety, tolerabil-ity and pharmacokinetics of ALN-RSV01, a novel RNAi antiviral therapeutic directed against respiratory syncytial virus (RSV) Antiviral Res. 2008;77:225–231. doi: 10.1016/j.antiviral.2007.11.009. [DOI] [PubMed] [Google Scholar]
  29. Du G, Yonekubo J, Zeng Y, Osisami M, Frohman MA. Design of expression vectors for RNA interference based on miRNAs and RNA splicing. FEBS J. 2006;273:5421–5427. doi: 10.1111/j.1742-4658.2006.05534.x. [DOI] [PubMed] [Google Scholar]
  30. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature. 2001;411:494–498. doi: 10.1038/35078107. [DOI] [PubMed] [Google Scholar]
  31. Elmen J, Thonberg H, Ljungberg K, Frieden M, Westergaard M, Xu Y, Wahren B, Liang Z, Orum H, Koch T, Wahlestedt C. Locked nucleic acid (LNA) mediated improvements in siRNA stability and functionality. Nucleic Acids Res. 2005;33:439–447. doi: 10.1093/nar/gki193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ely A, Naidoo T, Mufamadi S, Crowther C, Arbuthnot P. Expressed anti-HBV primary microRNA shuttles inhibit viral replication efficiently in vitro and in vivo. Mol Ther. 2008;16:1105–1112. doi: 10.1038/mt.2008.82. [DOI] [PubMed] [Google Scholar]
  33. Fedorov Y, Anderson EM, Birmingham A, Reynolds A, Karpilow J, Robinson K, Leake D, Marshall WS, Khvorova A. Off-target effects by siRNA can induce toxic phenotype. RNA. 2006;12:1188–1196. doi: 10.1261/rna.28106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Ge Q, Filip L, Bai A, Nguyen T, Eisen HN, Chen J. Inhibition of influenza virus production in virus-infected mice by RNA interference. Proc Natl Acad Sci USA. 2004;101:8676–8681. doi: 10.1073/pnas.0402486101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Giladi H, Ketzinel-Gilad M, Rivkin L, Felig Y, Nussbaum O, Galun E. Small interfering RNA inhibits hepatitis B virus replication in mice. Mol Ther. 2003;8:769–776. doi: 10.1016/s1525-0016(03)00244-2. [DOI] [PubMed] [Google Scholar]
  36. Gitlin L, Stone JK, Andino R. Poliovirus escape from RNA interference: short interfering RNA—target recognition and implications for therapeutic approaches. J Virol. 2005;79:1027–1035. doi: 10.1128/JVI.79.2.1027-1035.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Gonzalez-Carmona MA, Schussler S, Serwe M, Alt M, Ludwig J, Sproat BS, Steigerwald R, Hoffmann P, Quasdorff M, Schildgen O, Caselmann WH. Hammerhead ribozymes with cleavage site specificity for NUH and NCH display significant anti—hepatitis C viral effect in vitro and in recombinant HepG2 and CCL13 cells. J Hepatol. 2006;44:1017–1025. doi: 10.1016/j.jhep.2005.10.022. [DOI] [PubMed] [Google Scholar]
  38. Grimm D, Streetz KL, Jopling CL, Storm TA, Pandey K, Davis CR, Marion P, Salazar F, Kay MA. Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature. 2006;441:537–541. doi: 10.1038/nature04791. [DOI] [PubMed] [Google Scholar]
  39. Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP. MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell. 2007;27:91–105. doi: 10.1016/j.molcel.2007.06.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Gu S, Ji J, Kim JD, Yee JK, Rossi JJ. Inhibition of infectious human immunodeficiency virus type 1 virions via lentiviral vector encoded short antisense RNAs. Oligonucleotides. 2006;16:287–295. doi: 10.1089/oli.2006.16.287. [DOI] [PubMed] [Google Scholar]
