Abstract
RNA interference is a natural mechanism by which small interfering (si)RNA operates to specifically and potently down-regulate the expression of a target gene. This down-regulation has been thought to predominantly function at the level of the messenger (m)RNA, post-transcriptional gene silencing (PTGS). Recently, the discovery that siRNAs can function to suppress a gene’s expression at the level of transcription, i.e., transcriptional gene silencing (TGS), has created a major paradigm shift in mammalian RNAi. These recent findings significantly broaden the role RNA, specifically siRNAs and potentially microRNAs, plays in the regulation of gene expression as well as the breadth of potential siRNA target sites. Indeed, the specificity and simplicity of design makes the use of siRNAs to target and suppress virtually any gene or gene promoter of interest a realized technology. Furthermore, since siRNAs are a small nucleic acid reagent, they are unlikely to elicit an immune response, making them a theoretically good future therapeutic. This review will focus on the development, delivery, and potential therapeutic use of antiviral siRNAs in treating viral infections as well as emerging viral threats.
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Banerjea A, Li MJ, Bauer G, Remling L, Lee NS, Rossi J, Akkina R (2003) Inhibition of HIV-1 by lentiviral vector-transduced siRNAs in T lymphocytes differentiated in SCID-hu mice and CD34+ progenitor cell-derived macrophages. Mol Ther 8:62–71
Bennasser Y, Le SY, Benkirane M, Jeang KT (2005) Evidence that HIV-1 encodes an siRNA and a suppressor of RNA silencing. Immunology 22:607–619
Bernstein E, Caudy AA, Hammond SM, Hannon GJ (2001) Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409:363–366
Bernstein E, Kim SY, Carmell MA, Murchison EP, Alcorn H, Li MZ, Mills AA, Elledge SJ, Anderson KV, Hannon GJ (2003) Dicer is essential for mouse development. Nat Genet 35:215–217
Boerger AL, Snitkovsky S, Young JAT (1999) Retroviral vectors preloaded with a viral receptor-ligand bridge protein are targeted to specific cell types. Proc Natl Acad Sci USA 96:9867–9872
Bosher JM, Dugourcq P, Sookhareea S, Labouesse M(1999)RNA interference can target pre-mRNA: consequences for gene expression in a Caenorhabditis elegans operon. Genetics 153:1245–1256
Browning MT, Schmidt RD, Lew KA, Rizvi TA (2001) Primate and feline lentivirus vector RNA packaging and propagation by heterologous lentivirus virions. J Virol 75:5129–5140
Buchschacher GL, Wong-Staal F (2000) Development of lentiviral vectors for gene therapy for human diseases. Blood 95:2499–2504
Castanotto D, Rossi JJ (2004) Construction and transfection of PCR products expressing siRNAs or shRNAs in mammalian cells. Methods Mol Biol 252:509–514
Coburn GA, Cullen BR (2002) Potent and specific inhibition of human immunodeficiency virus type 1 replication by RNA interference. J Virol 76:9225–9231
Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC (1998) Potent and specific genetic interference by double stranded RNA in Caenorhabditis elegans. Nature 391:806–811
Gervaix A, West D, Leoni LM, Richman DD, Wong-Staal F, Corbeil J (1997) A new reporter cell line to monitor HIV infection and drug susceptibility in vitro. Proc Natl Acad Sci U S A 94:4653–4658
Gitlin L, Karelsky S, Andino R (2002) Short interfering RNA confers intracellular antiviral immunity in human cells. Nature 26:1–5
Goujon C, Jarrosson-Wuilleme L, Bernaud J, Rigal D, Darlix J, Cimarelli A (2003) Heterologous human immunodeficiency virus type 1 lentiviral vectors packaging a simian immunodeficiency virus-derived genome display a specific postentry transduction defect in dendritic cells. J Virol 787:9295–9304
Hamada M, Ohtsuka T, Kawaida R, Koizumi M, Morita K, Furukawa H, Imanishi T, Miyagishi M, Taira K (2002) Effects on RNA interference in gene expression (RNAi) in cultured mammalian cells of mismatches and the introduction of chemical modifications at the 3′-ends of siRNAs. Antisense Nucleic Acid Drug Dev 12:301–309
Hamilton A, Voinnet O, Chappell L, Baulcombe D (2002) Two classes of short interfering RNA in RNA silencing. EMBO J 21:4671–4679
Holen T, Amarzguioui M, Wiiger MT, Babaie E, Prydz H (2002) Positional effects of short interfering RNAs targeting the human coagulation trigger tissue factor. Nucleic Acids Res 30:1757–1766
