Abstract
Lentiviral vectors portend a promising system to deliver antiviral genes for treating viral infections such as HIV-1 as they are capable of stably transducing both dividing and nondividing cells. Recently, small interfering RNAs (siRNAs) have been shown to be quite efficacious in silencing target genes. RNA interference is a natural mechanism, conserved in nature from Yeast to Humans, by which siRNAs operate to specifically and potently downregulate the expression of a target gene either transcriptionally (targeted to DNA) or post-transcriptionally (targeted to mRNA). The specificity and relative simplicity of siRNA design insinuate that siRNAs will prove to be favorable therapeutic agents. Since siRNAs are a small nucleic acid reagents, they are unlikely to elicit an immune response and genes encoding these siRNAs can be easily manipulated and delivered by lentiviral vectors to target cells. As such, lentiviral vectors expressing siRNAs represent a potential therapeutic approach for the treatment of viral infections such as HIV-1. This review will focus on the development, lentiviral based delivery, and the potential therapeutic use of siRNAs in treating viral infections.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Montgomery MK, Xu S, Fire A . RNA as a target of double-stranded RNA-mediated genetic interference in Caenorhabditis elegans. Proc Natl Acad Sci USA 1998; 95: 15502–15507.
Nishikura K . A short primer on RNAi: RNA-directed RNA polymerase acts as a key catalyst. Cell 2001; 107: 415–418.
Sharp PA . RNA interference. Genes Develop 2001; 15: 485–490.
Sui G, Soohoo C, Affar E, Gay F, Shi Y, Forrester WC et al. A DNA vector-based RNAi technology to suppress gene expression in mammalian cells. Proc Natl Acad Sci USA 2002; 99: 5515–5520.
Chendrimada TP, Gregory RI, Kumaraswamy E, Norman J, Cooch N, Nishikura K et al. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 2005; 436: 740–744.
Haase A, Jaskiewicz L, Zhang H, Laine S, Sack R, Gatignol A et al. TRBP, a regulator of cellular PKR and HIV-1 virus expression, interacts with Dicer and functions in RNA silencing. EMBO J 2005; 6 (10): 961–967.
Liu J, Valencia-Sanchez MA, Hannon GJ, Parker R . MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies. Nat Cell Biol 2005; 7: 719–723.
Liu J, Carmell MA, Rivas FV, Marsden CG, Thomson JM, Song JJ et al. Argonaute2 Is the Catalytic Engine of Mammalian RNAi. Science 2004; 305 (5689): 1437–1441.
Martinez J, Patkaniowska A, Urlaub H, Luhrmann R, Tuschl T . Single-stranded antisense siRNAs guide target RNA cleavage in RNAi. Cell 2002; 110: 563–574.
Hamada M, Ohtsuka T, Kawaida R, Koizumi M, Morita K, Furukawa H et al. 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 2002; 12: 301–309.
Sijen T, Vign I, Rebocho A, Blokland R, Roelofs D, Mol J et al. Transcriptional and posttranscriptional gene silencing are mechanistically related. Curr Biol 2001; 11: 436–440.
Pal-Bhadra M, Bhadra U, Birchler JA . RNAi related mechanisms affect both transcriptional and posttranscriptional transgene silencing in Drosophila. Mol Cell 2002; 9: 315–327.
Bosher JM, Dugourcq P, Sookhareea S, Labouesse M . RNA interference can target Pre-mRNA: consequences for gene expression in a Caenorhabditis elegans operon. Genetics 1999; 153: 1245–1256.
Kawasaki H, Taira K . Induction of DNA methylation and gene silencing by short interfering RNAs in human cells. Nature 2004; 9: 211–217.
Morris KV, Chan SW, Jacobsen SE, Looney DJ . Small interfering RNA-induced transcriptional gene silencing in human cells. Science 2004; 305 (5688): 1289–1292.
Morris KV, Chan SW, Jacobsen SE, Looney DJ . Small interfering RNA-induced transcriptional gene silencing in human cells. Science 2004; 305: 1289–1292.
Kawasaki H, Taira K, Morris KV . siRNA induced transcriptional gene silencing in mammalian cells. Cell Cycle 2005; 4 (3): 442–448.
Castanotto D, Rossi JJ . Construction and transfection of PCR products expressing siRNAs or shRNAs in mammalian cells. Methods Mol Biol 2004; 252: 509–514.
Morris KV, Chung C, Witke W, Looney DJ . Inhibition of HIV-1 replication by siRNA targeting conserved regions of gag/pol. RNA Biol 2004; 1: 114–117.
Holen T, Amarzguioui M, Wiiger MT, Babaie E, Prydz H . Positional effects of short interfering RNAs targeting the human coagulation trigger Tissue Factor. Nucleic Acids Res 2002; 30: 1757–1766.
Schwarz DSEA . Asymmetry in the assembly of the RNAi enzyme complex. Cell 2003; 115: 199–208.