  41. Guo S, Huang F, Guo P. Construction of folate-conjugated pRNA of bacteriophage phi29 DNA packaging motor for delivery of chimeric siRNA to nasopharyngeal carcinoma cells. Gene Ther. 2006;13:814–820. doi: 10.1038/sj.gt.3302716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Haasnoot J, Westerhout EM, Berkhout B. RNA interference against viruses: strike and coun-terstrike. Nat Biotechnol. 2007;25:1435–1443. doi: 10.1038/nbt1369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Hamasaki K, Nakao K, Matsumoto K, Ichikawa T, Ishikawa H, Eguchi K. Short interfering RNA-directed inhibition of hepatitis B virus replication. FEBS Lett. 2003;543:51–54. doi: 10.1016/s0014-5793(03)00400-9. [DOI] [PubMed] [Google Scholar]
  44. He ML, Zheng B, Peng Y, Peiris JS, Poon LL, Yuen KY, Lin MC, Kung HF, Guan Y. Inhibition of SARS-associated coronavirus infection and replication by RNA interference. JAMA. 2003;290:2665–2666. doi: 10.1001/jama.290.20.2665. [DOI] [PubMed] [Google Scholar]
  45. Held DM, Kissel JD, Thacker SJ, Michalowski D, Saran D, Ji J, Hardy RW, Rossi JJ, Burke DH. Cross-clade inhibition of recombinant HIV-1, HIV-2 and SIVcpz reverse transcriptases by RNA pseudoknot aptamers. J Virol. 2007;81:5375–5384. doi: 10.1128/JVI.01923-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Hu-Lieskovan S, Heidel JD, Bartlett DW, Davis ME, Triche TJ. Sequence-specific knockdown of EWS-FLI1 by targeted, nonviral delivery of small interfering RNA inhibits tumor growth in a murine model of metastatic Ewing's sarcoma. Cancer Res. 2005;65:8984–8992. doi: 10.1158/0008-5472.CAN-05-0565. [DOI] [PubMed] [Google Scholar]
  47. Iversen PL. Phosphorodiamidate morpholino oligomers: favorable properties for sequence-specific gene inactivation. Curr Opin Mol Ther. 2001;3:235–238. [PubMed] [Google Scholar]
  48. Jackson AL, Linsley PS. Noise amidst the silence: off-target effects of siRNAs? Trends Genet. 2004;20:521–524. doi: 10.1016/j.tig.2004.08.006. [DOI] [PubMed] [Google Scholar]
  49. Jackson AL, Bartz SR, Schelter J, Kobayashi SV, Burchard J, Mao M, Li B, Cavet G, Linsley PS. Expression profiling reveals off-target gene regulation by RNAi. Nat Biotechnol. 2003;21:635–637. doi: 10.1038/nbt831. [DOI] [PubMed] [Google Scholar]
  50. Jacque JM, Triques K, Stevenson M. Modulation of HIV-1 replication by RNA interference. Nature. 2002;418:435–438. doi: 10.1038/nature00896. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Jakobsen MR, Haasnoot J, Wengel J, Berkhout B, Kjems J. Efficient inhibition of HIV-1 expression by LNA modified antisense oligonucleotides and DNAzymes targeted to functionally selected binding sites. Retrovirology. 2007;4:29. doi: 10.1186/1742-4690-4-29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. James W. Aptamers in the virologists' toolkit. J Gen Virol. 2007;88:351–364. doi: 10.1099/vir.0.82442-0. [DOI] [PubMed] [Google Scholar]
  53. Klein C, Bock CT, Wedemeyer H, Wustefeld T, Locarnini S, Dienes HP, Kubicka S, Manns MP, Trautwein C. Inhibition of hepatitis B virus replication in vivo by nucleoside analogues and siRNA. Gastroenterology. 2003;125:9–18. doi: 10.1016/s0016-5085(03)00720-0. [DOI] [PubMed] [Google Scholar]
