Therapeutic potential of RNA interference against cellular targets of HIV infection

Abstract

RNA interference is not only very promising in identifying new targets for drug development, siRNA/shRNA themselves may be directly used as therapeutic agents. In inhibiting viral infections by RNA interference, both viral targets and cellular proteins have been evaluated. Most of the early studies in this field had chosen viral targets for RNA interference. However, recent efforts are mainly focusing on cellular proteins for RNA silencing due to the realization that a variety of viral responses substantially minimize siRNA effects. With the application of siRNA approaching, many new cellular targets relevant to HIV infection have been identified. The value of siRNA/shRNA in the treatment of AIDS is largely dependent on better understanding of the biology of HIV replication. Efforts in the identification of cellular processes with the employment of siRNA/shRNA have shed some new lights on our understanding of how HIV infection occurs. Furthermore, the relative specific effects and simplicity of design makes siRNA/shRNA themselves to be favorable drug leads.

Fig. 1

Diagram illustrating the mechanisms of RNAi in breaking down the mRNA of viral and cellular targets. The siRNA, double strands RNA, and shRNA need to penetrate the cell membrane before they are able to perform RNA interference. The RNA interference mediated by double strands RNA is DICER dependent, whereas the effects of exogenous siRNA and shRNA are DICER independent, which is similar to the mechanism of microRNA that cleaves RNA by RISC

Fig. 2

Cellular proteins evaluated by RNAi against specific steps of HIV life cycle. In addition to the cellular targets with known mechanisms inhibiting the four process of HIV infection as numerically marked, the inhibition of SOCS on pre-entry, the inhibition of bystander killing to non-infected CD4/CD8 cells, and some cellular targets with either more than one mechanisms or unknown mechanisms are also illustrated