W-S Park ¹, M Hayafune ¹, N Miyano-Kurosaki ^{1, 2}, and H Takaku ^{1, 2},

¹ Department of Industrial Chemistry, Faculty of Engineering, Chiba Institute of Technology, Tsudanuma, Narashino, Chiba, Japan

² High Technology Research Center, Chiba Institute of Technology, Tsudanuma, Narashino, Chiba, Japan

Correspondence to: Dr H Takaku, Department of Industrial Chemistry, Faculty of Engineering and High Technology Research Center, Chiba Institute of Technology, 2-17-1 Tsudanuma, Narashino, Chiba 275-0016, Japan

RNA interference (RNAi) is triggered by the presence of a double-stranded RNA (dsRNA) in the cell, and results in the silencing of homologous gene expression by the specific degradation of an mRNA containing the same sequence. dsRNA-mediated RNAi can be used in a wide variety of eucaryotes to induce the sequence-specific inhibition of gene expression. Synthetic 21-23 nucleotide (nt) small interfering RNAs (siRNAs) with 2-nt 3' overhangs were recently found to mediate efficient sequence-specific mRNA degradation in mammalian cells. Here, we show that synthetic siRNAs targeted against the viral structural Env proteins encoded by HIV-1 can specifically suppress the expression of HIV-1 genes. The siRNA-mediated RNAi also had advantages over antisense RNA-mediated inhibition, in terms of both the ease of designing effective antiviral agents and their potency. Especially, our best env-specific siRNAs, E7145 targeted to the central region of the V3 loop and E7490 targeted to the CD4 binding site of conserved regions on gp120, significantly inhibited the HIV-1 gene expression. Furthermore, E7145 and E7490 were effective against HIV-1NL4-3
replication in PBMCs for a relatively long time (14 days). Therefore, the use of synthetic siRNAs provides a simple, rapid, and cost-effective tool for new anti-HIV-1 gene therapeutics.

Additional References for RNA as a Therapeutic Agent:

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8. Frenster JH, "Oncogenes as Molecular Targets within Active Chromatin", in: AACR-NCI-EORTC International Conference: "Molecular Targets and Cancer Therapeutics: Discovery, Development, and Clinical Validation", Washington, DC, November 16-19, 1999, and Published in: Clinical Cancer Research, vol. 5, suppl. l, p. 3855s, (624), (November, 1999).

9. Frenster JH, "Activation of DNA Transcription within Repressed Chromatin", 14th John Innes Symposium, September 5-8, 2001.

10. Maruo S, Nanbo A, and Takada K, "Replacement of the Epstein-Barr Virus Plasmid with the EBER Plasmid in Burkitt's Lymphoma cells", J. Virology, vol. 75, no. 20, pp. 9977-9982 (October, 2001).

11. Frenster JH, "Yeast  RNA  Re-Programming  of  Already-Active  Mammalian Chromatin", RNA2002, p. 592, (June, 2002).

12. Lanz RB, Chua SS, Barron N, Söder BM, DeMayo F, and O'Malley BW, "Steroid Receptor RNA Activator Stimulates Proliferation as Well as Apoptosis In Vivo", Mol. Cell. Biol., vol. 23, no. 20, pp. 7163-7176 (October, 2003).

13. Frenster JH, "Ultrastructural Probes of Active DNA Sites, and the RNA Activators of DNA".

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euchromatin: "the most active portion of the genome within the cell nucleus".