  54. Kleinman ME, Yamada K, Takeda A, Chandrasekaran V, Nozaki M, Baffi JZ, Albuquerque RJ, Yamasaki S, Itaya M, Pan Y, Appukuttan B, Gibbs D, Yang Z, Kariko K, Ambati BK, Wilgus TA, DiPietro LA, Sakurai E, Zhang K, Smith JR, Taylor EW, Ambati J. Sequence-and target-independent angiogenesis suppression by siRNA via TLR3. Nature. 2008;452:591–597. doi: 10.1038/nature06765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Kohn DB, Bauer G, Rice CR, Rothschild JC, Carbonaro DA, Valdez P, Hao Q, Zhou C, Bahner I, Kearns K, Brody K, Fox S, Haden E, Wilson K, Salata C, Dolan C, Wetter C, Aguilar-Cordova E, Church J. A clinical trial of retroviral—mediated transfer of a rev-responsive element decoy gene into CD34(+) cells from the bone marrow of human immunodeficiency virus-1-infected children. Blood. 1999;94:368–371. [PubMed] [Google Scholar]
  56. Konishi M, Wu CH, Wu GY. Inhibition of HBV replication by siRNA in a stable HBV-producing cell line. Hepatology. 2003;38:842–850. doi: 10.1053/jhep.2003.50416. [DOI] [PubMed] [Google Scholar]
  57. Konstantinova P, de Vries W, Haasnoot J, Ter Brake O, de Haan P, Berkhout B. Inhibition of human immunodeficiency virus type 1 by RNA interference using long—hairpin RNA. Gene Ther. 2006;13:1403–1413. doi: 10.1038/sj.gt.3302786. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Konstantinova P, Ter Brake O, Haasnoot J, de Haan P, Berkhout B. Trans-inhibition of HIV-1 by a long hairpin RNA expressed within the viral genome. Retrovirology. 2007;4:15. doi: 10.1186/1742-4690-4-15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Kusov Y, Kanda T, Palmenberg A, Sgro JY, Gauss-Muller V. Silencing of hepatitis A virus infection by small interfering RNAs. J Virol. 2006;80:5599–5610. doi: 10.1128/JVI.01773-05. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Larsen HJ, Bentin T, Nielsen PE. Antisense properties of peptide nucleic acid. Biochim Biophys Acta. 1999;1489:159–166. doi: 10.1016/s0167-4781(99)00145-1. [DOI] [PubMed] [Google Scholar]
  61. Lee NS, Dohjima T, Bauer G, Li H, Li MJ, Ehsani A, Salvaterra P, Rossi J. Expression of small interfering RNAs targeted against HIV-1 rev transcripts in human cells. Nat Biotechnol. 2002;20:500–505. doi: 10.1038/nbt0502-500. [DOI] [PubMed] [Google Scholar]
  62. Levine BL, Humeau LM, Boyer J, MacGregor RR, Rebello T, Lu X, Binder GK, Slepushkin V, Lemiale F, Mascola JR, Bushman FD, Dropulic B, June CH. Gene transfer in humans using a conditionally replicating lentiviral vector. Proc Natl Acad Sci USA. 2006;103:17372–17377. doi: 10.1073/pnas.0608138103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Li BJ, Tang Q, Cheng D, Qin C, Xie FY, Wei Q, Xu J, Liu Y, Zheng BJ, Woodle MC, Zhong N, Lu PY. Using siRNA in prophylactic and therapeutic regimens against SARS coronavirus in Rhesus macaque. Nat Med. 2005a;11:944–951. doi: 10.1038/nm1280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Li MJ, Bauer G, Michienzi A, Yee JK, Lee NS, Kim J, Li S, Castanotto D, Zaia J, Rossi JJ. Inhibition of HIV-1 infection by lentiviral vectors expressing Pol III-promoted anti-HIV RNAs. Mol Ther. 2003;8:196–206. doi: 10.1016/s1525-0016(03)00165-5. [DOI] [PubMed] [Google Scholar]
  65. Li MJ, Kim J, Li S, Zaia J, Yee JK, Anderson J, Akkina R, Rossi JJ. Long-term inhibition of HIV-1 infection in primary hematopoietic cells by lentiviral vector delivery of a triple combination of anti-HIV shRNA, anti-CCR5 ribozyme, and a nucleolar-localizing TAR decoy. Mol Ther. 2005b;12:900–909. doi: 10.1016/j.ymthe.2005.07.524. [DOI] [PubMed] [Google Scholar]
  66. Liu R, Paxton WA, Choe S, Ceradini D, Martin SR, Horuk R, MacDonald ME, Stuhlmann H, Koup RA, Landau NR. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell. 1996;86:367–377. doi: 10.1016/s0092-8674(00)80110-5. [DOI] [PubMed] [Google Scholar]
