Silencing Persistent Virus Infections By Rna Interference

Persistent viral infections cause major diseases in humans and very few current treatments result in high rates of successful virus clearance and cure. Viruses that establish persistent infections have evolved various strategies to escape both innate and adaptive host immune responses. There are difficulties associated with the treatment of persistent viral infections: one is that treatment may not start until several years after infection, when the viral targets may be disseminated or harbored by particular cells or subcellular compartments, and/or may be present in various forms (double-stranded, covalently closed circular or integrated). Moreover, a large population of viral mutants may be present in the infected host before treatment begins, allowing rapid viral escape. The discovery of RNA interference has provided an opportunity to investigate and develop novel and highly specific treatments to combat persistent virus infections. Several in vitro models of infection with single-stranded RNA viruses have been used to investigate the possibility of curing persistent viral infections with specific small interfering RNAs (siRNAs). In such systems, successful siRNA treatments leading to virus eradication have been reported for lymphocytic choriomeningitis virus and poliovirus infections, whereas substantial inhibition of viral replication has been achieved for several other infections, including hepatitis C virus and human immunodeficiency virus infections. However, these studies are just beginning and need to be extended. In this review, we will describe these findings and discuss how RNA interference may help overcome the particular hurdles encountered in the treatment of persistent virus infections.