Meister G, Tuschl T . Mechanisms of gene silencing by double-stranded RNA. Nature 2004; 431: 343–349.
Novina CD, Murray MF, Dykxhoorn DM, Beresford PJ, Riess J, Lee S et al. siRNA-directed inhibition of HIV-1 infection. Nat Med 2002; 8: 681–686.
Tuschl T . Expanding small RNA interference. Nat Biotechnol 2002; 20: 446–448.
Song E, Lee S, Dykxhoorn DM, Novina C, Zhang D, Crawford K et al. Sustained Small Interfering RNA-Mediated Human Immunodeficiency Virus Type 1 Inhibition in Primary Macrophages. J Virol 2003; 77: 7174–7181.
Scherr M, Rossi JJ . Rapid determination and quantitation of the accessibility to native RNAs by antisense oligodeoxynucleotides in murine cell extracts. Nucleic Acids Res 1998; 26: 5079–5085.
Richman DD, Corbeil J, Looney D, Ignacio C, Spector SA, Sullivan J et al. Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J Virol 1994; 68: 1660–1666.
Coburn GA, Cullen BR . Potent and Specific Inhibition of Human Immunodeficiency Virus Type 1 Replication by RNA interference. J Virol 2002; 76: 9225–9231.
Lee NS, Dohjima T, Bauer G, Li H, Li M, Ehsani A et al. Expression of small interfering RNAs targeted against HIV-1 rev transcripts in human cells. Nat Biotechnol 2002; 19: 500–505.
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.
Jacque J, Triques K, Stevenson M . Modulation of HIV-1 replication by RNA interference. Nature 2002; 26: 1–4.
Qin X, An D, 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 2002; 100: 183–188.
Radhakrishnan SK, Layden TJ, Gartel AL . RNA interference as a new strategy against viral hepatitis. Virology 2004; 323: 173–181.
Llave C, Kasschau KD, Carrington JC . Virus-encoded suppressor of posttranscriptional gene silencing targets a maintenance step in the silencing pathway. Proc Natl Acad Sci USA 2000; 97: 13401–13406.
Johansen LK, Carrington JC . Silencing on the spot. Induction and suppression of RNA silencing in the Agrobacterium-mediated transient expression system. Plant Physiol 2001; 126: 930–938.
Mallory AC, Ely L, Smith TH, Marathe R, Anandalakshmi R, Fagard M et al. HC-Pro suppression of transgene silencing eliminates the small RNAs but not transgene methylation or the mobile signal. Plant Cell 2001; 13: 571–583.
Hamilton A, Voinnet O, Chappell L, Baulcombe D . Two classes of short interfering RNA in RNA silencing. EMBO J 2002; 21: 4671–4679.
Li H, Li WX, Ding SW . Induction and suppression of RNA silencing by an animal virus. Science 2002; 296: 1319–1321.
Mallory AC, Reinhart BJ, Bartel D, Vance VB, Bowman LH . A viral suppressor of RNA silencing differentially regulates the accumulation of short interfering RNAs and micro-RNAs in tobacco. Proc Natl Acad Sci USA 2002; 99: 15228–15233.
Gitlin L, Karelsky S, Andino R . Short interfering RNA confers intracellular antiviral immunity in human cells. Nature 2002; 26: 1–5.
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.
Banerjea A, Li MJ, Bauer G, Remling L, Lee NS, Rossi J et al. 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 2003; 8: 62–71.
Paddison PJ, Caudy AA, Sachidanandam R, Hannon GJ . Short hairpin activated gene silencing in mammalian cells. Methods Mol Biol 2004; 265: 85–100.
Wu X, Li Y, Crise B, Burgess SM . Transcription Start Regions in the Human Genome Are Favored Targets for MLV Integration. Science 2003; 300: 1749–1751.
Buchschacher GL, Wong-Staal F . Development of lentiviral vectors for gene therapy for human diseases. Blood 2000; 95: 2499–2504.
Greber UF, Fassati A . Nuclear Import of Viral DNA Genomes. Traffic 2003; 4: 136–143.
Gervaix A, Schwarz L, Law P, Ho AD, Looney D, Wong-Staal F . Gene Therapy Targeting Peripheral Blood CD34+ Hematopoietic Stem Cells of HIV-Infected Individuals. Human Gene Ther 1997; 8: 2229–2238.
Yam PY, Li S, Wu JU, Jazaia JA, Yee J . Design of HIV Vectors for Efficient Gene Delivery into Human Hematopoietic Cells. Mol Ther 2002; 5: 479–484.
Poeschla E, Corbeau P, Wong-Staal F . Development of HIV vectors for anti-HIV gene therapy. Proc Natl Acad Sci USA 1996; 93: 11395–11399.