  67. Liu S, Asparuhova M, Brondani V, Ziekau I, Klimkait T, Schumperli D. Inhibition of HIV-1 multiplication by antisense U7 snRNAs and siRNAs targeting cyclophilin A. Nucleic Acids Res. 2004;32:3752–3759. doi: 10.1093/nar/gkh715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Liu YP, Haasnoot J, Berkhout B. Design of extended short hairpin RNAs for HIV-1 inhibition. Nucleic Acids Res. 2007;35:5683–5693. doi: 10.1093/nar/gkm596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Liu YP, Haasnoot J, Ter Brake O, Berkhout B, Konstantinova P. Inhibition of HIV-1 by multiple siRNAs expressed from a single microRNA polycistron. Nucleic Acids Res. 2008;36:2811–2824. doi: 10.1093/nar/gkn109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Lu A, Zhang H, Zhang X, Wang H, Hu Q, Shen L, Schaffhausen BS, Hou W, Li L. Attenuation of SARS coronavirus by a short hairpin RNA expression plasmid targeting RNA-dependent RNA polymerase. Virol. 2004;324:84–89. doi: 10.1016/j.virol.2004.03.031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Macpherson JL, Boyd MP, Arndt AJ, Todd AV, Fanning GC, Ely JA, Elliott F, Knop A, Raponi M, Murray J, Gerlach W, Sun LQ, Penny R, Symonds GP, Carr A, Cooper DA. Long-term survival and concomitant gene expression of ribozyme-transduced CD4 + T-lymphocytes in HIV-infected patients. J Gene Med. 2005;7:552–564. doi: 10.1002/jgm.705. [DOI] [PubMed] [Google Scholar]
  72. Martinez MA, Gutierrez A, Arman-Ugon M, Blanco J, Parera M, Gomez J, Clotet B, Este JA. Suppression of chemokine receptor expression by RNA interference allows for inhibition of HIV-1 replication. AIDS. 2002;16:2385–2390. doi: 10.1097/00002030-200212060-00002. [DOI] [PubMed] [Google Scholar]
  73. McCaffrey AP, Nakai H, Pandey K, Huang Z, Salazar FH, Xu H, Wieland SF, Marion PL, Kay MA. Inhibition of hepatitis B virus in mice by RNA interference. Nat Biotechnol. 2003;21:639–644. doi: 10.1038/nbt824. [DOI] [PubMed] [Google Scholar]
  74. McHutchison JG, Patel K, Pockros P, Nyberg L, Pianko S, Yu RZ, Dorr FA, Kwoh TJ. A phase I trial of an antisense inhibitor of hepatitis C virus (ISIS 14803), administered to chronic hepatitis C patients. J Hepatol. 2006;44:88–96. doi: 10.1016/j.jhep.2005.09.009. [DOI] [PubMed] [Google Scholar]
  75. Monia BP, Lesnik EA, Gonzalez C, Lima WF, McGee D, Guinosso CJ, Kawasaki AM, Cook PD, Freier SM. Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as antisense inhibitors of gene expression. J Biol Chem. 1993;268:14514–14522. [PubMed] [Google Scholar]
  76. Morrissey DV, Blanchard K, Shaw L, Jensen K, Lockridge JA, Dickinson B, McSwiggen JA, Vargeese C, Bowman K, Shaffer CS, Polisky BA, Zinnen S. Activity of stabilized short interfering RNA in a mouse model of hepatitis B virus replication. Hepatology. 2005a;41:1349–1356. doi: 10.1002/hep.20702. [DOI] [PubMed] [Google Scholar]
  77. Morrissey DV, Lockridge JA, Shaw L, Blanchard K, Jensen K, Breen W, Hartsough K, Machemer L, Radka S, Jadhav V, Vaish N, Zinnen S, Vargeese C, Bowman K, Shaffer CS, Jeffs LB, Judge A, Maclachlan I, Polisky B. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat Biotechnol. 2005b;23:1002–1007. doi: 10.1038/nbt1122. [DOI] [PubMed] [Google Scholar]
