Human Immunodeficiency Virus Type 1 Escapes from RNA Interference-Mediated Inhibition
Atze T. Das,Thijn R. Brummelkamp,Ellen M. Westerhout,Monique Vink,Mandy Madiredjo,René Bernards,Ben Berkhout +6 more
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TL;DR: It is reported here that an siRNA directed against the viral Nef gene (siRNA-Nef) confers resistance to HIV-1 replication, and RNAi could become a realistic gene therapy approach with which to overcome the devastating effect of HIV- 1 on the immune system.
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Abstract: Short-term assays have suggested that RNA interference (RNAi) may be a powerful new method for intracellular immunization against human immunodeficiency virus type 1 (HIV-1) infection. However, RNAi has not yet been shown to protect cells against HIV-1 in long-term virus replication assays. We stably introduced vectors expressing small interfering RNAs (siRNAs) directed against the HIV-1 genome into human T cells by retroviral transduction. We report here that an siRNA directed against the viral Nef gene (siRNA-Nef) confers resistance to HIV-1 replication. This block in replication is not absolute, and HIV-1 escape variants that were no longer inhibited by siRNA-Nef appeared after several weeks of culture. These RNAi-resistant viruses contained nucleotide substitutions or deletions in the Nef gene that modified or deleted the siRNA-Nef target sequence. These results demonstrate that efficient inhibition of HIV-1 replication through RNAi is possible in stably transduced cells. Therefore, RNAi could become a realistic gene therapy approach with which to overcome the devastating effect of HIV-1 on the immune system. However, as is known for antiviral drug therapy against HIV-1, antiviral approaches involving RNAi should be used in a combined fashion to prevent the emergence of resistant viruses.
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Citations
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