Nature Biotechnology22, 1573 - 1578 (2004)
Published online: 28 November 2004; | doi:10.1038/nbt1040
Negative feedback inhibition of HIV-1 by TAT-inducible expression of siRNA
Hoshang J Unwalla, Ming-Jie Li, James D Kim, Hai Tang Li, Ali Ehsani, Jessica Alluin
& John J Rossi
Division of Molecular Biology, Beckman Research Institute of The City of Hope, Duarte, California
91010, USA.
Correspondence should be addressed to John J Rossi jrossi@coh.org
Here we demonstrate that an inducible anti-HIV short hairpin RNA (shRNA) expressed from a Pol II promoter inhibits HIV-1 gene expression in mammalian cells. Our strategy is based on a promoter system in which the HIV-1 LTR is fused to the Drosophila hsp70 minimal heat shock promoter. This system is inducible by HIV-1 TAT, which functions in a negative feedback loop to activate transcription of an shRNA directed against HIV-1 rev. Upon induction the shRNA is processed to an siRNA that guides inhibition of HIV replication in cultured T-lymphocytes and hematopoietic stem cell−derived monocytes. The fusion promoter system may be safer than drug-inducible systems for shRNA-mediated gene therapy against HIV as the shRNAs are only expressed following HIV infection.
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