  78. Ni B, Shi X, Li Y, Gao W, Wang X, Wu Y. Inhibition of replication and infection of severe acute respiratory syndrome–associated coronavirus with plasmid-mediated interference RNA. Antivir Ther. 2005;10:527–533. [PubMed] [Google Scholar]
  79. Nishitsuji H, Kohara M, Kannagi M, Masuda T. Effective suppression of human immunodeficiency virus type 1 through a combination of short- or long–hairpin RNAs targeting essential sequences for retroviral integration. J Virol. 2006;80:7658–7666. doi: 10.1128/JVI.00078-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Novina CD, Murray MF, Dykxhoorn DM, Beresford PJ, Riess J, Lee SK, Collman RG, Lieberman J, Shankar P, Sharp PA. siRNA—directed inhibition of HIV—1 infection. Nat Med. 2002;8:681–686. doi: 10.1038/nm725. [DOI] [PubMed] [Google Scholar]
  81. Peracchi A. Prospects for antiviral ribozymes and deoxyribozymes. Rev Med Virol. 2004;14:47–64. doi: 10.1002/rmv.415. [DOI] [PubMed] [Google Scholar]
  82. Petersen M, Wengel J. LNA: a versatile tool for therapeutics and genomics. Trends Biotech-nol. 2003;21:74–81. doi: 10.1016/S0167-7799(02)00038-0. [DOI] [PubMed] [Google Scholar]
  83. Ping YH, Chu CY, Cao H, Jacque JM, Stevenson M, Rana TM. Modulating HIV-1 replication by RNA interference directed against human transcription elongation factor SPT5. Retro-virology. 2004;1:46. doi: 10.1186/1742-4690-1-46. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Pyrc K, Bosch BJ, Berkhout B, Jebbink MF, Dijkman R, Rottier P, vander Hoek L. Inhibition of HCoV-NL63 infection at early stages of the replication cycle. Antim Ag Chemoth. 2006;50:2000–2008. doi: 10.1128/AAC.01598-05. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Qin XF, An DS, Chen ISY, Baltimore D. Inhibiting HIV-1 infection in human T cells by lentiviral–mediated delivery of small interfering RNA against CCR5. Proc Natl Acad Sci USA. 2003;100:183–188. doi: 10.1073/pnas.232688199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Rana TM. Illuminating the silence: understanding the structure and function of small RNAs. Nat Rev Mol Cell Biol. 2007;8:23–36. doi: 10.1038/nrm2085. [DOI] [PubMed] [Google Scholar]
  87. Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, Farber C-M, Saragosti S, Lapoumeroulie C, Cognaux J, Forceille C, Muyldermans G, Verhofstede C, Burtonboy G, Georges M, Imai T, Rana S, Yi Y, Smyth RJ, Collman RG, Doms RW, Vassart G, Parmentier M. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature. 1996;382:722–725. doi: 10.1038/382722a0. [DOI] [PubMed] [Google Scholar]
  88. Santoro SW, Joyce GF. A general purpose RNA-cleaving DNA enzyme. Proc Natl Acad Sci USA. 1997;94:4262–4266. doi: 10.1073/pnas.94.9.4262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Schiffelers RM, Ansari A, Xu J, Zhou Q, Tang Q, Storm G, Molema G, Lu PY, Scaria PV, Woodle MC. Cancer siRNA therapy by tumor selective delivery with ligand–targeted sterically stabilized nanoparticle. Nucleic Acids Res. 2004;32:e149. doi: 10.1093/nar/gnh140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  90. Shin D, Kim SI, Kim M, Park M. Efficient inhibition of hepatitis B virus replication by small interfering RNAs targeted to the viral X gene in mice. Virus Res. 2006;119:146–153. doi: 10.1016/j.virusres.2005.12.012. [DOI] [PubMed] [Google Scholar]