Jacque J, Triques K, Stevenson M (2002) Modulation of HIV-1 replication by RNA interference. Nature 26:1–4
Jeffery L, Nakielny S (2004) Components of the DNA methylation system of chromatin control are RNA-binding proteins. J Biol Chem 279:49479–49487
Johansen LK, Carrington JC (2001) Silencing on the spot. Induction and suppression of RNA silencing in the Agrobacterium-mediated transient expression system. Plant Physiol 126:930–938
Kawasaki H, Taira K (2004) Induction of DNA methylation and gene silencing by short interfering RNAs in human cells. Nature 9:211–217
Kawasaki H, Taira K, Morris KV (2005) siRNA induced transcriptional gene silencing in mammalian cells. Cell Cycle 3:442–448
Kobinger GP, Weiner DJ, Yu Q, Wilson JM (2001) Filovirus-pseudotyped lentiviral vector can efficiently and stably transduce airway epithelia in vivo. Nat Biotechnol 19:225–230
Lee NS, Rossi JJ (2004) Control of HIV-1 replication by RNA interference. Virus Res 102:53–58
Lee NS, Dohjima T, Bauer G, Li H, Li M, Ehsani A, Salvaterra P, Rossi J (2002) Expression of small interfering RNAs targeted against HIV-1 rev transcripts in human cells. Nat Biotechnol 19:500–505
Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Radmark O, Kim S, Kim VN (2003) The nuclear RNase III Drosha initiates microRNA processing. Nature 425:415–419
Li H, Li WX, Ding SW (2002) Induction and suppression of RNA silencing by an animal virus. Science 296:1319–1321
Liu J, Carmell MA, Rivas FV, Marsden CG, Thomson JM, Song JJ, Hammond SM, Joshua-Tor L, Hannon GJ (2004) Argonaute2 is the catalytic engine of mammalian RNAi. Science 305:1437–1441
Llave C, Kasschau KD, Carrington JC (2000) Virus-encoded suppressor of posttranscriptional gene silencing targets amaintenance step in the silencing pathway. Proc Natl Acad Sci USA 97:13401–13406
Lund E, Guttinger S, Calado A, Dahlberg JE, Kutay U (2004) Nuclear export of microRNA precursors. Science 303:95–98
Mallory AC, Ely L, Smith TH, Marathe R, Anandalakshmi R, Fagard M, Vaucheret H, Pruss G, Bowman L, Vance VB (2001) HC-Pro suppression of transgene silencing eliminates the small RNAs but not transgene methylation or the mobile signal. Plant Cell 13:571–583
Mallory AC, Reinhart BJ, Bartel D, Vance VB, Bowman LH (2002) A viral suppressor of RNA silencing differentially regulates the accumulation of short interfering RNAs and micro-RNAs in tobacco. Proc Natl Acad Sci U S A 99:15228–15233
Martinez J, Patkaniowska A, Urlaub H, Luhrmann R, Tuschl T (2002) Single-stranded antisense siRNAs guide target RNA cleavage in RNAi. Cell 110:563–574
Matzke MA, Primig M, Trnovsky J, Matzke AJM (1989) Reversible methylation and inactivation of marker genes in sequentially transformed tobacco plants. EMBO J 8:643–649
Meissner W, Rothfels H, Schafer B, Seifart K (2001) Development of an inducible pol III transcription system essentially requiring a mutated form of the TAT-binding protein. Nucleic Acids Res 29:1672–1682
Montgomery MK, Xu S, Fire A (1998) RNA as a target of double-stranded RNA-mediated genetic interference in Caenorhabditis elegans. Proc Natl Acad Sci USA 95:15502–15507
Morris KV, Chung C, Witke W, Looney DJ (2004) Inhibition of HIV-1 replication by siRNA targeting conserved regions of gag/pol. RNA Biol 1:114–117
Morris KV, Chan SW, Jacobsen SE, Looney DJ (2004a) Small interfering RNA-induced transcriptional gene silencing in human cells. Science 305:1289–1292
Morris KV, Gilbert J, Wong-Staal F, Gasmi M, Looney DJ (2004b) Transduction of cell lines and primary cells by FIV-packaged HIV vectors. Mol Ther 10:181–190
Ngo H, Tschudi C, Gull K, Ullu E (1998) Double-stranded RNA induces mRNA degradation in Trypanosoma brucei. Proc Natl Acad Sci USA 95:14687–14692
Nishikura K (2001) A short primer on RNAi: RNA-directed RNA polymerase acts as a key catalyst. Cell 107:415–418
Novina CD, Murray MF, Dykxhoorn DM, Beresford PJ, Riess J, Lee S, Collman RG, Leiberman J, Shankar P, Sharp PA (2002) siRNA-directed inhibition of HIV-1 infection. Nat Med 8:681–686
Pasquinelli AE (2002) MicroRNAs: deviants no longer. Trends Genet 18:171–173
Pasquinelli AE, Ruvkun G (2002) Control of developmental timing by micrornas and their targets. Annu Rev Cell Dev Biol 18:495–513
Poeschla E, Corbeau P, Wong-Staal F (1996) Development of HIV vectors for anti-HIV gene therapy. Proc Natl Acad Sci U S A 93:11395–11399
