Human/mammalian RNAi pathway and therapeutic options.

Shown in the center is the enzymatic cascade leading from nuclearly expressed primary micro-RNAs (pri-miRNAs) to cytoplasmically active mature miRNAs. The three key cellular enzymes/proteins in this pathway (Drosha, Exportin and Dicer) are shown in italics. The right side summarizes options to reprogram this endogenous pathway for therapeutic intervention: viral vector-mediated nuclear expression of miRNAs or shRNAs, or alternatively, cytoplasmic delivery of siRNAs (mimicking mature miRNAs). The different vector options are described in the text. The left side shows examples of pathogenic viruses as some of the most clinically relevant RNAi targets, and ways how they have evolved to highjack and control human RNAi mechanisms. These include the expression of virally encoded miRNAs, or the exploitation of cellular counterparts, as well as the inhibition of key steps in the RNAi pathway. If successful, therapeutic RNAi can lead to the suppression of target (viral) gene expression (and virus replication). However, in particular RNA viruses can counteract RNAi by mutational escape.

Abbreviations: RISC, RNA-induced silencing complex; Ad VA, adenovirus VA RNA; HIV Tat, HIV Tat protein; HCV, hepatitis C virus.