  91. Silva JM, Li MZ, Chang K, Ge W, Golding MC, Rickles RJ, Siolas D, Hu G, Paddison PJ, Schlabach MR, Sheth N, Bradshaw J, Burchard J, Kulkarni A, Cavet G, Sachidanandam R, McCombie WR, Cleary MA, Elledge SJ, Hannon GJ. Second-generation shRNA libraries covering the mouse and human genomes. Nat Genet. 2005;37:1281–1288. doi: 10.1038/ng1650. [DOI] [PubMed] [Google Scholar]
  92. Soifer HS, Zaragoza A, Peyvan M, Behlke MA, Rossi JJ. A potential role for RNA interference in controlling the activity of the human LINE-1 retrotransposon. Nucleic Acids Res. 2005;33:846–856. doi: 10.1093/nar/gki223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Stein D, Foster E, Huang SB, Weller D, Summerton J. A specificity comparison of four antisense types: morpholino, 2′-O-methyl RNA, DNA, and phosphorothioate DNA. Antisense Nucleic Acid Drug Dev. 1997;7:151–157. doi: 10.1089/oli.1.1997.7.151. [DOI] [PubMed] [Google Scholar]
  94. Surabhi RM, Gaynor RB. RNA interference directed against viral and cellular targets inhibits human immunodeficiency virus type 1 replication. J Virol. 2002;76:12963–12973. doi: 10.1128/JVI.76.24.12963-12973.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Swayze EE, Siwkowski AM, Wancewicz EV, Migawa MT, Wyrzykiewicz TK, Hung G, Monia BP, Bennett CF. Antisense oligonucleotides containing locked nucleic acid improve potency but cause significant hepatotoxicity in animals. Nucleic Acids Res. 2007;35:687–700. doi: 10.1093/nar/gkl1071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Tam OH, Aravin AA, Stein P, Girard A, Murchison EP, Cheloufi S, Hodges E, Anger M, Sachidanandam R, Schultz RM, Hannon GJ. Pseudogene–derived small interfering RNAs regulate gene expression in mouse oocytes. Nature. 2008;453:534–538. doi: 10.1038/nature06904. [DOI] [PMC free article] [PubMed] [Google Scholar]
  97. Tan WB, Jiang S, Zhang Y. Quantum–dot based nanoparticles for targeted silencing of HER2/neu gene via RNA interference. Biomaterials. 2007;28:1565–1571. doi: 10.1016/j.biomaterials.2006.11.018. [DOI] [PubMed] [Google Scholar]
  98. Ter Brake O, Berkhout B. A novel approach for inhibition of HIV-1 by RNA interference: counteracting viral escape with a second generation of siRNAs. J RNAi Gene Silencing. 2005;1(2):56–65. [PMC free article] [PubMed] [Google Scholar]
  99. Ter Brake O, Konstantinova P, Ceylan M, Berkhout B. Silencing of HIV-1 with RNA interference: a multiple shRNA approach. Mol Ther. 2006;14:883–892. doi: 10.1016/j.ymthe.2006.07.007. [DOI] [PubMed] [Google Scholar]
  100. Ter Brake O, ’t Hooft K, Liu YP, Centlivre M, von Eije KJ, Berkhout B. Lentiviral vector design for multiple shRNA expression and durable HIV-1 inhibition. Mol Ther. 2008;16:557–564. doi: 10.1038/sj.mt.6300382. [DOI] [PubMed] [Google Scholar]
  101. Tompkins SM, Lo CY, Tumpey TM, Epstein SL. Protection against lethal influenza virus challenge by RNA interference in vivo. Proc Natl Acad Sci USA. 2004;101:8682–8686. doi: 10.1073/pnas.0402630101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  102. Triboulet R, Mari B, Lin YL, Chabl–Bessia C, Bennasser Y, Lebrigand K, Cardinaud B, Maurin T, Barbry P, Baillat V, Reynes J, Corbeau P, Jeang KT, Benkirane M. Suppression of microRNA–silencing pathway by HIV–1 during virus replication. Science. 2007;315:1579–1582. doi: 10.1126/science.1136319. [DOI] [PubMed] [Google Scholar]
