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UvA-DARE ( Digital Academic Repository ) Combinatorial RNAi against HIV-1
| Content Provider | Semantic Scholar |
|---|---|
| Copyright Year | 2009 |
| Abstract | RNAi-based gene therapy is a powerful approach to treat viral infections because of its high efficiency and sequence-specificity. The HIV-1 based lentiviral vector system is suitable for the delivery of RNAi inducers to HIV-1 susceptible cells due to its potency to transduce non-dividing cells, including hematopoietic stem cells, and its ability for stable transgene delivery into the host cell genome. The presence of antiviral shRNA and miRNA cassettes can negatively affect the lentiviral vector titers, which was tested for antiHIV-1 shRNAs and miRNAs. We show that shRNAs that target the vector genomic RNA strongly reduced lentiviral vector titers, but inhibition of the RNAi pathway via saturation could rescue vector production. The presence of miRNAs in the vector RNA genome (sense orientation) results in a minor titer reduction due to Drosha processing. Vectors with the miRNAs in the antisense orientation have significant reduced titers due to self-targeting of the fully complementary vector target sequence by the mature miRNA. Another major cause for titer reduction of miRNA-vectors is likely due to promoter interference. The use of inducible promoters for expression of miRNA is therefore highly recommended. These results are important for further development and clinical application of lentiviral vectors encoding RNAi inducers. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | https://pure.uva.nl/ws/files/808848/70056_09.pdf |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
