Combinatorial RNAi strategies against HIV-1 and other escape-prone viruses

Abstract: 

RNA interference (RNAi) is an evolutionarily conserved mechanism in which double-stranded RNA (dsRNA) induces sequence-specific gene silencing. RNAi as a gene suppression tool holds great promise for basic research and multiple applications. RNAi strategies with a single inhibitor have received much attention and some are currently being tested in clinical trials as potential drug for infectious diseases, cancer and genetic disorders. Although very successful, such an RNAi mono-therapy is not always sufficient. For example, several proteins should be silenced simultaneously for the elucidation of cross-talk between signalling pathways. Furthermore, development of a durable RNAi therapy for viral infections and cancer may also require the use of multiple inhibitors, as this may prevent the selection of virus variants or cancer cells that escape from the RNAi therapy by mutation of the target gene. Therefore, several combinatorial RNAi strategies have been developed and recent reports demonstrated the potency of this approach by targeting multiple viral genes or oncogenes. At the same time, combinatorial RNAi may also increase the risk of saturation of the endogenous RNAi pathway and off-target effects. This review summarizes the latest experimental advances in combinatorial RNAi research and gene therapy approaches, in particular against escape-prone viruses, like the human immunodeficiency virus type 1 (HIV-1).