  103. Tuerk C, MacDougal S, Gold L. RNA pseudoknots that inhibit human immunodeficiency virus type 1 reverse transcriptase. Proc Natl Acad Sci USA. 1992;89:6988–6992. doi: 10.1073/pnas.89.15.6988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  104. Turner JJ, Fabani M, Arzumanov AA, Ivanova G, Gait MJ. Targeting the HIV–1 RNA leader sequence with synthetic oligonucleotides and siRNA: chemistry and cell delivery. Biochim Biophys Acta. 2006;1758:290–300. doi: 10.1016/j.bbamem.2005.10.013. [DOI] [PubMed] [Google Scholar]
  105. Van Aerschot A. Oligonucleotides as antivirals: dream or realistic perspective? Antiviral Res. 2006;71:307–316. doi: 10.1016/j.antiviral.2006.03.003. [DOI] [PubMed] [Google Scholar]
  106. Vitravene Study Group A randomized controlled clinical trial of intravitreous fomivirsen for treatment of newly diagnosed peripheral cytomegalovirus retinitis in patients with AIDS. Am J Ophthalmol. 2002;133:467–474. doi: 10.1016/s0002-9394(02)01327-2. [DOI] [PubMed] [Google Scholar]
  107. Voinnet O. Induction and suppression of RNA silencing: insights from viral infections. Nat Rev Genet. 2005;6:206–220. doi: 10.1038/nrg1555. [DOI] [PubMed] [Google Scholar]
  108. von Eije KJ, Ter Brake O, Berkhout B. Human immunodeficiency virus type 1 escape is restricted when conserved genome sequences are targeted by RNA interference. J Virol. 2008;82:2895–2903. doi: 10.1128/JVI.02035-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  109. Wahlestedt C, Salmi P, Good L, Kela J, Johnsson T, Hokfelt T, Broberger C, Porreca F, Lai J, Ren K, Ossipov M, Koshkin A, Jakobsen N, Skouv J, Oerum H, Jacobsen MH, Wengel J. Potent and nontoxic antisense oligonucleotides containing locked nucleic acids. Proc Natl Acad Sci USA. 2000;97:5633–5638. doi: 10.1073/pnas.97.10.5633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  110. Wang Z, Ren L, Zhao X, Hung T, Meng A, Wang J, Chen YG. Inhibition of severe acute respiratory syndrome virus replication by small interfering RNAs in mammalian cells. J Virol. 2004;78:7523–7527. doi: 10.1128/JVI.78.14.7523-7527.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  111. Warfield KL, Swenson DL, Olinger GG, Nichols DK, Pratt WD, Blouch R, Stein DA, Aman MJ, Iversen PL, Bavari S. Gene–specific countermeasures against Ebola virus based on anti– sense phosphorodiamidate morpholino oligomers. PLoS Pathog. 2006;2:e1. doi: 10.1371/journal.ppat.0020001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  112. Watanabe T, Sudoh M, Miyagishi M, Akashi H, Arai M, Inoue K, Taira K, Yoshiba M, Kohara M (2006a) Intracellular–diced dsRNA has enhanced efficacy for silencing HCV RNA and overcomes variation in the viral genotype. Gene Ther 883–892 [DOI] [PubMed]
  113. Watanabe T, Takeda A, Tsukiyama T, Mise K, Okuno T, Sasaki H, Minami N, Imai H. Identification and characterization of two novel classes of small RNAs in the mouse germline: retrotransposon-derived siRNAs in oocytes and germline small RNAs in testes. Genes Dev. 2006b;20:1732–1743. doi: 10.1101/gad.1425706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  114. Watanabe T, Totoki Y, Toyoda A, Kaneda M, Kuramochi-Miyagawa S, Obata Y, Chiba H, Kohara Y, Kono T, Nakano T, Surani MA, Sakaki Y, Sasaki H. Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes. Nature. 2008;453:539–543. doi: 10.1038/nature06908. [DOI] [PubMed] [Google Scholar]
  115. Weinberg MS, Ely A, Barichievy S, Crowther C, Mufamadi S, Carmona S, Arbuthnot P. Specific inhibition of HBV replication in vitro and in vivo with expressed long hairpin RNA. Mol Ther. 2007;15:534–541. doi: 10.1038/sj.mt.6300077. [DOI] [PubMed] [Google Scholar]
