Toward a durable treatment of HIV-1 infection using RNA interference.

ABSTRACT

RNA interference (RNAi) is a cellular mechanism that mediates sequence-specific gene silencing at the posttranscriptional level. RNAi can be used as an antiviral approach against human pathogens. An attractive target for RNAi therapeutics is the human immunodeficiency virus type 1 (HIV-1), and the first clinical trial using a lentiviral gene therapy was initiated in early 2008. In this chapter, we focus on some basic principles of such an RNAi-based gene therapy against HIV-1. This includes the subjects of target site selection within the viral RNA genome, the phenomenon of viral escape, and therapeutic strategies to prevent viral escape. The latter antiescape strategies include diverse combinatorial RNAi approaches that are all directed against the HIV-1 RNA genome. As an alternative strategy, we also discuss the possibilities and restrictions of targeting cellular cofactors that are essential for virus replication, but less important for cell physiology.