Unwalla, H.J., Li, M.J., Kim, J.D., Li, H.T., Ehsani, A., Alluin, J., Rossi, J.J. (2004). Negative feedback inhibition of HIV-1 by TAT-inducible expression of siRNA.  Nat. Biotechnol. 22(12): 1573--1578.

FBrf0180559

Research paper

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.