Tat-regulated expression of RNA interference: Triggers for the treatment of HIV infection

Current HIV/AIDS Reports

Volumn 5, Issue 1, 2008, Pages 40-43

  Unwalla, Hoshang ^b   Rossi, John J ^a  

^a CITY OF HOPE NATIONAL MEDICAL CENTER   (United States)

^b NONE

Author keywords

[No Author keywords available]

Indexed keywords

ANTIRETROVIRUS AGENT; LENTIVIRUS VECTOR; OLIGONUCLEOTIDE; SHORT HAIRPIN RNA; TRANSACTIVATOR PROTEIN;

ANTIVIRAL THERAPY; ARTICLE; GENE EXPRESSION; GENE SILENCING; GENETIC TRANSDUCTION; HEMATOPOIETIC CELL; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; NONHUMAN; PROMOTER REGION; PROTEIN EXPRESSION; RNA INTERFERENCE; RNA SEQUENCE; SEQUENCE ANALYSIS; TARGET CELL; VIRAL GENE DELIVERY SYSTEM; VIRAL GENE THERAPY; VIRUS MUTANT; VIRUS REPLICATION;

CELL LINE; CELLS, CULTURED; GENETIC VECTORS; HEMATOPOIETIC STEM CELLS; HIV INFECTIONS; HIV LONG TERMINAL REPEAT; HSP70 HEAT-SHOCK PROTEINS; HUMANS; LENTIVIRUS; PROMOTER REGIONS (GENETICS); RNA INTERFERENCE; RNA, SMALL INTERFERING; RNA, VIRAL; T-LYMPHOCYTES; TAT GENE PRODUCTS, HUMAN IMMUNODEFICIENCY VIRUS; TRANSDUCTION, GENETIC;

EID: 41649098052     PISSN: 15483568     EISSN: 15483576     Source Type: Journal    
DOI: 10.1007/s11904-008-0007-3     Document Type: Article

References (28)