Price MA, Case SS, Carbonaro DA, Yu XJ, Petersen D, Sabo KM et al. Expression from second-generation feline immunodeficiency virus vectors is impaired in human hematopoietic cells. Mol Ther 2002; 6: 645–652.
Quinonez R, Sutton RE . Lentiviral Vectors for gene delivery into cells. DNA Cell Biol 2002; 12: 937–951.
White SM, Renda M, Nam NY, Klimatcheva E, Zhu Y, Fisk J et al. Lentivirus vectors using human and simian immunodeficiency virus elements. J Virol 1999; 73: 2832–2840.
Browning MT, Schmidt RD, Lew KA, Rizvi TA . Primate and feline lentivirus vector RNA packaging and propagation by heterologous lentivirus virions. J Virol 2001; 75: 5129–5140.
Goujon C, Jarrosson-Wuilleme L, Bernaud J, Rigal D, Darlix J, Cimarelli A . 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 2003; 787: 9295–9304.
Morris KV, Gilbert J, Wong-Staal F, Gasmi M, Looney DJ . Transduction of cell lines and primary cells by FIV-packaged HIV vectors. Mol Ther 2004; 10: 181–190.
Kobinger GP, Weiner DJ, Yu Q, Wilson JM . Filovirus-psuedotyped lentiviral vector can efficiently and stably transduce airway epithelia in vivo. Nat Biotechnol 2001; 19: 225–230.
Sandrin V, Russell SJ, Cosset FL . Targeting retroviral and lentiviral vectors. Curr Topics Microbiol Immunol 2003; 281: 137–178.
Boerger AL, Snitkovsky S, Young JAT . Retroviral vectors preloaded with a viral receptor-ligand bridge protein are targeted to specific cell types. Proc Natl Acad Sci USA 1999; 96: 9867–9872.
Sledz CA, Holko M, De Veer MJ, Silverman RH, Williams BR . Activation of the interferon system by short-interfering RNAs. Nat Cell Biol 2003; 5: 834–839.
Pebernard S, Iggo RD . Determinants of interferon-stimulated gene induction by RNAi vectors. Differentiation 2004; 72: 103–111.
Persengiev SP, Zhu X, Green MR . Nonspecific, concentration-dependent stimulation and repression of mammalian gene expression by small interfering RNAs (siRNAs). RNA 2004; 10: 12–18.
Michienzi AEA . RNA-mediated inhibition of HIV in a gene therapy setting. Ann NY Acad Sci 2003; 1002: 63–71.
Amado RGEA . Anti-human immunodeficiency virus hematopoietic progenitor cell-delivered ribozyme in a phase I study: myeloid and lymphoid reconstitution in human immunodeficiency virus type-1-infected patients. Hum Gene Ther 2004; 15: 251–262.
Morris MC, Vidal P, Chaloin L, Heitz F, Divita G . A new peptide vector for efficient delivery of oligonucleotides into mammalian cells. Nucleic Acids Res 1997; 25: 2730–2736.
Ritter W, Plank C, Lausier J, Rudolph C, Zink D, Reinhardt D et al. A novel transfecting peptide comprising a tetrameric nuclear localization sequence. J Mol Med 2003; 81: 708–717.
Kawasaki H, Taira K . Induction of DNA methylation and gene silencing by short interfering RNAs in human cells. Nature 2004; 431 (7005): 211–217.
Ting AH, Schuebel KE, Herman JG, Baylin SB . Short double-stranded RNA induces transcriptional gene silencing in human cancer cells in the absence of DNA methylation. Nat Genet 2005; 37 (8): 906–910.
Sioud M, Sorensen DR . Cationic liposome-mediated delivery of siRNAs in adult mice. Biochem Biophys Res Commun 2003; 312: 1220–1225.
Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J et al. The nuclear RNase III Drosha initiates microRNA processing. Nature 2003; 425: 415–419.
Lund E, Guttinger S, Calado A, Dahlberg JE, Kutay U . Nuclear export of microRNA precursors. Science 2004; 303: 95–98.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Morris, K., Rossi, J. Lentiviral-mediated delivery of siRNAs for antiviral therapy. Gene Ther 13, 553–558 (2006). https://doi.org/10.1038/sj.gt.3302688
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.gt.3302688
Keywords
This article is cited by
-
Engineering siRNA therapeutics: challenges and strategies
Journal of Nanobiotechnology (2023)
-
Regulatory elements in vectors containing the ctEF-1α first intron and double enhancers for an efficient recombinant protein expression system
Scientific Reports (2018)
-
hTERT gene knockdown enhances response to radio- and chemotherapy in head and neck cancer cell lines through a DNA damage pathway modification
Scientific Reports (2018)
-
Current Transport Systems and Clinical Applications for Small Interfering RNA (siRNA) Drugs
Molecular Diagnosis & Therapy (2018)
-
Emerging Diagnostic and Therapeutic Strategies for Tauopathies
Current Neurology and Neuroscience Reports (2017)