  116. Westerhout EM, Ooms M, Vink M, Das AT, Berkhout B. HIV-1 can escape from RNA interference by evolving an alternative structure in its RNA genome. Nucleic Acids Res. 2005;33:796–804. doi: 10.1093/nar/gki220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  117. Westerhout EM, Vink M, Haasnoot PC, Das AT, Berkhout B. A conditionally replicating HIV–based vector that stably expresses an antiviral shRNA against HIV-1 replication. Mol Ther. 2006;14:268–275. doi: 10.1016/j.ymthe.2006.03.018. [DOI] [PubMed] [Google Scholar]
  118. Wilson JA, Richardson CD. Hepatitis C virus replicons escape RNA interference induced by a short interfering RNA directed against the NS5b coding region. J Virol. 2005;79:7050–7058. doi: 10.1128/JVI.79.11.7050-7058.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  119. Wu CJ, Huang HW, Liu CY, Hong CF, Chan YL. Inhibition of SARS-CoV replication by siRNA. Antiviral Res. 2005a;65:45–48. doi: 10.1016/j.antiviral.2004.09.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  120. Wu HL, Huang LR, Huang CC, Lai HL, Liu CJ, Huang YT, Hsu YW, Lu CY, Chen DS, Chen PJ. RNA interference–mediated control of hepatitis B virus and emergence of resistant mutant. Gastroenterology. 2005b;128:708–716. doi: 10.1053/j.gastro.2004.12.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  121. Xuan B, Qian Z, Hong J, Huang W. EsiRNAs inhibit Hepatitis B virus replication in mice model more efficiently than synthesized siRNAs. Virus Res. 2006;118:150–155. doi: 10.1016/j.virusres.2005.12.005. [DOI] [PubMed] [Google Scholar]
  122. Yang N, Kazazian HH., Jr L1 retrotransposition is suppressed by endogenously encoded small interfering RNAs in human cultured cells. Nat Struct Mol Biol. 2006;13:763–771. doi: 10.1038/nsmb1141. [DOI] [PubMed] [Google Scholar]
  123. Ying C, De Clercq E, Neyts J. Selective inhibition of hepatitis B virus replication by RNA interference. Biochem Biophys Res Commun. 2003;309:482–484. doi: 10.1016/j.bbrc.2003.08.021. [DOI] [PubMed] [Google Scholar]
  124. Ying RS, Zhu C, Fan XG, Li N, Tian XF, Liu HB, Zhang BX. Hepatitis B virus is inhibited by RNA interference in cell culture and in mice. Antiviral Res. 2007;73:24–30. doi: 10.1016/j.antiviral.2006.05.022. [DOI] [PubMed] [Google Scholar]
  125. Zamecnik PC, Stephenson ML. Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc Natl Acad Sci USA. 1978;75:280–284. doi: 10.1073/pnas.75.1.280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  126. Zhang W, Yang H, Kong X, Mohapatra S, Juan-Vergara HS, Hellermann G, Behera S, Singam R, Lockey RF, Mohapatra SS. Inhibition of respiratory syncytial virus infection with in-tranasal siRNA nanoparticles targeting the viral NS1 gene. Nat Med. 2005;11:56–62. doi: 10.1038/nm1174. [DOI] [PubMed] [Google Scholar]
  127. Zhang Y, Li T, Fu L, Yu C, Li Y, Xu X, Wang Y, Ning H, Zhang S, Chen W, Babiuk LA, Chang Z. Silencing SARS-CoV Spike protein expression in cultured cells by RNA interference. FEBS Lett. 2004;560:141–146. doi: 10.1016/S0014-5793(04)00087-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  128. Zhou N, Fang J, Mukhtar M, Acheampong E, Pomerantz RJ. Inhibition of HIV–1 fusion with small interfering RNAs targeting the chemokine coreceptor CXCR4. Gene Ther. 2004;11:1703–1712. doi: 10.1038/sj.gt.3302339. [DOI] [PubMed] [Google Scholar]

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