1. Fire A, Xu S, Montgomery MK, et al.: Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998, 391:806-811.
2. Hannon GJ: RNA interference. Nature 2002, 418:244-251.
3. Montgomery MK: RNA interference: historical overview and significance. Methods Mol Biol 2004, 265:3-21.
4. Bernstein E, Caudy AA, Hammond SM, Hannon GJ: Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 2001, 409:363-366.
5. Bitko V, Barik S: An endoplasmic reticulum-specific stress-activated caspase (caspase-12) is implicated in the apoptosis of A549 epithelial cells by respiratory syncytial virus. J Cell Biochem 2001, 80:441-454.
6. Chendrimada TP, Gregory RI, Kumaraswamy E, et al.: TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 2005, 436:740-744. An important discovery of a cofactor for Dicer, the TAR RNA binding protein (TRBP) is involved in binding siRNAs and handing them to the effector argonautes in RISC. Importantly, TRBP is an inhibitor of double-stranded RNA-activated protein kinase, which itself is activated by double-stranded RNAs. TRBP was first discovered as a HIV TAR element binding protein and may also play a role in preventing HIV TAR from activating double-stranded RNA-activated protein kinase.
7. Caplen NJ, Parrish S, Imani F, et al.: Specific inhibition of gene expression by small double-stranded RNAs in invertebrate and vertebrate systems. Proc Natl Acad Sci U S A 2001, 98:9742-9747.
8. Elbashir SM, Harborth J, Lendeckel W, et al.: Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 2001, 411:494-498.
9. Lee NS, et al.: Expression of small interfering RNAs targeted against HIV-1 rev transcripts in human cells. Nat Biotechnol 2002, 20:500-505.
10. Xia H, Mao Q, Paulson HL, Davidson BL: siRNA-mediated gene silencing in vitro and in vivo. Nat Biotechnol 2002, 20:1006-1010.
11. An DS, Xie Y, Mao SH, et al.: Efficient lentiviral vectors for short hairpin RNA delivery into human cells. Hum Gene Ther 2003, 14:1207-1212.
12. Jackson AL, Bartz SR, Schelter J, et al.: Expression profiling reveals off-target gene regulation by RNAi. Nat Biotechnol 2003, 21:635-637.
13. Scacheri PC, Rozenblatt-Rosen O, Caplen NJ, et al.: Short interfering RNAs can induce unexpected and divergent changes in the levels of untargeted proteins in mammalian cells. Proc Natl Acad Sci U S A 2004, 101:1892-1897.
14. Jackson AL, Burchard J, Leake D, et al.: Position-specific chemical modification of siRNAs reduces "off-target" transcript silencing. RNA 2006, 12:1197-1205. This study confirms that most off-targeting mediated by siRNAs is via the first two to eight nucleotides serving as "seed sequences" for illicit binding to the 3′ untranslated regions of nontargeted mRNAs. The authors show that a 2′ OMe modification of the sugar on the second base can abrogate this effect. Because expressed hairpins cannot be modified at this position, caution needs to be used when expressing shRNAs ectopically in cells because the seed sequences of the sense and antisense strands can bind to non-targeted 3′ UTRs and cause nontargeted RNAi.
15. Yi R, Qin Y, Macara IG, Cullen BR: Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev 2003, 17:3011-3016.
16. Tang G: siRNA and miRNA: an insight into RISCs. Trends Biochem Sci 2005, 30:106-114.
17. Unwalla HJ, Li HT, Bahner I, et al.: Novel Pol II fusion promoter directs human immunodeficiency virus type 1-inducible coexpression of a short hairpin RNA and protein. J Virol 2006, 80:1863-1873. This study demonstrates that Tat-inducible expression from an LTR-minimal hsp70 promoter expression can read through a minimal polyA sequence. By fusing an open reading frame of the Rev M10 inhibitory protein downstream of the minimal polyA signal, a readthrough transcript that expresses both shRNA and M10 protein occurs but only in the presence of Tat. This study has implications for novel anti-HIV therapeutic approaches using combinations of shRNAs and dominant negative proteins.
18. Unwalla HJ, Li MJ, Kim JD, et al.: Negative feedback inhibition of HIV-1 by TAT-inducible expression of siRNA. Nat Biotechnol 2004, 22:1573-1578.
19. Wianny F, Zernicka-Goetz M: Specific interference with gene function by double-stranded RNA in early mouse development. Nat Cell Biol 2000, 2:70-75.
20. Kennerdell JR, Carthew RW: Use of dsRNA-mediated genetic interference to demonstrate that frizzled and frizzled 2 act in the wingless pathway. Cell 1998, 95:1017-1026.
21. Lipardi C, Wei Q, Paterson BM: RNAi as random degradative PCR: siRNA primers convert mRNA into dsRNAs that are degraded to generate new siRNAs. Cell 2001, 107:297-307.
22. Sijen T, Fleenor J, Simmer F, et al.: On the role of RNA amplification in dsRNA-triggered gene silencing. Cell 2001, 107:465-476.
23. Krumm A, Meulia T, Groudine M: Common mechanisms for the control of eukaryotic transcriptional elongation. Bioessays 1993, 15:659-665.
24. Garriga J, Grana X: Cellular control of gene expression by T-type cyclin/CDK9 complexes. Gene 2004, 337:15-23.
25. Grimm D, Streetz KL, Jopling CL, et al.: Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 2006, 441:537-541. This study describes fatalities in mice due to high levels of expression of shRNAs in murine livers. The authors show that the endogenous microRNAs are reduced, a consequence of competition with the ectopically expressed shRNAs for exportin 5, and perhaps with other factors downstream of Drosha processing.
26. Wiznerowicz M, Trono D: Conditional suppression of cellular genes: lentivirus vector-mediated drug-inducible RNA interference. J Virol 2003, 77:8957-8961.
27. Matsukura S, Jones PA, Takai D: Establishment of conditional vectors for hairpin siRNA knockdowns. Nucleic Acids Res 2003, 31:e77.
28. Aagaard L, Rossi JJ: RNAi therapeutics: principles, prospects and challenges. Adv Drug Deliv Rev 2007, 59:75-86. A tet-inducible shRNA expression system is described in which the shRNA is targeting Drosha, the RNase enzyme that processes pre-miRNAs. This vector has the inducible shRNA and the tet repressor on the same lentiviral vector construct, making it a fully portable, inducible system.