Price MA, Case SS, Carbonaro DA, Yu XJ, Petersen D, Sabo KM, Curran MA, Engel BC, Margarian H, Abkowitz JL, Nolan GP, Kohn DB (2002) Expression from second-generation feline immunodeficiency virus vectors is impaired in human hematopoietic cells. Mol Ther 6:645–652
Qin X, An D, Chen ISY, Baltimore D (2002) Inhibiting HIV-1 infection in human T cells by lentiviral mediated delivery of small interfering RNA against CCR5. Proc Natl Acad Sci USA 100:183–188
Quinonez R, Sutton RE (2002) Lentiviral Vectors for gene delivery into cells. DNA Cell Biol 12:937–951
Radhakrishnan S, Gordon J, Del Valle L, Cui J, Khalili K (2004) Intracellular approach for blocking JC virus gene expression by using RNA interference during viral infection. J Virol 78:7264–7269
Richman DD, Havlir D, Corbeil J, Looney D, Ignacio C, Spector SA, Sullivan J, Cheeseman S, Barringer K, Pauletti D (1994) Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J Virol 68:1660–1666
Sandrin V, Russell SJ, Cosset FL (2003) Targeting retroviral and lentiviral vectors. Curr Top Microbiol Immunol 281:137–178
Scherr M, Rossi JJ (1998) Rapid determination and quantitation of the accessibility to native RNAs by antisense oligodeoxynucleotides in murine cell extracts. Nucleic Acids Res 26:5079–5085
Schwarz DS, Hutvagner G, Du T, Xu Z, Aronin N, Zamore PD (2003) Asymmetry in the assembly of the RNAi enzyme complex. Cell 115:199–208
Sharp PA (2001) RNA interference. Genes Dev 15:485–490
Sioud M, Sorensen DR (2003) Cationic liposome-mediated delivery of siRNAs in adult mice. Biochem Biophys Res Commun 312:1220–1225
Sledz CA, Holko M, de Veer MJ, Silverman RH, Williams BR (2003) Activation of the interferon system by short-interfering RNAs. Nat Cell Biol 5:834–839
Song E, S Lee, Dykxhoorn DM, Novina C, Zhang D, Crawford K, Cerny J, Sharp PA, Leiberman J, Manjunath N, Shankar P (2003) Sustained small interfering RNA-mediated human immunodeficiency virus type 1 inhibition in primary macrophages. J Virol 77:7174–7181
Sorensen DR, Leirdal M, Sioud M (2003) Gene silencing by systemic delivery of synthetic siRNAs in adult mice. J Mol Biol 327:761–766
Sui G, Soohoo C, Affar E, Gay F, Shi Y, Forrester WC, Shi Y (2002) A DNA vector-based RNAi technology to suppress gene expression in mammalian cells. Proc Natl Acad Sci USA 99:5515–5520
Sumimoto H, Miyagishi M, Miyoshi H, Taira K, Kawakami Y (2003) Development of an efficient small interfering RNA (siRNA) expression system with a lentiviral vector. Mol Ther 7:S34
Surabhi RM, Gaynor RB (2002) RNA interference directed against viral and cellular targets inhibits human immunodeficiency virus type 1 replication. J Virol 76:12963–12973
Tijsterman M, Ketting RF, Plasterk RH (2002) The genetics of RNA silencing. Annu Rev Genet 36:489–519
Tuschl T (2002) Expanding small RNA interference. Nat Biotechnol 20:446–448
Volpe TA, Kidner C, Hall IM, Teng G, Grewal SIS, Martienssen RA (2002) Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi. Science 297:1833–1837
Wassenegger M (2000) RNA-directed DNA methylation. Plant Mol Biol 43:203–220
Wassenegger M, Graham MW, Wang MD (1994) RNA-directed de novo methylation of genomic sequences in plants. Cell 76:567–576
Westerhout EM, Ooms M, Vink M, Das AT, Berkhout B (2005) HIV-1 can escape from RNA interference by evolving an alternative structure in its RNA genome. Nucleic Acids Res 33:796–804
White SM, Renda M, Nam NY, Klimatcheva E, Zhu Y, Fisk J, Halterman M, Rimel BJ, Federoff H, Pandya S, Rosenblatt JR, Planelles V (1999) Lentivirus vectors using human and simian immunodeficiency virus elements. J Virol 73:2832–2840
Wu X, Li Y, Crise B, Burgess SM (2003) Transcription start regions in the human genome are favored targets for MLV integration. Science 300:1749–1751
Yam PY, Li S, Wu JU, Hu J, Zaia JA, Yee J (2002) Design of HIV vectors for efficient gene delivery into human hematopoietic cells. Mol Ther 5:479–484
Zeng Y, Cullen BR (2002) RNA interference in human cells is restricted to the cytoplasm. RNA 8:855–860
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Morris, K., Rossi, J. (2006). Antiviral Applications of RNAi. In: Erdmann, V., Barciszewski, J., Brosius, J. (eds) RNA Towards Medicine. Handbook of Experimental Pharmacology, vol 173. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-27262-3_6
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DOI: https://doi.org/10.1007/3-540-27262-3_6
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